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Can the Flow of Medicines be Improved? Fundamental Pharmacokinetic and Pharmacological Principles toward Improving Phase II Survival
Abstract
In an effort to uncover systematic learnings that can be applied to improve compound survival, an analysis was performed on data from Phase II decisions for 44 programs at Pfizer. It was found that not only were the majority of failures caused by lack of efficacy but also that, in a large number of cases (43%), it was not possible to conclude whether the mechanism had been tested adequately. A key finding was that an integrated understanding of the fundamental pharmacokinetic/pharmacodynamic principles of exposure at the site of action, target binding and expression of functional pharmacological activity (termed together as the 'three Pillars of survival') all determine the likelihood of candidate survival in Phase II trials and improve the chance of progression to Phase III.
... 4 Upon antibody binding, these mAb-target complexes undergo cellular internalization and degradation that manifests as targetmediated drug disposition (TMDD) where the pharmacokinetic (PK) behavior of the drug depends on its dose, concentration, and time. 5 Whilst TMDD can complicate the doseresponse analysis and prediction, it also lends support to the three pillars of therapeutic drug discovery 6 since the process characterizes the tissue penetration and target engagement properties of the drug at the site of action and elsewhere. ...
... In the case where the membrane-bound target was split between the organ interstitial and vascular spaces, the effective concentrations mTarget int+vas,Organ in organ interstitial and vascular plasma compartments were calculated according to Equation 6: ...
... Of these three, only the receptor-mediated internalization route is linked to TMDD 42,43 and hence provides good evidence of target engagement at the site of action according to Three Pillar framework. 6 Extensive research on EGFR and HER2 internalization and turnover dynamics in the absence and presence of different ligands, such as EGF in the case of EGFR or a mAb in the case of HER2, has revealed an intricate system whereby receptor-ligand complex internalization, recycling and degradation processes interlink depending on the cell type, receptor surface concentration, any homo-and heterodimerization, the presence, concentration and nature of the ligands, if known, and even the epitope/s involved. 28,39,[44][45][46][47][48][49][50][51][52] In principle, these features can be studied and characterized in vitro, but the effort is considerable with no guarantee that the cells in culture are quantitatively representative to those in tissue environment. ...
Model-informed drug discovery advocates the use of mathematical modeling and simulation for improved efficacy in drug discovery. In the case of monoclonal antibodies (mAbs) against cell membrane antigens, this requires quantitative insight into the target tissue concentration levels. Protein mass spectrometry data are often available but the values are expressed in relative, rather than in molar concentration units that are easier to incorporate into pharmacokinetic models. Here, we present an empirical correlation that converts the parts per million (ppm) concentrations in the PaxDb database to their molar equivalents that are more suitable for pharmacokinetic modeling. We evaluate the insight afforded to target tissue distribution by analyzing the likely tumor-targeting accuracy of mAbs recognizing either epidermal growth factor receptor or its homolog HER2. Surprisingly, the predicted tissue concentrations of both these targets exceed the Kd values of their respective therapeutic mAbs. Physiologically based pharmacokinetic (PBPK) modeling indicates that in these conditions only about 0.05% of the dosed mAb is likely to reach the solid tumor target cells. The rest of the dose is eliminated in healthy tissues via both nonspecific and target-mediated processes. The presented approach allows evaluation of the interplay between the target expression level in different tissues that determines the overall pharmacokinetic properties of the drug and the fraction that reaches the cells of interest. This methodology can help to evaluate the efficacy and safety properties of novel drugs, especially if the off-target cell degradation has cytotoxic outcomes, as in the case of antibody-drug conjugates.
... These aspects are vital for the success of a drug candidate during clinical trials ( Figure 12). For this reason, the use of PET imaging targeting the CNS is considered a promising tool in both preclinical and clinical processes [76]. The output of PET imaging depends on the chemical nature of the radiotracer and the physiological conditions of the living subjects. ...
... These aspects are for the success of a drug candidate during clinical trials ( Figure 12). For this reaso use of PET imaging targeting the CNS is considered a promising tool in both prec and clinical processes [76]. The output of PET imaging depends on the chemical nat the radiotracer and the physiological conditions of the living subjects. ...
Esterases are hydrolases that catalyze the hydrolysis of esters into the corresponding acids and alcohols. The development of fluorescent probes for detecting esterases is of great importance due to their wide spectrum of biological and industrial applications. These probes can provide a rapid and sensitive method for detecting the presence and activity of esterases in various samples, including biological fluids, food products, and environmental samples. Fluorescent probes can also be used for monitoring the effects of drugs and environmental toxins on esterase activity, as well as to study the functions and mechanisms of these enzymes in several biological systems. Additionally, fluorescent probes can be designed to selectively target specific types of esterases, such as those found in pathogenic bacteria or cancer cells. In this review, we summarize the recent fluorescent probes described for the visualization of cell viability and some applications for in vivo imaging. On the other hand, positron emission tomography (PET) is a nuclear-based molecular imaging modality of great value for studying the activity of enzymes in vivo. We provide some examples of PET probes for imaging acetylcholinesterases and butyrylcholinesterases in the brain, which are valuable tools for diagnosing dementia and monitoring the effects of anticholinergic drugs on the central nervous system.
... Phase 2 trials subsequently support a clinical proof-ofconcept (POC), representing early evidence of clinical efficacy to enable decision-making on progression to larger, registrational phase 3 trials [98]. POM and POC are key de-risking steps in the development path of a new medicine, and each of these milestones is associated with an increased probability of future clinical success [99]. A multi-disciplinary approach is often taken to support POM and POC milestones, including direct and/or indirect measurements of PK, PD, clinical endpoints, and mathematical modeling. ...
Flow cytometry is a mainstay technique in cell biology research, where it is used for phenotypic analysis of mixed cell populations. Quantitative approaches have unlocked a deeper value of flow cytometry in drug discovery research. As the number of drug modalities and druggable mechanisms increases, there is an increasing drive to identify meaningful biomarkers, evaluate the relationship between pharmacokinetics and pharmacodynamics (PK/PD), and translate these insights into the evaluation of patients enrolled in early clinical trials. In this review, we discuss emerging roles for flow cytometry in the translational setting that supports the transition and evaluation of novel compounds in the clinic.
... The significance of these areas of knowledge has been further enhanced by growing awareness of the direct relationship between the drug levels reached in different body compartments and the corresponding pharmacological effects, and by the opportunity to predict the in vivo performance of a drug product (typically reflected by plasma drug concentrations or rate and amount of drug absorbed) from in vitro performance (Emami 2006). In fact, retrospective analyses of the causes of failure of drug candidates at clinical trials in leading pharmaceutical companies have revealed that in about one third of the cases, lack of efficacy is correlated with inadequate drug exposure (Morgan et al. 2012;Cook et al. 2014). Furthermore, last generation pharmaceutical carriers (e.g., pharmaceutical nanocarriers) have recently been introduced which, for the first time in history, could directly impact on the fate of a drug within the body, providing specific (or targeted) distribution and modifying elimination kinetics (Talevi and Castro 2017). ...
Biopharmaceutics and Pharmacokinetics are pharmaceutical disciplines that are useful for improving the outcome of drug therapies, assisting drug product development, and establishing pharmacokinetics-pharmacodynamics models and in vitro-in vivo correlations. Here, we introduce some essential lexicons that will be used throughout this volume and discuss the relationship between drug exposure and the pharmacological response to drug therapy in the framework of the free drug hypothesis.
... [54][55][56] As such, whilst providing a readout of the capacity of an antivenom's ability to neutralise a fixed dose of venom, the assay does not consider the pharmacokinetic or pharmacodynamic properties of either the venom or the therapy being tested. [57][58][59] 2) The high dose of venom administered (above lethal) typically rapidly overwhelm the model (i.e., cause lethality in minutes) and so the model is unable to mimic delays in therapy administration which always occur in human treatment. ...
On the 26th January 2023, a free to attend, ‘improving in vivo snake venom research: a community discussion’ meeting was held virtually. This webinar brought together researchers from around the world to discuss current neutralisation of venom lethality mouse assays that are used globally to assess the efficacy of therapies for snakebite envenoming. The assay’s strengths and weaknesses were highlighted, and we discussed what improvements could be made to refine and reduce animal testing, whilst supporting preclinical antivenom and drug discovery for snakebite envenoming. This report summarises the issues highlighted, the discussions held, with additional commentary on key perspectives provided by the authors.
... The use of pharmacodynamic biomarkers to demonstrate target engagement in early clinical development is key to assuring proof of pharmacology in target tissue. The concept of three pillars of drug development was outlined by industry leaders more than a decade ago, where the roadmap requires demonstrating target engagement as essential before advancing new candidates to subsequent stages (Morgan et al., 2012). Demonstration of proof of concept is challenging in drugs that target nervous system disorders due to the need to show target engagement of drugs that cross the blood-brain barrier and show dose-responsive signals that can be measured in a central compartment. ...
A rich pipeline of therapeutic candidates is advancing for Parkinson’s disease, many of which are targeting the underlying pathophysiology of disease. Emerging evidence grounded in novel genetics and biomarker discoveries is illuminating the true promise of precision medicine-based therapeutic strategies for PD. There has been a growing effort to investigate disease-modifying therapies by designing clinical trials for genetic forms of PD - providing a clearer link to underlying pathophysiology. Leading candidate genes based on human genetic findings that are under active investigation in an array of basic and translational models include SNCA, LRRK2, and GBA. Broad investigations across mechanistic models show that these genes signal through common molecular pathways, namely, autosomal lysosomal pathways, inflammation and mitochondrial function. Therapeutic clinical trials to date based on genetically defined targets have not yet achieved approvals; however, much is to be learned from such pioneering trials. Fundamental principles of drug development that include proof of pharmacology in target tissue are critical to have confidence in advancing such precision-based therapies. There is a clear need for downstream biomarkers of leading candidate therapies to demonstrate proof of mechanism. The current regulatory landscape is poised and primed to support translational modeling strategies for the effective advancement of PD disease-modifying therapeutic candidates. A convergence of rich complex data that is available, the regulatory framework of model informed drug development (MIDD), and the new biological integrated staging frameworks when combined are collectively setting the stage for advancing new approaches in PD to accelerate progress. This perspective review highlights the potential of quantitative systems pharmacology (QSP) modeling in contributing to the field and hastening the pace of progress in advancing collaborative approaches for urgently needed PD disease-modifying treatments.
... 6,15,16 A number of biopharmaceu�cal companies have explored ways to improve their decision-making regarding which R&D projects to con�nue and which to terminate, by increasing the quality of informa�on available to decision-makers, the quality of the decision-making process itself, or both. 17,18,19 In par�cular, a number of companies have laudably introduced asset-level frameworks that require valida�on that scien�sts are pursuing the "right biological target" to have an effect on the disease, using the "right molecule" to engage the target both effec�vely and safely, tes�ng the hypothesis in the "right pa�ents" to see an effect, and so on. 20,21,22 It is plausible that these efforts, coupled with a significant increase in known disease targets with human valida�on via "omics tools," 23,24,25 are behind the recent improvements in R&D success rates and cost of failure. ...
In this paper, we investigate what conditions need to be in place to make progress in combating a disease using a case-control design: we compare cases (diseases with a successful therapy) to controls (diseases without a successful therapy). We find five conditions ('hurdles') must typically be cleared for success: (A) understanding of biological drivers, (B) ability to modulate biology, (C) availability of translational models, (D1) ability to identify patients, and (D2) ability to measure clinical response. This framework is similar to ones deployed to evaluate individual drug candidates but is employed here to make inferences about entire diseases. It can be used to identify diseases most ready for progress, where efforts should be focused to make progress in diseases that are currently intractable, and where the industry could benefit from development of tools to address the hurdle that is most commonly the last to be cleared across diseases-namely, (C) translational models.
... Accurate predictions of candidate drug properties at an early stage are critical for improving the efficiency of this process. To elicit the desired effect, candidate drugs must reach a specific concentration at the target site of the body over a certain time period [Morgan et al., 2012]. Predicting whether candidate drugs will reach the desired concentration over a certain period at the target site requires understanding the processes of absorption, distribution, metabolism and excretion (ADME) of drugs from the human body. ...
The development of accurate predictions for a new drug's absorption, distribution, metabolism, and excretion profiles in the early stages of drug development is crucial due to high candidate failure rates. The absence of comprehensive, standardised, and updated pharmacokinetic (PK) repositories limits pre-clinical predictions and often requires searching through the scientific literature for PK parameter estimates from similar compounds. While text mining offers promising advancements in automatic PK parameter extraction, accurate Named Entity Recognition (NER) of PK terms remains a bottleneck due to limited resources. This work addresses this gap by introducing novel corpora and language models specifically designed for effective NER of PK parameters. Leveraging active learning approaches, we developed an annotated corpus containing over 4,000 entity mentions found across the PK literature on PubMed. To identify the most effective model for PK NER, we fine-tuned and evaluated different NER architectures on our corpus. Fine-tuning BioBERT exhibited the best results, achieving a strict F 1 score of 90.37% in recognising PK parameter mentions, significantly outperforming heuristic approaches and models trained on existing corpora. To accelerate the development of end-to-end PK information extraction pipelines and improve pre-clinical PK predictions, the PK NER models and the labelled corpus were released open source at https://github.com/PKPDAI/PKNER.
... A clear understanding of drug exposure at the site of action, target binding and functional pharmacological activity is key for optimal design of phase II clinical trials. (Morgan et al., 2012) MR309, a selective σ1R antagonist, was well tolerated in early clinical trials at a daily dose of 400 mg and signals of preliminary efficacy for acute CIPN were observed in patients with colorectal cancer receiving an oxaliplatin-containing regimen (Abadias, Escriche, Vaque, Sust & Encina, 2013;Bruna et al., 2018) and in patients with chronic PSNP lasting for >6 months. (EU Clinical Trials Register (EudraCT 2012-000402-30)) Here, we confirm the occupancy of brain σ1R by MR309 following administration of clinically meaningful doses, and demonstrate a quantitative relationship between plasma concentration of MR309 and target occupancy, enabling optimised dose selection in future studies. ...
Background and purpose: Preclinical studies of MR309, a selective sigma1 receptor (σ1R) antagonist, support a potential role in treating neuropathic pain. We report two studies that provide insight into the pharmacokinetics (PK) and brain σ1R binding of MR309. Experimental approach: Steady-state PK of MR309 (400 mg QD and 200 mg BID for 10 days; EudraCT 2015-001818-99 [PK study]) and the relationship between MR309 plasma exposure and brain σ1R occupancy (EudraCT 2017-000670-11 [PET study]) were investigated in healthy volunteers. Positron emission tomography (PET) using the σ1R ligand [11C]SA4503 was conducted at baseline, 2h and 8h after a single dose of MR309 (200–800 mg). The relationship between brain σ1R occupancy and MR309 exposure was explored using data-driven model fitting. Key results: MR309 was well tolerated, brain σ1R occupancy ranged between 30.5% and 74.9% following single-dose MR309 (n=7). MR309 BID provided a plasma PK profile with less fluctuation than QD dosing (n=16). MR309 200 mg BID yielded average steady state plasma concentrations between 2000 and 4000 ng/mL in the PK study, which corresponded to an estimated brain σ1R occupancy of 59–74%. Conclusions and implications: MR309 200 mg BID dose was below the 75% σ1R occupancy threshold expected to elicit maximal antinociceptive effect as observed in neuropathic pain models. Further investigations of MR309 for neuropathic pain will require higher brain σ1R occupancy, and establish the optimal dose by elucidating the clinical impact of a broad range of brain σ1R occupancy across different neuropathic pain indications.
... Ideally, such preclinical models should be able to reflect human skin pharmacokinetics (PK) and pharmacodynamics (PD) under in vivo conditions where active drug absorption and clearance are occurring. Any sampling method used in in vivo conditions should ideally be able to measure the pharmacologically active unbound drug concentrations in the local tissue, preferably at the drug's target site, according to the free drug hypothesis [10][11][12][13]. Dermal microdialysis (dMD) has been used to measure the rate and extent of absorption of topically administered drugs in humans and animals [6,14], including pigs and minipigs [6,15]. ...
Purpose
Accurate methods to determine dermal pharmacokinetics are important to increase the rate of clinical success in topical drug development. We investigated in an in vivo pig model whether the unbound drug concentration in the interstitial fluid as determined by dermal open flow microperfusion (dOFM) is a more reliable measure of dermal exposure compared to dermal biopsies for seven prescription or investigational drugs. In addition, we verified standard dOFM measurement using a recirculation approach and compared dosing frequencies (QD versus BID) and dose strengths (high versus low drug concentrations).
Methods
Domestic pigs were topically administered seven different drugs twice daily in two studies. On day 7, drug exposures in the dermis were assessed in two ways: (1) dOFM provided the total and unbound drug concentrations in dermal interstitial fluid, and (2) clean punch biopsies after heat separation provided the total concentrations in the upper and lower dermis.
Results
dOFM showed sufficient intra-study precision to distinguish interstitial fluid concentrations between different drugs, dose frequencies and dose strengths, and had good reproducibility between studies. Biopsy concentrations showed much higher and more variable values. Standard dOFM measurements were consistent with values obtained with the recirculation approach.
Conclusions
dOFM pig model is a robust and reproducible method to directly determine topical drug concentration in dermal interstitial fluid. Dermal biopsies were a less reliable measure of dermal exposure due to possible contributions from drug bound to tissue and drug associated with skin appendages.
... Whereas some decision-making frameworks (e.g., 3 Pillar and 5R) have been widely appreciated and deployed across therapeutic areas, the consistent application of these principles can be challenging in oncology due to the complexity of the disease and patient populations, as well as the accelerated development timelines often required, as reviewed earlier. [41][42][43] Engaging in discussions with the FDA regarding dose selection strategies in early development can be important for a successful application. Sharing all relevant information used to support dosing decisions will facilitate FDA's ability to provide specific recommendations. ...
Project Optimus is a US Food and Drug Administration Oncology Center of Excellence initiative aimed at reforming the dose selection and optimization paradigm in oncology drug development. This project seeks to bring together pharmaceutical companies, international regulatory agencies, academic institutions, patient advocates, and other stakeholders. Although there is much promise in this initiative, there are several challenges that need to be addressed, including multidimensionality of the dose optimization problem in oncology, the heterogeneity of cancer and patients, importance of evaluating long‐term tolerability beyond dose‐limiting toxicities, and the lack of reliable biomarkers for long‐term efficacy. Through the lens of Totality of Evidence and with the mindset of model‐informed drug development, we offer insights into dose optimization by building a quantitative knowledge base integrating diverse sources of data and leveraging quantitative modeling tools to build evidence for drug dosage considering exposure, disease biology, efficacy, toxicity, and patient factors. We believe that rational dose optimization can be achieved in oncology drug development, improving patient outcomes by maximizing therapeutic benefit while minimizing toxicity.
... The average cost of a new approved drug reaching about a billion dollars also reflects the additional effort required for reaching the 'higherhanging fruit', which has not been matched with improved likelihood in clinical success rates (Schlander et al. 2021). The reasons for latestage failures were analysed by Morgan et al. (2012) who formulated the paradigm of 'Three Pillars of Pharmaceutical Survival' to overcome at least some of the inadequacies. ...
... As such, a translational framework for assessing novel neurologically-active compounds that has become established in the field in recent years is the "three pillars" approach. This was first outlined by [100] and subsequently further developed with specific reference to neuroimaging methods [101], the three pillars being: (1) tissue exposure (2) target engagement, and (3) pharmacologic activity. Tissue exposure (does the compound enter the brain in clinically significant concentrations at clinically tolerable doses?) can be established by radiolabelling the drug with a suitable radionuclide and conducting a PET biodistribution study [102][103][104]. ...
Psychedelic therapy (PT) is an emerging paradigm with great transdiagnostic potential for treating psychiatric disorders, including depression, addiction, post-traumatic stress disorder, and potentially others. ‘Classic’ serotonergic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), which have a key locus of action at the 5-HT2A receptor, form the main focus of this movement, but substances including ketamine, 3,4-Methylenedioxymethamphetamine (MDMA) and ibogaine also hold promise. The modern phase of development of these treatment modalities in the early 21st century has occurred concurrently with the wider use of advanced human neuroscientific research methods; principally neuroimaging. This can potentially enable assessment of drug and therapy brain effects with greater precision and quantification than any previous novel development in psychiatric pharmacology. We outline the major trends in existing data and suggest the modern development of PT has benefitted greatly from the use of neuroimaging. Important gaps in existing knowledge are identified, namely: the relationship between acute drug effects and longer-term (clinically-relevant) effects, the precise characterisation of effects at the 5-HT2A receptor and relationships with functional/clinical effects, and the possible impact of these compounds on neuroplasticity. A road-map for future research is laid out, outlining clinical studies which will directly address these three questions, principally using combined Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) methods, plus other adjunct techniques. Multimodal (PET/MRI) studies using modern PET techniques such as the 5-HT2A-selective ligand [11 C]Cimbi-36 (and other ligands sensitive to neuroplasticity changes) alongside MRI measures of brain function would provide a ‘molecular-functional-clinical bridge’ in understanding. Such results would help to resolve some of these questions and provide a firmer foundation for the ongoing development of PT.
... As in all fields of drug therapy, knowing the right molecular target and having a drug that perturbs that target is central to effective treatment, but it is not sufficient in itself. It is also necessary to know how and how long the target is being engaged and modulated in vivo at a therapeutic level [1][2][3][4]. ...
Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. They have shown significant therapeutic value in cancer and neurodegenerative diseases by disassembling epichaperomes, which are assemblies of tightly bound chaperones and other factors that serve as scaffolding platforms to pathologically rewire protein–protein interactions. To investigate their impact on epichaperomes in vivo, we conducted pharmacokinetic and target occupancy measurements for zelavespib and monitored epichaperome assemblies biochemically in a mouse model. Our findings provide evidence of the intricate mechanism through which zelavespib modulates epichaperomes in vivo. Initially, zelavespib becomes trapped when epichaperomes bound, a mechanism that results in epichaperome disassembly, with no change in the expression level of epichaperome constituents. We propose that the initial trapping stage of epichaperomes is a main contributing factor to the extended on-target residence time observed for this agent in clinical settings. Zelavespib’s residence time in tumors seems to be dictated by target disassembly kinetics rather than by frank drug–target unbinding kinetics. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases.
... Following this framework provides a mechanistic link between the drug and target allowing the therapeutic hypothesis to be tested and provides confidence to advance a drug to laterstage clinical development to confirm efficacy (reviewed in refs. 3,4). ...
Small-molecule drugs have enabled the practice of precision oncology for genetically defined patient populations since the first approval of imatinib in 2001. Scientific and technology advances over this 20-year period have driven the evolution of cancer biology, medicinal chemistry, and data science. Collectively, these advances provide tools to more consistently design best-in-class small-molecule drugs against known, previously undruggable, and novel cancer targets. The integration of these tools and their customization in the hands of skilled drug hunters will be necessary to enable the discovery of transformational therapies for patients across a wider spectrum of cancers.
Significance
Target-centric small-molecule drug discovery necessitates the consideration of multiple approaches to identify chemical matter that can be optimized into drug candidates. To do this successfully and consistently, drug hunters require a comprehensive toolbox to avoid following the “law of instrument” or Maslow's hammer concept where only one tool is applied regardless of the requirements of the task. Combining our ever-increasing understanding of cancer and cancer targets with the technological advances in drug discovery described below will accelerate the next generation of small-molecule drugs in oncology.
... Analysis of drug-development programmes run by pharmaceutical companies has highlighted the importance of understanding drug mechanisms and target binding at the sites of action. These factors are associated with the likelihood of candidate success in phase II trials and improve the chance of progression to phase III 41 . Moreover, finding the right target paired with the right tissue is acknowledged as an indicator of programme success 42 . ...
Immune-mediated inflammatory diseases (IMIDs) are responsible
for substantial global disease burden and associated health-care
costs. Traditional models of research and service delivery silo their management within organ-based medical disciplines. Very often patients with disease in one organ have comorbid involvement in another, suggesting shared pathogenic pathways. Moreover, different IMIDs are often treated with the same drugs (including glucocorticoids, immunoregulators and biologics). Unlocking the cellular basis of
these diseases remains a major challenge, leading us to ask why,
if these diseases have so much in common, they are not investigated in a common manner. A tissue-based, cellular understanding of inflammation might pave the way for cross-disease, cross-discipline basket trials (testing one drug across two or more diseases) to reduce the risk of failure of early-phase drug development in IMIDs. This new approach will enable rapid assessment of the efficacy of new therapeutic agents in cross-disease translational research in humans.
... A crucial stage for the development of new drugs in this multi-step process is the step from phase 2 to phase 3. Data from phase 2 studies are often used to develop the protocol and trial design for phase 3, including planning sample size requirements based on treatment effect sizes observed in phase 2 4 . Failure of expected endpoints in phase 3 is associated with major use of resources and financial burden but, more importantly, the exposure of study participants to potentially ineffective treatments and risk of harm 5 . ...
Introduction:
Phase 2 trials are fundamental to the rational and efficient design of phase 3 trials. We aimed to determine the relationship of treatment effect size estimates from phase 2 and phase 3 clinical trials on advanced therapeutics in inflammatory bowel disease.
Methods:
MEDLINE, EMBASE, CENTRAL, and the Cochrane library were searched from inception to December 19, 2022, to identify paired phase 2 and 3 placebo-controlled induction studies of advanced therapeutics for Crohn's disease (CD) and ulcerative colitis (UC). Treatment effect sizes were expressed as a risk ratio (RR) between the active arm and placebo arm. For the same therapeutics, RR from phase 2 trials were divided by the RR from phase 3 trial to quantify the relationship of effect sizes between phases.
Results:
Twenty-two studies (9 phase 2 trials, 13 phase 3 trials) were included for CD and 30 studies (12 phase 2 trials, 18 phase 3 trials) for UC. In UC (pooled RR 0.72; 95% confidence interval [CI]: 0.58-0.86; RR <1 indicate smaller treatment effect sizes in phase 2 trials), but not CD (pooled RR 1.01; 95% CI: 0.84-1.18), phase 2 trials systematically underestimated treatment effect sizes for the primary endpoint compared to phase 3 trials. The underestimation was observed for clinical, but not endoscopic endpoints in UC.
Conclusions:
Treatment effect sizes for the primary and clinical endpoints were similar across clinical trial phases in CD, but not UC, where only endoscopic endpoints were comparable. This will help inform clinical development plans and future trial design.
... These aspects are vital for the success of a drug candidate during clinical trials ( Figure 12). For this reason, the use of PET imaging targeting CNS is considered a promising tool in both preclinical and clinical processes [73]. The output of PET imaging depends on the chemical nature of the radiotracer and the physiological conditions of the living subjects. ...
Esterases are hydrolases that catalyze the hydrolysis of esters into the corresponding acids and alcohols. The development of fluorescent probes for detecting esterases is of great importance due to their wide spectrum of biological and industrial applications. These probes can provide a rapid and sensitive method for detecting the presence and activity of esterases in various samples, including biological fluids, food products, and environmental samples. Fluorescent probes can also be used for monitoring the effects of drugs and environmental toxins on esterase activity, as well as to study the functions and mechanisms of these enzymes in several biological systems. Additionally, fluorescent probes can be designed to selectively target specific types of esterases, such as those found in pathogenic bacteria or cancer cells. In this review, we summarize the recent fluorescent probes described for the visualization of cell viability and some applications for in vivo imaging. On the other hand, Positron Emission Tomography (PET) is a nuclear-based molecular imaging modality of great value to study the activity of enzymes in vivo. We provide some examples of PET probes for imaging acetylcholinesterases and butyrylcholinesterases in brain, which are valuable tools for diagnosing dementia and monitoring the effects of anticholinergic drugs on the central nervous system.
... (2) Another problem is the incompatibility between the doses of medicine used in basic research and those used in clinical practice. Due to receptor affinity, some drugs that show significant neuroprotective effects at concentrations higher than clinically applied often fail to improve patient prognosis after entering clinical studies (Muir, 2006;Morgan et al., 2012), and their clinical application value is limited. ...
Studies on the neuroprotective effects of anesthetics were carried out more than half a century ago. Subsequently, many cell and animal experiments attempted to verify the findings. However, in clinical trials, the neuroprotective effects of anesthetics were not observed. These contradictory results suggest a mismatch between basic research and clinical trials. The Stroke Therapy Academic Industry Roundtable X (STAIR) proposed that the emergence of endovascular thrombectomy (EVT) would provide a proper platform to verify the neuroprotective effects of anesthetics because the haemodynamics of patients undergoing EVT is very close to the ischaemia–reperfusion model in basic research. With the widespread use of EVT, it is necessary for us to re-examine the neuroprotective effects of anesthetics to guide the use of anesthetics during EVT because the choice of anesthesia is still based on team experience without definite guidelines. In this paper, we describe the research status of anesthesia in EVT and summarize the neuroprotective mechanisms of some anesthetics. Then, we focus on the contradictory results between clinical trials and basic research and discuss the causes. Finally, we provide an outlook on the neuroprotective effects of anesthetics in the era of endovascular therapy.
... This preexisting information expedites the development of second or further indications, compared with a de novo drug; it also lowers development costs and increases the overall chance of surviving the clinical phase (unless efficacy for the new indication is not corroborated in humans or unexpected and significant adverse disease-drug interactions are observed). Notably, safety issues, inadequate PK, and insufficient exposure at the site of action are among the most common causes of failure in the preclinical and clinical development stages [7,8]. A retrospective analysis of small-molecule drug development projects in AstraZeneca between 2005 and 2010 revealed that safety issues explain the shutting down of 82%, 62% and 35% at preclinical, Phase I and Phase IIa stages, respectively, with failures due to lack of efficacy progressively increasing from preclinical to Phase IIb studies. ...
Introduction:
Over the last decades, there has been substantial debate around the apparent drop in productivity in the pharmaceutical sector. The development of second or further medical uses for known drugs is a possible answer to expedite the development of new therapeutic solutions. Computational methods are among the main strategies for exploring drug repurposing opportunities in a systematic manner.
Areas covered:
This article reviews three general approximations to systematically discover new therapeutic uses for existing drugs: disease-, target-, and drug-centric approaches, along with some recently reported computational methods associated with them.
Expert opinion:
Computational methods are essential for organizing and analyzing the large volume of available biomedical data, which has grown exponentially in the era of big data. The clearest trend in the field involves the use of integrative approaches where different types of data are combined into multipartite networks. Every aspect of computer-guided drug repositioning has currently incorporated state-of-the-art machine learning tools to boost their pattern recognition and predictive capabilities. Remarkably, a majority of the recently reported platforms are publicly available as web apps or open-source software. The introduction of nationwide electronic health records provides invaluable real-world data to detect unknown relationships between approved drug treatments and diseases.
... This technique scans the patient's body and measures the photon emission of the administered radiotracer after positron decay for localization and quantification providing an in-depth 3D observation way of administrated radiotracer's biological fate [28,29]. The possibility of using PET in drug development was demonstrated in neuroscience drug discovery for the quantitative assessment of new chemical entities' exposure in the central nervous system [30]. Nevertheless, current PET scanners are not capable of studying whole-body drug pharmacokinetics because of the limited t axial field of view (FOV) [31,32]. ...
Serving as targeting ligands, aptamers have shown promise in precision medicine. However, the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’ clinical translation. To bridge this gap, here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68 (68Ga) radiolabeled aptamers. The specificity and binding affinity of a radiolabeled aptamer, named 68Ga[Ga]-NOTA-SGC8, were maintained as proven in vitro. Further preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity, potential mutation risks, or genotoxicity at high dosage (40 mg/kg). Based on this result, a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles, as well as biosafety, of the radiolabeled SGC8 aptamer in the human body. Taking advantage of the cutting-edge total-body PET, the aptamers’ distribution pattern in the human body was acquired in a dynamic fashion. This study revealed that radiolabeled aptamers are harmless to normal organs and most of them are accumulated in the kidney and cleared from the bladder via urine, which agrees with preclinical studies. Meanwhile, a physiologically based pharmacokinetic model of aptamer was developed, which could potentially predict therapeutic responses and plan personalized treatment strategies. This research studied the biosafety and dynamic pharmacokinetics of aptamers in the human body for the first time, as well as demonstrated the capability of novel molecular imaging fashion in drug development.
In the ever-evolving landscape of biomedical research, the emergence of New Biological Entities (NBEs) has escorted in a model lift in the field of therapeutic development. This chapter offers an extensive exploration of New Biological Entities (NBEs), encompassing their development, mechanisms of action, inherent features, the intricacies of their development journey, and notable case studies showcasing successful NBEs. Additionally, it delves into the potential applications of NBEs across diverse disease domains, elucidating their profound influence on the healthcare landscape. NBEs, often comprising novel biomolecules such as monoclonal antibodies, gene therapies, or cell-based therapies, have exhibited remarkable versatility and efficacy in treating a wide spectrum of diseases. Their targeted mechanisms of action and enhanced safety profiles make them promising candidates for previously intractable conditions. The advent of biotechnology and advanced genomics has accelerated the discovery and development of NBEs, enabling precision medicine like never before. The chapter explores into the transformative potential of NBEs in various therapeutic areas, from cancer and autoimmune disorders to neurodegenerative diseases and rare genetic conditions. Their ability to modulate intricate biological pathways and offer tailored treatment options holds promise for a future where diseases are not just managed but cured. Furthermore, the chapter highlights the regulatory challenges and manufacturing complexities associated with NBEs and underscores the importance of continued research and innovation to unlock their full therapeutic potential. In conclusion, NBEs represent a groundbreaking frontier in healthcare, offering new hope for patients and reshaping the landscape of modern medicine.
Ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family inhibitor, was evaluated in patients with ulcerative colitis (UC) in a phase 2b trial. Model‐informed drug development strategies were applied to bridge observations from phase 2b to predictions for a proposed phase 3 study design to assess the probability of achieving the target efficacy outcome. A longitudinal exposure‐response model of the time course of the 4 Mayo subscores (rectal bleeding, stool frequency, physician's global assessment, and endoscopic subscore) in patients with UC receiving placebo or ritlecitinib was developed using population modeling approaches and an item response theory framework. The quantitative relationships between the 4 Mayo subscores accommodated the prediction of composite endpoints such as total Mayo score and partial Mayo score (key endpoints from phase 2b), and modified clinical remission and endoscopic remission (proposed phase 3 endpoints). Clinical trial simulations using the final model assessed the probability of candidate ritlecitinib dosing regimens (including those tested in phase 2b and alternative) and phase 3 study designs for achieving target efficacy outcomes benchmarked against an approved treatment for moderate‐to‐severe UC. The probabilities of achieving target modified clinical remission and endoscopic improvement outcomes at both weeks 8 and 52 for ritlecitinib 100 mg once daily was 74.8%. Model‐based assessment mitigated some of the risk associated with proceeding to pivotal phase 3 trials with dosing regimens of which there was limited clinical experience.
Dravet syndrome is a severe genetic epilepsy primarily caused by de novo mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening seizures that are largely resistant to available anti-seizure medications. Preclinical Dravet syndrome animal models are a valuable tool to identify candidate anti-seizure medications for these patients. Among these, scn1lab mutant zebrafish, exhibiting spontaneous seizure-like activity, are particularly amenable to large-scale drug screening. Thus far, we have screened more than 3000 drug candidates in scn1lab zebrafish mutants, identifying valproate, stiripentol, and fenfluramine e.g., Food and Drug Administration approved drugs, with clinical application in the Dravet syndrome population. Successful phenotypic screening in scn1lab mutant zebrafish is rigorous and consists of two stages: (i) a locomotion-based assay measuring high-velocity convulsive swim behavior and (ii) an electrophysiology-based assay, using in vivo local field potential recordings, to quantify electrographic seizure-like events. Historically, nearly 90% of drug candidates fail during translation from preclinical models to the clinic. With such a high failure rate, it becomes necessary to address issues of replication and false positive identification. Leveraging our scn1lab zebrafish assays is one approach to address these problems. Here, we curated a list of nine anti-seizure drug candidates recently identified by other groups using preclinical Dravet syndrome models: 1-Ethyl-2-benzimidazolinone, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat. First-stage locomotion-based assays in scn1lab mutant zebrafish identified only 1-Ethyl-2-benzimidazolinone, chlorzoxazone and lisuride. However, second-stage local field potential recording assays did not show significant suppression of spontaneous electrographic seizure activity for any of the nine anti-seizure drug candidates. Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of anti-seizure medications.
Biased signalling is a natural result of GPCR allosteric function and should be expected from any and all synthetic and natural agonists. Therefore, it may be encountered in all agonist discovery projects and must be considered as a beneficial (or possible detrimental) feature of new candidate molecules. While bias is detected easily, the synoptic nature of GPCR signalling makes translation of simple in vitro bias to complex in vivo systems problematic. The practical outcome of this is a difficulty in predicting the therapeutic value of biased signalling due to the failure of translation of identified biased signalling to in vivo agonism. This is discussed in this review as well as some new ways forward to improve this translation process and better exploit this powerful pharmacologic mechanism.
Immune checkpoint inhibitors (ICIs) are a powerful treatment modality for various types of cancer. The effectiveness of ICIs is intimately connected to the binding status of antibodies to receptors. However, validated means to accurately evaluate target specificity and predict antibody efficacy in vivo are lacking. A novel peptide-based probe called Al[¹⁸F]F-NOTA-PCP1 was developed and validated for its specificity to PD-L1 in A549, U87MG, GL261, and GL261-iPDL1 cell lines, as well as in xenograft models. Then the probe was used in PET/CT scans to determine the binding status of PD-L1 antibodies (atezolizumab, avelumab, and durvalumab) in U87MG xenograft model mice. Moreover, Al[¹⁸F]F-NOTA-PCP1 was used to evaluate the impact of different treatment times and doses. Al[¹⁸F]F-NOTA-PCP1 PET/CT can be used to evaluate the interaction between PD-L1 and antibodies to determine the effectiveness of immunotherapy. By quantifying target engagement, the probe has the potential to predict the efficacy of immunotherapy and optimize the dose and treatment schedules for PD-L1 immunotherapy. This imaging agent could be a valuable tool in guiding personalized treatment strategies and improving cancer patient outcomes.
Dravet syndrome (DS) is a severe genetic epilepsy primarily caused by de novo mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening seizures that are largely resistant to available anti-seizure medications (ASM). Preclinical DS animal models are a valuable tool to identify candidate ASMs for these patients. Among these, scn1lab mutant zebrafish exhibiting spontaneous seizure-like activity are particularly amenable to large-scale drug screening. Prior screening in a scn1lab mutant zebrafish line generated using N-ethyl-N-nitrosourea (ENU) identified valproate, stiripentol, and fenfluramine e.g., Federal Drug Administration (FDA) approved drugs with clinical application in the DS population. Successful phenotypic screening in scn1lab mutant zebrafish consists of two stages: (i) a locomotion-based assay measuring high-velocity convulsive swim behavior and (ii) an electrophysiology-based assay, using in vivo local field potential (LFP) recordings, to quantify electrographic seizure-like events. Using this strategy more than 3000 drug candidates have been screened in scn1lab zebrafish mutants. Here, we curated a list of nine additional anti-seizure drug candidates recently identified in preclinical models: 1-EBIO, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat. First-stage locomotion-based assays in scn1lab mutant zebrafish identified only 1-EBIO, chlorzoxazone and lisuride. However, second-stage LFP recording assays did not show significant suppression of spontaneous electrographic seizure activity for any of the nine anti-seizure drug candidates. Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of ASMs.
Introduction:
Psychiatry is one of the medical disciplines that suffers most from a lack of innovation in its therapeutic arsenal. Many failures in drug candidate trials can be explained by pharmacological properties that have been poorly assessed upstream, in terms of brain passage, brain target binding and clinical outcomes. Positron emission tomography can provide pharmacokinetic and pharmacodynamic data to help select candidate-molecules for further clinical trials.
Areas covered:
This review aims to explain and discuss the various methods using positron-emitting radiolabeled molecules to trace the cerebral distribution of the drug-candidate or indirectly measure binding to its therapeutic target. More than an exhaustive review of PET studies in psychopharmacology, this article highlights the contributions this technology can make in drug discovery applied to psychiatry.
Expert opinion:
PET neuroimaging is the only technological approach that can, in vivo in humans, measure cerebral delivery of a drug candidate, percentage and duration of target binding, and even the pharmacological effects. PET studies in a small number of subjects in the early stages of the development of a psychotropic drug can therefore provide the pharmacokinetic/pharmacodynamic data required for subsequent clinical evaluation. While PET technology is demanding in terms of radiochemical, radiopharmacological and nuclear medicine expertise, its integration into the development process of new drugs for psychiatry has great added value.
Dose-response analysis is often applied to the quantification of drug-effect especially for slowly responding disease end points where a comparison is made across dose levels after a particular period of treatment. It has long been recognized that exposure - response is more appropriate than dose-response. However, trials necessarily are designed as dose-response experiments. Second, a wide range of functional forms are used to express relationships between dose and response. These considerations are also important for clinical development because pharmacokinetic (PK; and variability) plus pharmacokinetic-pharmacodynamic modeling may allow one to anticipate the shape of the dose-response curve and so the trial design. Here, we describe how the location and steepness of the dose response is determined by the PKs of the compound being tested and its exposure-response relationship in terms of potency (location), efficacy (maximum effect) and Hill coefficient (steepness). Thus, the location (50% effective dose [ED50 ]) is dependent not only on the potency (half-maximal effective concentration) but also the compound's PKs. Similarly, the steepness of the dose response is shown to be a function of the half-life of the drug. It is also shown that the shape of relationship varies dependent on the assumed time course of the disease. This is important in the context of drug-discovery where the in vivo potencies of compounds are compared as well as when considering an analysis of summary data (for example, model-based meta-analysis) for clinical decision making.
Introduction:
Introduced about 50 years ago, the model of Xenopus oocytes for the expression of recombinant proteins has gained a broad spectrum of applications. The authors herein review the benefits brought from using this model system, with a focus on modeling neurological disease mechanisms and application to drug discovery.
Areas covered:
Using multiple examples spanning from ligand gated ion channels to transporters, this review presents, in the light of the latest publications, the benefits offered from using Xenopus oocytes. Studies range from the characterization of gene mutations to the discovery of novel treatments for disorders of the central nervous system (CNS).
Expert opinion:
Development of new drugs targeting CNS disorders has been marked by failures in the translation from preclinical to clinical studies. As progress in genetics and molecular biology highlights large functional differences arising from a single to a few amino acid exchanges, the need for drug screening and functional testing against human proteins is increasing. The use of Xenopus oocytes to enable precise modeling and characterization of clinically relevant genetic variants constitutes a powerful model system that can be used to inform various aspects of CNS drug discovery and development.
As pharmaceutical development moves from early stage in vitro experimentation to later in vivo and subsequent clinical trials, data and knowledge are acquired across multiple time and length scales, from the subcellular to whole patient cohort scale. Realising the potential of this data for informing decision making in pharmaceutical development requires the individual and combined application of machine learning (ML) and mechanistic multiscale mathematical modelling approaches. Here we outline how these two approaches, both individually and in tandem, can be applied at different stages of the drug discovery and development pipeline to inform decision making compound development. The importance of discerning between knowledge and data is highlighted in informing the initial use of ML or mechanistic Quantitative Systems Pharmacology (QSP) models. We discuss the application of sensitivity and structural identifiability analyses of QSP models in informing future experimental studies, to which ML may be applied, as well as how ML approaches can be used to inform mechanistic model development. Relevant literature studies are highlighted and we close by discussing caveats regarding the application of each approach in an age of constant data acquisition. Significance Statement We consider when best to apply Machine Learning (ML) and mechanistic Quantitative Systems Pharmacology (QSP) approaches in the context of the drug discovery and development pipeline. We discuss the importance of prior knowledge and data available for the system of interest and how this informs the individual and combined application of ML and QSP approaches at each stage of the pipeline.
Effective portfolio management is crucial for innovation and sustaining revenue in pharmaceutical companies. This article holistically reviews trends, challenges, and approaches to pharmaceutical portfolio management and focuses, in particular, on cognitive biases in portfolio decision-making. Portfolio managers strongly rely on external innovation and face increasing competitive pressure and portfolio complexity. The ability to address biases and make robust decisions remains a challenge. Portfolio management practitioners most commonly face confirmation bias, champion bias, or misaligned incentives, which they seek to mitigate through expert input, team diversity, and rewarding truth-seeking. Ultimately, highest-quality portfolio management decision-making could be enabled by three factors: high-quality data, structured review processes, and comprehensive mitigating measures against biases in decision-making.
Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signalling. Consequently, it has emerged as a promising target for novel analgesics, yet to date no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3 and 10 mg/kg, p.o.) dose‐dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30 and 100 mg, p.o.) dose‐dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend towards inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde‐induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross‐species differences in potency of the compound at TRPA1. Exposure‐response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde‐evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.
Over the past decade, remarkable advances have been witnessed in the development of small-molecule probes. These molecular tools have been widely applied for interrogating proteins, pathways and drug-target interactions in preclinical research. While novel structures and designs are commonly explored in probe development, the clinical translation of small-molecule probes remains limited, primarily due to safety and regulatory considerations. Recent synergistic developments - interfacing novel chemical probes with complementary analytical technologies - have introduced and expedited diverse biomedical opportunities to molecularly characterize targeted drug interactions directly in the human body or through accessible clinical specimens (e.g., blood and ascites fluid). These integrated developments thus offer unprecedented opportunities for drug development, disease diagnostics and treatment monitoring. In this review, we discuss recent advances in the structure and design of small-molecule probes with novel functionalities and the integrated development with imaging, proteomics and other emerging technologies. We further highlight recent applications of integrated small-molecule technologies for the molecular analysis of drug-target interactions, including translational applications and emerging opportunities for whole-body imaging, tissue-based measurement and blood-based analysis.
Targeted protein degradation (TPD) has emerged as a potentially transformational therapeutic modality with considerable promise. Molecular glue degraders remodel the surface of E3 ligases inducing interactions with neosubstrates resulting in their polyubiquitination and proteasomal degradation. Molecular glues are clinically precedented and have demonstrated the ability to degrade proteins-of-interest (POIs) previously deemed undruggable due to the absence of a traditional small molecule binding pocket. Heterobifunctional proteolysis targeting chimeras (PROTACs) possess ligands for an E3 complex and the POI which are chemically linked together, and similarly hijack the ubiquitin machinery to deplete the target. There has been a recent surge in the number of degraders entering clinical trials, particularly directed towards cancer. Nearly all utilize CRL4CRBN as the E3 ligase, and a relatively limited diversity of POIs are currently targeted. In this review, we provide an overview of the degraders in clinical trials and provide a perspective on the lessons learned from their development and emerging human data that will be broadly useful to those working in the TPD field.
In 2008 the role of clinical imaging in oncology drug development was reviewed. The review outlined where imaging was being applied and considered the diverse demands across the phases of drug development. A limited set of imaging techniques was being used, largely based on structural measures of disease evaluated using established response criteria such as response evaluation criteria in solid tumours (RECIST). Beyond structure, functional tissue imaging such as dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) and metabolic measures using [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) were being increasingly incorporated. Specific challenges related to the implementation of imaging were outlined including standardisation of scanning across study centres and consistency of analysis and reporting. More than a decade on the needs of modern drug development are reviewed, how imaging has evolved to support new drug development demands, the potential to translate state-of-the-art methods into routine tools and what is needed to enable the effective use of this broadening clinical trial toolset. In this review we challenge the clinical and scientific imaging community to help refine existing clinical trial methods and innovate to deliver the next generation of techniques. Strong industry-academic partnerships and pre-competitive opportunities to co-ordinate efforts will ensure imaging technologies maintain a crucial role delivering innovative medicines to treat cancer.
Completely revised and updated, the 2nd edition of The Handbook of Medicinal Chemistry draws together contributions from authoritative practitioners to provide a comprehensive overview of the field as well as insight into the latest trends and research. An ideal companion for students in medicinal chemistry, drug discovery and drug development, while also communicating core principles, the book places the discipline within the context of the burgeoning platform of new modalities now available to drug discovery. The book also highlights the role chemistry has to play in wider target validation and translational technologies.
This is a carefully curated compilation of writing from global experts using their broad experience of medicinal chemistry, project leadership and drug discovery and development from an industry, academic and charity perspective to provide unparalleled insight into the field.
Completely revised and updated, the 2nd edition of The Handbook of Medicinal Chemistry draws together contributions from authoritative practitioners to provide a comprehensive overview of the field as well as insight into the latest trends and research. An ideal companion for students in medicinal chemistry, drug discovery and drug development, while also communicating core principles, the book places the discipline within the context of the burgeoning platform of new modalities now available to drug discovery. The book also highlights the role chemistry has to play in wider target validation and translational technologies.
This is a carefully curated compilation of writing from global experts using their broad experience of medicinal chemistry, project leadership and drug discovery and development from an industry, academic and charity perspective to provide unparalleled insight into the field.
Completely revised and updated, the 2nd edition of The Handbook of Medicinal Chemistry draws together contributions from authoritative practitioners to provide a comprehensive overview of the field as well as insight into the latest trends and research. An ideal companion for students in medicinal chemistry, drug discovery and drug development, while also communicating core principles, the book places the discipline within the context of the burgeoning platform of new modalities now available to drug discovery. The book also highlights the role chemistry has to play in wider target validation and translational technologies.
This is a carefully curated compilation of writing from global experts using their broad experience of medicinal chemistry, project leadership and drug discovery and development from an industry, academic and charity perspective to provide unparalleled insight into the field.
Chrysanthemum morifolium Ramat. is a kind of food and drug dual-use traditional Chinese medicine possessing multiple pharmacological and biochemical benefits. In our study, a rapid and high-throughput method based on Surface plasmon resonance (SPR) biosensor technology was developed and verified for screening potential xanthine oxidase (XOD) inhibitors exemplarily in the Chrysanthemum morifolium Ramat. Coupled with ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS), 14 XOD-binders were identified. In the SPR-based biosensor and molecular docking analysis, most compounds exhibited a strong affinity and binding kinetic property (association rate constant, Kon and dissociation rate constant, Koff) for XOD and could be regarded as potential inhibitors. More importantly, to further accurately assess target occupancy of candidate compounds in vivo, a mathematical model was established and verified involving three crucial intrinsic kinetic processes (Pharmacokinetics, Binding kinetic and Target kinetic). Overall, the proposed screening and assessment strategy could be proved an effective theoretical basis for further pharmacodynamic evaluation.
GDC-9545 (giredestrant) is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader that is being developed as a best-in-class drug candidate for early-stage and advanced drug-resistant breast cancer. GDC-9545 was designed to improve the poor absorption and metabolism of its predecessor GDC-0927, for which development was halted due to a high pill burden. This study aimed to develop physiologically-based pharmacokinetic/pharmacodynamic (PBPK-PD) models to characterize the relationships between oral exposure of GDC-9545 and GDC-0927 and tumor regression in HCI-013 tumor-bearing mice, and to translate these PK-PD relationships to a projected human efficacious dose by integrating clinical PK data. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the animal and human Simcyp V20 Simulator (Certara) and adequately described each compound's systemic drug concentrations and antitumor activity in the dose-ranging xenograft experiments in mice. The established PK-PD relationship was translated to a human efficacious dose by substituting mouse PK for human PK. PBPK input values for human clearance were predicted using allometry and in vitro in vivo extrapolation approaches and human volume of distribution was predicted from simple allometry or tissue composition equations. The integrated human PBPK-PD model was used to simulate TGI at clinically relevant doses. Translating the murine PBPK-PD relationship to a human efficacious dose projected a much lower efficacious dose for GDC-9545 than GDC-0927. Additional sensitivity analysis of key parameters in the PK-PD model demonstrated that the lower efficacious dose of GDC-9545 is a result of improvements in clearance and absorption. The presented PBPK-PD methodology can be applied to support lead optimization and clinical development of many drug candidates in discovery or early development programs.
A primary objective of pharmacokinetic-pharmacodynamic (PKPD) reasoning is to identify key in vivo drug and system proper¬ties, enabling prediction of the magnitude and time course of drug responses under physiological and pathological conditions in animals and man. Since the pharmacological response generated by a drug is highly dependent on the actual system used to study its action, knowledge about its potency and efficacy at a given concentration or dose is insufficient to obtain a proper understanding of its pharmacodynamic profile. Hence, the output of PKPD activities extends beyond the provision of quantitative measures (models) of results, to the design of future protocols. Furthermore, because PKPD integrates DMPK (e.g. clearance) and pharmacology (e.g. potency),it provides an anchor point for compound selection, and, as such, should be viewed as an important weapon in medicinal chemistry. Here we outline key PK concepts relevant to PD, and then consider real-life experiments to illustrate the importance to the medicinal chemist of data obtained by PKPD. Useful assumptions and potential pitfalls are described, providing a holistic view of the plethora of determinants behind in vitro-in vivo correlations. By condensing complexity to simplicity, there are not only consequences for experimental design, and for the ranking and design of compounds, but it is also possible to make important predictions such as the impact of changes in drug potency and kinetics. In short, by using quantitative methods to tease apart pharmacodynamic complexities such as temporal differences and changes in plasma protein binding, it is possible to target the changes necessary for improving a compound's profile.
The pharmaceutical industry is under growing pressure from a range of environmental issues, including major losses of revenue owing to patent expirations, increasingly cost-constrained healthcare systems and more demanding regulatory requirements. In our view, the key to tackling the challenges such issues pose to both the future viability of the pharmaceutical industry and advances in healthcare is to substantially increase the number and quality of innovative, cost-effective new medicines, without incurring unsustainable R&D costs. However, it is widely acknowledged that trends in industry R&D productivity have been moving in the opposite direction for a number of years. Here, we present a detailed analysis based on comprehensive, recent, industry-wide data to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity. We then propose specific strategies that could have the most substantial impact in improving R&D productivity.
In addition to CD4, the human immunodeficiency virus (HIV) requires a coreceptor for entry into target cells. The chemokine receptors CXCR4 and CCR5, members of the G protein-coupled receptor superfamily, have been identified as the principal coreceptors for T cell line-tropic and macrophage-tropic HIV-1 isolates, respectively. The updated coreceptor repertoire includes numerous members, mostly chemokine receptors and related orphans. These discoveries provide a new framework for understanding critical features of the basic biology of HIV-1, including the selective tropism of individual viral variants for different CD4+ target cells and the membrane fusion mechanism governing virus entry. The coreceptors also provide molecular perspectives on central puzzles of HIV-1 disease, including the selective transmission of macrophage-tropic variants, the appearance of T cell line-tropic variants in many infected persons during progression to AIDS, and differing susceptibilities of individuals to infection and disease progression. Genetic findings have yielded major insights into the in vivo roles of individual coreceptors and their ligands; of particular importance is the discovery of an inactivating mutation in the CCR5 gene which, in homozygous form, confers strong resistance to HIV-1 infection. Beyond providing new perspectives on fundamental aspects of HIV-1 transmission and pathogenesis, the coreceptors suggest new avenues for developing novel therapeutic and preventative strategies to combat the AIDS epidemic.
We describe here the identification and properties of SCH-C (SCH 351125), a small molecule inhibitor of HIV-1 entry via the CCR5 coreceptor. SCH-C, an oxime-piperidine compound, is a specific CCR5 antagonist as determined in multiple receptor binding and signal transduction assays. This compound specifically inhibits HIV-1 infection mediated by CCR5 in U-87 astroglioma cells but has no effect on infection of CXCR4-expressing cells. SCH-C has broad and potent antiviral activity in vitro against primary HIV-1 isolates that use CCR5 as their entry coreceptor, with mean 50% inhibitory concentrations ranging between 0.4 and 9 nM. Moreover, SCH-C strongly inhibits the replication of an R5-using HIV-1 isolate in SCID-hu Thy/Liv mice. SCH-C has a favorable pharmacokinetic profile in rodents and primates with an oral bioavailability of 50-60% and a serum half-life of 5-6 h. On the basis of its novel mechanism of action, potent antiviral activity, and in vivo pharmacokinetic profile, SCH-C is a promising new candidate for therapeutic intervention of HIV infection.
UK-427,857 (4, 4-difluoro-N-[(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl]cyclohexanecarboxamide) is a novel CCR5 antagonist undergoing investigation for use in the treatment of human immunodeficiency virus (HIV) infection. Pharmacokinetic and metabolism studies have been performed in mouse, rat, dog, and human after single and multiple administration by oral and intravenous routes. The compound has physicochemical properties that are borderline for good pharmacokinetics, being moderately lipophilic (log D(7.4) 2.1) and basic (pK(a) 7.3), possessing a number of H-bonding functionalities, and with a molecular weight of 514. The compound was incompletely absorbed in rat (approximately 20-30%) but well absorbed in dog (>70%). Based on in vitro studies in Caco-2 cells, UK-427,857 has relatively poor membrane permeability, and transcellular flux is enhanced in the presence of inhibitors of P-glycoprotein. Further evidence for the involvement of P-glycoprotein in restricting the oral absorption of UK-427,857 was obtained in P-glycoprotein null mice (mdr1a/mdr1b knockout). In these animals, AUC after oral administration was 3-fold higher than in control animals. In oral dose escalation studies in humans, the compound demonstrated nonlinear pharmacokinetics, with increased dose-normalized exposure with increased dose size, consistent with saturation of P-glycoprotein. The oral dose-exposure relationship of UK-427,857 in humans was not reflected in either rat or dog. In animal species and humans, UK-427,857 undergoes some metabolism, with parent compound the major component present in the systemic circulation and excreta. Elimination of radioactive dose was primarily via the feces. In rat, parent compound was secreted via bile and directly into the gastrointestinal tract. Metabolites were products of oxidative metabolism and showed a high degree of structural consistency across species.
Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 microM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using maraviroc for the treatment of HIV-1 infection and AIDS.
Mechanistic PKPD models are now advocated not only by academic and industrial researchers, but also by regulators. A recent development in this area is based on the growing realisation that innovation could be dramatically catalysed by creating synergy at the interface between Systems Biology and PKPD, two disciplines which until now have largely existed in 'parallel universes' with a limited track record of impactful collaboration. This has led to the emergence of systems pharmacology. Broadly speaking, this is the quantitative analysis of the dynamic interactions between drug(s) and a biological system to understand the behaviour of the system as a whole, as opposed to the behaviour of its individual constituents; thus, it has become the interface between PKPD and systems biology. It applies the concepts of Systems Engineering, Systems Biology, and PKPD to the study of complex biological systems through iteration between computational and/or mathematical modelling and experimentation. Application of systems pharmacology can now impact across all stages of drug research and development, ranging from very early discovery programs to large-scale Phase 3/4 patient studies, and has the potential to become an integral component of a new 'enhanced quantitative drug discovery and development' (EQD3) R&D paradigm.
Well-conducted Phase II clinical trials provide the data required to determine whether there is a case to be made, both scientifically and commercially, for progressing a drug candidate into Phase III trials. At present, however, Phase II success rates are lower than at any other phase of development.
A series of novel non-peptide corticotropin releasing factor type-1 receptor (CRF(1)) antagonists were found to display varying degrees of insurmountable and non-competitive behaviour in functional in vitro assays. We describe how we attempted to relate this behaviour to ligand receptor-binding kinetics in a quantitative manner and how this resulted in the development and implementation of an efficient pharmacological screening method based on principles described by Motulsky and Mahan.
A non-equilibrium binding kinetic assay was developed to determine the receptor binding kinetics of non-peptide CRF(1) antagonists. Nonlinear, mixed-effects modelling was used to obtain estimates of the compounds association and dissociation rates. We present an integrated pharmacokinetic-pharmacodynamic (PKPD) approach, whereby the time course of in vivo CRF(1) receptor binding of novel compounds can be predicted on the basis of in vitro assays.
The non-competitive antagonist behaviour appeared to be correlated to the CRF(1) receptor off-rate kinetics. The integrated PKPD model suggested that, at least in a qualitative manner, the in vitro assay can be used to triage and select compounds for further in vivo investigations.
This study provides evidence for a link between ligand offset kinetics and insurmountable/non-competitive antagonism at the CRF(1) receptor. The exact molecular pharmacological nature of this association remains to be determined. In addition, we have developed a quantitative framework to study and integrate in vitro and in vivo receptor binding kinetic behaviour of CRF(1) receptor antagonists in an efficient manner in a drug discovery setting.
The Centre for Medicines Research International has noted that the average for the combined success rate at Phase III and submission has fallen to ~50% in recent years. To learn more about the causes for Phase III and submission failures, Thomson Reuters Life Science Consulting analysed the reasons for these failures between 2007 and 2010.
Rising expenditure in pharmaceutical R&D has not been matched by increased productivity. There is an urgent need to solve the current high levels of pipeline attrition. Changing the current failed model of drug discovery and development, in which high numbers of candidate drugs are produced and high attrition is accepted, is essential. A different model is needed, in which the focus shifts to identifying better-quality candidate drugs that allow scientifically robust testing of disease and targets in humans. Lowering the risks of compound-based attrition in small-molecule drug discovery and development (ie, addressing toxicity, specificity, potency, duration and exposure) is achievable by improved control of physical properties and by setting more demanding candidate criteria. Separating the key scientific experiment--proof-of-concept clinical trials in humans--from commercial development imperatives is a necessary step for the industry.
The application of physiologically-based pharmacokinetic (PBPK) modeling is coming of age in drug development and regulation, reflecting significant advances over the past 10 years in the predictability of key pharmacokinetic (PK) parameters from human in vitro data and in the availability of dedicated software platforms and associated databases. Specific advances and contemporary challenges with respect to predicting the processes of drug clearance, distribution, and absorption are reviewed, together with the ability to anticipate the quantitative extent of PK-based drug-drug interactions and the impact of age, genetics, disease, and formulation. The value of this capability in selecting and designing appropriate clinical studies, its implications for resource-sparing techniques, and a more holistic view of the application of PK across the preclinical/clinical divide are considered. Finally, some attention is given to the positioning of PBPK within the drug development and approval paradigm and its future application in truly personalized medicine.
PF-592379 is a potent, selective agonist of the dopamine 3 receptor, for the treatment of male erectile dysfunction and female sexual dysfunction. In vivo, PF-592379 has low-moderate clearance relative to liver blood flow of 6.3 and 8.5 ml/min/kg in dog and 44.8 and 58.2 ml/min/kg in rat. It has high permeability in Caco-2 cells and was completely absorbed in rat and dog pharmacokinetic studies with an oral bioavailability of 28% in both rats and 61 and 87% in the dogs. These data are consistent with the physicochemical properties of PF-592379, which indicate complete absorption by the transcellular route. Elimination of PF-592379 was predominantly metabolic in nature. In vitro routes of metabolism studies indicate that metabolism in the rat is a combination of P450 mechanisms and N-glucuronidation, whereas in dog and human, N-glucuronidation is the major route. NMR analysis indicates that N-glucuronidation is non-quaternary in nature and occurs on both the pyridyl amine and ring nitrogen. Rates of clearance via N-glucuronidation were predicted to be low in humans compared with acyl or phenolic glucuronidation. PF-592379 was predicted to have complete absorption from the gastrointestinal tract and an oral bioavailability of >60% in the clinic. Clinical data verified that PF-592379 is a low clearance compound in human, with a mean oral clearance of 6.5 ml/min/kg following a 200 mg oral dose. PF-592379 has ideal pharmacokinetic properties for an oral D3 agonist, intended for on demand dosing.
Proof of concept (POC) may be defined as the earliest point in the drug development process at which the weight of evidence suggests that it is "reasonably likely" that the key attributes for success are present and the key causes of failure are absent. POC is multidimensional but is focused on attributes that, if not addressed, represent a threat to the success of the project in crucial areas such as safety, efficacy, pharmaceutics, and commercial and regulatory issues. The appropriate weight of evidence is assessed through the use of mathematical models and by evaluating the consequences of advancing a candidate drug that is not safe, effective, or commercially viable, vs. failing to advance a candidate that possesses these attributes. Tools for POC include biomarkers, targeted populations, pharmacokinetic (PK)/pharmacodynamic (PD) modeling, simulation, and adaptive study designs. Challenges to the success of POCs include a shortage of skilled personnel, failure to integrate multiple disciplines and information, and the demand made by organizations for certainty.
This study utilizes both public and private data sources to estimate clinical phase transition and clinical approval probabilities for drugs in the development pipelines of the 50 largest pharmaceutical firms (by sales). The study examined the development histories of these investigational compounds from the time point at which they first entered clinical testing (1993-2004) through June 2009. The clinical approval success rate in the United States was 16% for self-originated drugs (originating from the pharmaceutical company itself) during both the 1993-1998 and the 1999-2004 subperiods. For all compounds (including licensed-in and licensed-out drugs in addition to self-originated drugs), the clinical approval success rate for the entire study period was 19%. The estimated clinical approval success rates and phase transition probabilities differed significantly by therapeutic class. The estimated clinical approval success rate for self-originated compounds over the entire study period was 32% for large molecules and 13% for small molecules. The estimated transition probabilities were also higher for all clinical phases with respect to large molecules.
Drug development projects have high attrition rates, often because efficacy and safety issues have not been foreseen. More effective prediction of 'translational success' could therefore have a key role in addressing the widely acknowledged problems with weak drug development pipelines. Here, I discuss how a scoring system to systematically assess key determinants of translational success, such as biomarkers and animal and human data, could help identify deficiencies and potential improvements, and increase the reliability of portfolio risk estimates.
The beta-chemokines MIP-1alpha, MIP-1beta and RANTES inhibit infection of CD4+ T cells by primary, non-syncytium-inducing (NSI) HIV-1 strains at the virus entry stage, and also block env-mediated cell-cell membrane fusion. CD4+ T cells from some HIV-1-exposed uninfected individuals cannot fuse with NSI HIV-1 strains and secrete high levels of beta-chemokines. Expression of the beta-chemokine receptor CC-CKR-5 in CD4+, non-permissive human and non-human cells renders them susceptible to infection by NSI strains, and allows env-mediated membrane fusion. CC-CKR-5 is a second receptor for NSI primary viruses.
Rare individuals have been multiply exposed to HIV-1 but remain uninfected. The CD4+ T-cells of two of these individuals, designated EU2 and EU3, are highly resistant in vitro to the entry of primary macrophagetropic virus but are readily infectable with transformed T-cell line adapted viruses. We report here on the genetic basis of this resistance. We found that EU2 and EU3 have a homozygous defect in CKR-5, the gene encoding the recently described coreceptor for primary HIV-1 isolates. These individuals appear to have inherited a defective CKR-5 allele that contains an internal 32 base pair deletion. The encoded protein is severely truncated and cannot be detected at the cell surface. Surprisingly, this defect has no obvious phenotype in the affected individuals. Thus, a CKR-5 allele present in the human population appears to protect homozygous individuals from sexual transmission of HIV-1. Heterozygous individuals are quite common (approximately 20%) in some populations. These findings indicate the importance of CKR-5 in HIV-1 transmission and suggest that targeting the HIV-1-CKR-5 interaction may provide a means of preventing or slowing disease progression.
The chemokine receptor CCR5 is an important co-receptor for cell fusion. A 32-bp deletion of the CCR5 gene, leading to complete absence of functional CCR5 expression, has been associated with resistance to human immunodeficiency virus (HIV) infection in homozygotes and slower HIV disease progression in heterozygotes. The objectives of this study were to assess the effects of this 32-bp deletion on transmission of HIV infection and on HIV disease progression in haemophilic individuals. Six HIV-negative patients from our centre, known to have been exposed to infectious factor VIII concentrates, have been analysed. Three of these patients possess the CCR5 32-bp deletion, two patients being homozygous. The presence of the CCR5 32-bp gene deletion has also been analysed in 71 HIV-positive patients. In this group of patients, there was a lower than expected incidence of the 32-bp deletion. Those who possess the 32-bp deletion progress to AIDS more slowly than those who do not (P = 0.05, log-rank test). Rates of CD4 loss were slower in those heterozygous for the gene deletion. We confirm that heterozygosity for the 32-bp gene deletion in CCR5 is partially protective against initial infection with HIV. In those heterozygous patients who became infected with HIV, disease progression was slower.
To establish the efficacy and safety of a fixed, 3-mg dose of apomorphine SL compared with placebo, and to compare 3 mg with 4 mg apomorphine SL in patients with erectile dysfunction.
This randomized, double-blind, crossover study included 296 heterosexual men with ED of various etiologies and severities. Two crossover groups were evaluated separately: 3 mg apomorphine SL vs. placebo (n = 194), and 3 vs. 4 mg apomorphine SL (n = 102). The primary efficacy variable was the percentage of attempts resulting in erections firm enough for intercourse; additional variables included the percentage of attempts resulting in intercourse and time to erection. Partner assessments were also analyzed.
3 mg apomorphine SL was significantly more effective than placebo (p<0.001) for the percentage of attempts resulting in erections firm enough for intercourse and resulting in intercourse, as assessed by both patients and partners. Median time to erection was 18.8 min. The 3-mg dose was not significantly different from 4 mg in the evaluation of efficacy variables, but the incidence of adverse events was higher with 4 mg. Nausea was the most common event, reported by 3.3% of patients on 3 mg vs. 14.1% on 4 mg; in the placebo comparison, nausea was reported by 7.0% of patients taking 3 mg apomorphine SL vs. 1.1% of those taking placebo.
3 mg apomorphine SL was significantly more effective than placebo and comparable to 4 mg, while offering an improved risk-benefit ratio.
The pharmaceutical industry faces considerable challenges, both politically and fiscally. Politically, governments around the world are trying to contain costs and, as health care budgets constitute a very significant part of governmental spending, these costs are the subject of intense scrutiny. In the United States, drug costs are also the subject of intense political discourse. This article deals with the fiscal pressures that face the industry from the perspective of R&D. What impinges on productivity? How can we improve current reduced R&D productivity?
Background:
The viral dynamics of human immunodeficiency virus (HIV) infection has been widely studied and expressed as mathematic equations. For most of the current registered antiretroviral drugs, the pharmacokinetics is well characterized and some relationships with the viral load-time profiles in plasma from HIV patients have been established. The integration of these models in a pharmacokinetic (PK)-pharmacodynamic (PD)-disease model can help toward a better understanding of the complexity of the interactions, as well as in the identification and clarification of the current model assumptions.
Methods:
This work describes the development of a generic PK-PD disease model for a short-term (10 days) monotherapy phase IIa study with a novel anti-HIV drug, maraviroc (UK-427,857). The disease component of the model was based on the model published by Bonhoeffer et al, which was adapted for short-term treatment and for the new mechanism of action, CCR5-receptor antagonism. The model parameters were derived from the literature, as well as from a model-based analysis of available phase IIa clinical data from another investigational antiretroviral drug. The PD component that links the plasma concentrations of maraviroc to the inhibition of virus replication was based on in vitro measurements of drug potency and took into account the difference in the in vitro and in vivo protein binding and the uncertainties regarding the interpretation of the in vitro to in vivo extrapolation of the 50% inhibitory concentration. Finally, the PK component was based on information obtained from a single-dose study in healthy volunteers.
Results:
The integrated PK-PD disease modeling allowed prediction of the effect on viral load of different maraviroc doses given as monotherapy to drug-naive patients.
Conclusions:
By making use of the available PK-PD disease model, the possible range of active oral doses for maraviroc in HIV-positive patients was estimated by simulation before any clinical trials were taking place. The use of a model-based approach for selecting doses for clinical phase IIa has improved and accelerated the drug's development. This model was a powerful tool for assisting in the design of clinical studies on new agents for treating HIV/acquired immunodeficiency syndrome.
To use a viral dynamics model to compare the effectiveness of in vivo viral inhibition of several doses of maraviroc (MVC;UK-427,857) and to use a modeling approach to support design decisions for a monotherapy study using various dosing regimens of maraviroc given with and without food.
The pharmacokinetic-pharmacodynamic model was developed using clinical data from a first monotherapy study (study A4001007). This was a randomized, double-blind, placebo-controlled, multicenter study of maraviroc in 44 asymptomatic HIV-1-infected patients. Patients received maraviroc under food restrictions at 25 mg once daily or 50, 100, or 300 mg twice daily, or placebo for 10 days.
Antiviral responses were assessed by measuring plasma HIV-1 RNA levels during screening, during randomization, at baseline, and daily during the 10 days of treatment and at days 11 to 15, 19, 22, 25, and 40. An integrated pharmacokinetic-pharmacodynamic model was developed using the mixed effects modeling approach with patients' pharmacokinetic profiles on the last day of treatment, HIV-1 RNA levels over time, and the individual viral susceptibility. The parameters derived from the viral dynamic model were used to calculate average viral inhibition fraction, decay rate of actively infected cells, and basic reproductive ratio for each treatment group. Monte Carlo simulation was then used to determine the distribution of viral load change across simulated patients over time for each regimen to be studied in another monotherapy study, A4001015.
The decline rate in the 300 mg twice daily group was comparable to that induced by potent protease inhibitor monotherapy, but was significantly slower than that in patients receiving combination therapy including both protease inhibitor and reverse transcriptase inhibitors. The efficacy of inhibition in vivo was estimated to range from 0.15 to 0.38 for the 25 mg once daily dose group and from 0.88 to 0.96 for the 300 mg twice daily dose group.
The model has aided the analysis and interpretation of the clinical data. The use of a model-based approach for selecting doses can accelerate drug development by replacing some arms or trials with simulations.
Drug development is, in essence, the answering of scientific questions related to the effects of the intended new medicine. This process starts with preclinical research and proceeds with clinical testing. Especially for innovative drugs, this proceeds along a number of cycles in which the questions are answered by learning from informative studies and subsequent confirmation in more pragmatic studies. Many first-in-human studies and other human pharmacology studies are not designed to be informative but use standard designs and answer generic questions about tolerability and safety. Despite several recent and eloquent pleas for more integrated and quantitative drug development, signs of a strong uptake of this are lacking. In this article, an orderly method for the determination of objective human pharmacology studies is given. The objectives of the study and the expected pharmacology and pharmacokinetics of the compound determine the optimal design; and several general design models and guidelines are given for the design of informative human pharmacology studies.