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Physiologically-based pharmacokinetic model assumptions in terms of clearance and relative CYP3A4 contribution
Source publication
Introduction:
Macitentan is a novel dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). It is metabolized by cytochrome P450 (CYP) enzymes, mainly CYP3A4, to its active metabolite ACT-132577.
Methods:
A physiological-based pharmacokinetic (PBPK) model was developed by combining observations from clinic...
Context in source publication
Context 1
... of Equation 2 using the observed AUC values for macitentan and ACT-132577 (corrected for the difference in molecular weight) after a single 10-mg macitentan dose [14] and the fraction of macitentan metabolized to ACT-132577 (60 %, see above) resulted in an ACT-132577 plasma clearance of 0.32 L/h. In vitro data using human liver microsomes and microsomes from cells expressing recombinant CYP3A4 indicated that ACT-132577 is also metabolized by CYP3A4. ACT- 132577 was found to be conjugated in vivo with glucose to form metabolite M 706 u, which represents 17 % of the dose [20]. The fraction of ACT-132577 that is not metabolized by CYP3A4 was, therefore, 17 % / 60 % = 27 %. The remainder of the ACT-132577 clearance (73 %) was assumed to be CYP3A4-mediated and was retrograde scaled to the units ‘ L/min/pmol enzyme’ as described for macitentan above. The remainder of the metabolic clearance was not assigned to a specific enzyme but rather to additional systemic clearance ( Table 1). Clearance of macitentan and its metabolite ACT-132577 and the contribution of CYP3A4 is depicted in Figure 1. The population selected for the trial design followed the experimental conditions of the clinical drug-drug interaction studies [14-17]. Ten virtual trials of ten subjects each were simulated (size: 100) per interaction study, in a male, healthy volunteer population. Food status, population and dosing regimen of the drug-drug interaction studies were matched in the simulations as detailed in the supplementary materials. A default coefficient of variation (C.V.) of 30 % was assumed for all compound input parameters in Simcyp except for the fraction absorbed, for which variation was assumed to be absent. Variation of all physiological parameters was based on the default variation in the healthy volunteer population database used in Simcyp. Half-lives were estimated with the Phoenix WinNonlin 6.3 software package (Pharsight) using non-compartmental PK analysis of the individual plasma concentration-time profile output from the PBPK model. The PBPK models of macitentan, ACT-132577 and the interacting drug were linked as depicted in Figure 2. All three PBPK models were run simultaneously so that the interaction was simulated over time. The PBPK models of carbamazepine, clarithromycin, cyclosporine, diltiazem, erythromycin, itraconazole, ketoconazole, phenytoin, rifampicin, saquinavir, ritonavir, verapamil and warfarin were used as given in the compound files included in version 12 of the Simcyp software. For details, see the supplementary ...
Citations
... The use of PBPK modeling to predict DDI liability, informing wording on drug labels, and replacing the need for some clinical DDI studies, is now commonplace within drug development. [6][7][8][9][10] Furthermore, PBPK has been increasingly used to guide clinical practice and drug combinations in some disease areas, such as HIV, cystic fibrosis, tuberculosis (TB), and coronavirus disease 2019 (COVID- 19). [11][12][13][14][15][16][17][18] In addition, PBPK modeling enables the prediction of drug PKs in different populations and has the potential to guide dose adjustment. ...
As part of a collaboration between Medicines for Malaria Venture (MMV), Certara UK and Monash University, physiologically-based pharmacokinetic (PBPK) models were developed for 20 antimalarials, using data obtained from standardized in vitro assays and clinical studies within the literature. The models have been applied within antimalarial drug development at MMV for more than 5 years. During this time, a strategy for their impactful use has evolved. All models are described in the supplementary material and are available to researchers. Case studies are also presented, demonstrating real-world development and clinical applications, including the assessment of the drug-drug interaction liability between combination partners or with co-administered drugs. This work emphasizes the benefit of PBPK modeling for antimalarial drug development and decision making, and presents a strategy to integrate it into the research and development process. It also provides a repository of shared information to benefit the global health research community.
... As macitentan is not a substrate of OATPs, the magnitude of interaction is lower than that seen with bosentan. No dose adjustment is recommended, but caution is required [77]. ...
Lopinavir-ritonavir combination is being used for the treatment of SARS-CoV-2 infection. A low dose of ritonavir is added to other protease inhibitors to take advantage of potent inhibition of cytochrome (CYP) P450 3A4, thereby significantly increasing the plasma concentration of coadministered lopinavir. Ritonavir also inhibits CYP2D6 and induces CYP2B6, CYP2C19, CYP2C9, and CYP1A2. This potent, time-dependent interference of major hepatic drug-metabolizing enzymes by ritonavir leads to several clinically important drug-drug interactions. A number of patients presenting with acute coronary syndrome and acute heart failure may have SARS-CoV-2 infection simultaneously. Lopinavir-ritonavir is added to their prescription of multiple cardiac medications leading to potential drug-drug interactions. Many cardiology, pulmonology, and intensivist physicians have never been exposed to clinical scenarios requiring co-prescription of cardiac and antiviral therapies. Therefore, it is essential to enumerate these drug-drug interactions, to avoid any serious drug toxicity, to consider alternate and safer drugs, and to ensure better patient care.
... Based on the previous population PK analysis [7] and the graphical exploration of the available data, a one-compartment disposition model for macitentan and aprocitentan with first-order elimination for the parent compound and first-order formation and elimination for the metabolite was selected as the base structural model. The fraction of macitentan transformed to aprocitentan could not be estimated directly owing to the absence of data after intravenous administration of aprocitentan, and therefore it was assumed to be 62%, based on in vitro findings and a physiologically based PK analysis [17]. Absorption and disposition models of different complexity were explored to best describe multiple peaks observed at higher macitentan doses. ...
... Following a daily administration of 10 mg, macitentan was characterized by an accumulation factor of 2.13, which is consistent with the value reported in the literature [9]. As no data on the administration of aprocitentan alone were used to develop the model, its formation from the parent drug could not be estimated and it was fixed to 62% of the total clearance of macitentan, based on prior information [17]. ...
Background
Macitentan and its active metabolite, aprocitentan, are non-peptide, potent, dual endothelin receptor antagonists. Macitentan is approved for the treatment of pulmonary arterial hypertension in adults, at a dose of 10 mg/day.Objective
The objective of this study was to develop a comprehensive population model to describe the pharmacokinetics of macitentan and aprocitentan in healthy adults and adult subjects with pulmonary arterial hypertension.Methods
Pharmacokinetic data of 452 subjects in nine studies, after single and repeated doses (dose range 0.2–600 mg), were pooled for a non-linear mixed-effects analysis and the assessment of covariates, i.e., body weight, age, sex, race, renal and hepatic impairment, health status (healthy volunteers vs patients with pulmonary arterial hypertension), and formulation (capsules vs tablets) on pharmacokinetic parameters.ResultsThe final model was an open one-compartment disposition model, with linear elimination for macitentan and linear formation and elimination for aprocitentan. A semi-mechanistic absorption model described the dose dependency and multiple peaks observed for macitentan. For a female patient with pulmonary arterial hypertension after oral administration at 10 mg, macitentan reached a maximum concentration after 9 h and, following daily dosing, reached steady state after 3 days with a twofold accumulation factor. The apparent volume of distribution was 34 L and clearance was 1.39 L/h. Aprocitentan reached maximum concentration after 51 h and steady state after 9 days, with a 12.5-fold accumulation factor. Body weight, sex, race, renal impairment, health status, and formulation were statistically significant covariates on pharmacokinetic parameters.Conclusions
The comprehensive population pharmacokinetic model adequately described the pharmacokinetics of macitentan and aprocitentan across different dose concentrations, regimens, and formulations. Several covariates significantly influenced the pharmacokinetics of macitentan and aprocitentan, but none was considered clinically relevant.
... Similar results have been observed for other CYP3A substrates. 29,30 Effects of erythromycin on substrate drugs appear to be highly dependent on erythromycin dose and frequency. A 2.47-and 6.53-fold increase in AUC of substrate drugs was observed following erythromycin 400 mg and 500 mg three times daily, respectively. ...
A physiologically based pharmacokinetic (PBPK) model was developed to evaluate and predict (1) the effect of concomitant cytochrome P450 3A (CYP3A) inhibitors or inducers on the exposures of zanubrutinib, (2) the effect of zanubrutinib on the exposures of CYP3A4, CYP2C8, and CYP2B6 substrates, and (3) the impact of gastric pH changes on the pharmacokinetics of zanubrutinib. The model was developed based on physicochemical and in vitro parameters, as well as clinical data, including pharmacokinetic data in patients with B‐cell malignancies and in healthy volunteers from two clinical drug‐drug interaction (DDI) studies of zanubrutinib as a victim of CYP modulators (itraconazole, rifampicin) or a perpetrator (midazolam). This PBPK model was successfully validated to describe the observed plasma concentrations and clinical DDIs of zanubrutinib. Model predictions were generally within 1.5‐fold of the observed clinical data. The PBPK model was used to predict untested clinical scenarios; these simulations indicated that strong, moderate, and mild CYP3A inhibitors may increase zanubrutinib exposures by approximately four‐fold, two‐ to three‐fold, and <1.5‐fold, respectively. Strong and moderate CYP3A inducers may decrease zanubrutinib exposures by two‐ to three‐fold or greater. The PBPK simulations showed that clinically relevant concentrations of zanubrutinib, as a DDI perpetrator, would have no or limited impact on the enzyme activity of CYP2B6 and CYP2C8. Simulations indicated that zanubrutinib exposures are not impacted by acid‐reducing agents. Development of a PBPK model for zanubrutinib as a DDI victim and perpetrator in parallel can increase confidence in PBPK models supporting zanubrutinib label dose recommendations.
... Although isoniazid and rifapentine are mainly metabolized in the liver, the uremic toxin might decrease cytochrome P450 enzymes and the efficiency of drug transport (18,19), reducing the metabolism of the LTBI regimen. In addition, rifapentine may have drug-drug interactions and might reduce the effects of some medications for the comorbidities among dialysis patients, such as hypertension (20). Such interactions may explain why two of the 3HP users in this study had hypertensive crisis leading to hospitalization due to reduced serum concentrations of amlodipine and bisoprolol. ...
Objectives
Although patients with end-stage renal disease receiving maintenance hemodialysis are at high risk for tuberculosis, the optimal treatment regimen for latent tuberculosis infection (LTBI) in this group has scarcely been studied for predictors of completion rate and adverse drug events (ADE).
Methods
We prospectively enrolled dialysis patients for LTBI intervention from three medical centers in Taiwan. LTBI treatments were three-month weekly rifapentine plus isoniazid (3HP) and nine-month daily isoniazid (9H). Completion rate, ADE, and reasons for treatment termination were recorded. Factors associated with treatment termination and ADE were analyzed using multivariate logistic regression.
Results
In all, 91 treatment courses (41 9H and 50 3HP) were surveyed. The completion rates were 61% for 9H and 82% for 3HP (p=0.046). Use of 9H and development of ≥grade 2 ADEs were associated with treatment termination. Hypersensitivity occurred in 29.2% of subjects in the 3HP group and 10.8% in the 9H group (p=0.035) and independently correlated with 3HP regimen, diabetes mellitus (DM) and peritoneal dialysis (PD). Similarly, the independent predictors of ≥grade 2 ADEs were use of 3HP regimen, presence of DM, and use of PD, whereas ≥grade 3 ADEs were associated with eosinophil >700/mm ³ after 2 weeks of LTBI treatment even after adjustment for age and gender.
Conclusions
For patients on dialysis, 3HP showed a higher rate of completion but also a higher rate of ≥grade 2 ADE than 9H. In addition, DM and PD were risk for ≥grade 2 ADE. Eosinophilia after 2-week treatment might be an alert for severe ADE.
... Macitentan has been shown to partition into liver by passive diffusion and is not a substrate of hepatic OATP transporters. 17,21 Unbound plasma concentrations are therefore a good approximation of free concentrations in the liver. ...
The dual endothelin receptor antagonist macitentan was approved in 2013 for the treatment of pulmonary arterial hypertension. Macitentan is an inducer of cytochrome P450 expression in vivo in animal species but not in man. In rat and dog, changes in P450 expression manifest as autoinduction upon repeat dosing. The induction pattern, however, significantly differed between both species, and between male and female rats. While macitentan exposure steadily declined with dose in the dog, P450 induction was saturable in the rat reaching levels of 40%‐60% and 60%‐80% at steady‐state in male and female animals, respectively. The nature and number of P450 enzymes involved in macitentan clearance were identified as a major reason for the observed species differences. In the dog, macitentan was metabolized by a single P450 enzyme, that is, Cyp3a12, whereas several members of the Cyp2c and Cyp3a families were involved in the rat. Macitentan selectively upregulated Cyp3a expression in rat, whereas the expression of the Cyp2c enzymes involved in macitentan metabolism remained mostly unchanged, eventually leading to a higher contribution of Cyp3a upon induction. Macitentan also induced CYP3A4 expression in human hepatocytes via initial activation of the human pregnane X receptor. No such induction was evident in humans at the therapeutic macitentan dose of 10 mg as shown in a clinical drug‐drug interaction study with the CYP3A4 substrate sildenafil.
... As for metabolism inhibition, PDE5i are CYP3A4 inhibitors as well, while riociguat, selexipag, endothelin receptor antagonist macitentan are CYP3A4 substrates and could similarly be competitive CYP3A4 inhibitors towards DOACs [62,63]. Endothelin receptor antagonist bosentan is a well-known CYP3A4 inducer [64]. ...
Pulmonary hypertension (PH)comprises a cluster of severe conditions characterized by elevated mean pulmonary arterial pressure. While targeted therapies have been approved over the last twenty years for pulmonary arterial hypertension (PAH)and chronic-thrombo-embolic PH (CTEPH), the possible role of anticoagulant therapy as a supportive treatment PAH is still debated. In PAH, anticoagulant use remains frequent, although evidence appear to be poor (recommendation class IIb-C in international guidelines). In CTEPH treatment, anticoagulants are highly recommended, because it often involves thrombosis (recommendation class I—C in international guidelines). Historically, PH patients have been treated with vitamin K antagonists (VKA), which are the only available oral anticoagulants. In this context, risk/benefit ratio of VKA is affected by the risk of major bleeding events. This drawback could be mitigated with direct oral anticoagulants (DOACs): in addition to being less constraining for patients, DOACs have shown a lower risk of major bleeding events in their already approved indications (venous thromboembolism, atrial fibrillation). However, DOACs have never been specifically assessed in PAH and CTEPH patients. Bioaccumulation risk should be considered if DOACs are prescribed in PAH and CTEPH patients, especially the risk of drug-drug interaction mediated by P-glycoprotein and cytochrome 3A4 with targeted therapies.
... The maximum concentration (C max ) in the blood is reached on average 8 h after macitentan is taken orally (Yu et al., 2015). Its bioavailability is~74% (de Kanter et al., 2016). ...
Macitentan is an endothelin receptor antagonist commonly used in the treatment of pulmonary arterial hypertension (PAH). A novel, rapid, simple and sensitive UPLC–MS/MS method was developed and validated for pharmacokinetic study and the determination of macitentan in PAH patients. Macitentan and bosentan which is used as internal standard were detected using APCI in positive ion and MRM mode by monitoring the mass transitions m/z 589.1→203.3 and 552.6→311.5, respectively. Chromatographic separation was performed on reverse phase C18 column (5 μm, 4.6 *150 mm) with a isocratic mobile phase, which consisted of water containing 0.2% acetic acid:acetonitrile (90:10, v/v) at a flow rate of 1 mL/min. Retention times were 1.97 and 1.72 min. for macitentan and IS, respectively. The calibration curve with high correlation coefficient (0.9996) was linear range 1‐500 ng/mL. The LLOQ and average recovery values were determined as 1 ng/mL and 89.8%, respectively. This method is the first UPLC‐MS/MS method developed and validated for the determination of macitentan from human plasma. The developed analytical method was fully validated for linearity, selectivity, specificity, accuracy, precision, sensitivity, stability, matrix effect and recovery according to FDA guidelines. The developed method applied successfully for pharmacokinetic study and the determination of macitentan in PAH patients.
... 41 The estimated oral bioavailability of macitentan is 74%. 42 The pharmacokinetics of macitentan and ACT132577 are not altered to a clinically significant extent by food. They are highly bound to plasma proteins (>99%), mainly to albumin and to a lesser extent to α 1 -acid glycoprotein. ...
Pulmonary arterial hypertension, a disease largely neglected until a few decades ago, is presently the object of intense studies by several research teams. Despite considerable progress, pulmonary arterial hypertension remains a major clinical problem, because it is not always easy to diagnose, treat, and prevent. The disease was considered incurable until the late 1990s, when Epoprostenol was introduced as the first tool against this illness. More recently, therapy for pulmonary arterial hypertension gained momentum after publication of the SERAPHIN and AMBITION trials, which also highlighted the importance of upfront therapy. This review also focuses on recent substudies from these trials and progress in drugs targeting the endothelin pathway. Future perspectives with regard to endothelin-receptor antagonists are also discussed.
... Default values for particle density of 1.2 g/ml, a supersaturation ratio of 10, a precipitation rate constant of 15 minutes, and a diffusion layer thickness of 30 mm were assumed. A full PBPK, perfusion-limited distribution model was applied using method 2 within Simcyp, with an assumed tissue-to-plasma partition coefficient (K p ) scalar of 0.5 (Rodgers and Rowland, 2007;de Kanter et al., 2016). Elimination was assumed to be driven by CYP3A4-mediated metabolism, on the basis of evidence for almorexant (Dingemanse et al., 2014), suvorexant (Cui et al., 2016), and ACT-541468 (A.T., unpublished observation) using the well-stirred liver and ADAM gut model with fraction unbound in the gut (f u,gut ) assumed to be 0.01. ...
The identification of new sleep drugs poses particular challenges in drug discovery due to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging in case inter-species differences are prominent. This report describes the discovery of the dual OX1 and OX2 receptor antagonist ACT-541468 out of a class of structurally related compounds by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied already early in drug discovery. While all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large inter-species differences in key factors determining their pharmacokinetic profile. Human PK models were built based on in vitro metabolism and physico-chemical data, and were then used to predict the time course of OX2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated based on OX2 receptor occupancy thresholds of about 65% derived from clinical data of two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery therefore has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met.
