Peter L Bonate

Astellas Pharmaceutical · Department of Global Clinical Pharmacology Exploratory Development (GCPED)

‘Are two populations the same or are they different’ is a question that is often faced in clinical pharmacology trials e.g., a pharmacokinetic trial studying a particular drug in racially different groups. To address this question, concentration–time data were simulated from a reference and test population, where in the latter the clearance, sample...

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

A correction to this paper has been published: https://doi.org/10.1007/s10928-021-09756-x

Cytomegalovirus (CMV) infection causes significant morbidity and mortality in immunocompromised transplant patients. ASP0113, a first‐in‐class DNA vaccine containing plasmids encoding CMV phosphoprotein 65 and glycoprotein B (gB), was evaluated in a phase 1b, subject‐blinded study in CMV‐seropositive (n = 13) and CMV‐seronegative (n = 12) healthy a...

Background Best practice to establish dosage regimens for “first-in-pediatric” clinical trials requires knowledge of efficacious and safe exposures in adults. Methods Pediatric equivalent doses were predicted for patients aged 6 months and <18 years using physiologically based pharmacokinetic (PBPK) modeling, and compared with predictions by allom...

L-praziquantel (PZQ) pharmacokinetic data were analyzed from two relative bioavailability Phase 1 studies in adult, healthy subjects with two new oral dispersion tablet (ODT) formulations of L-PZQ administered under various combinations of co-administration with food, water, and/or crushing. Linear mixed effects models adequately characterized the...

Background: Neonatal candidiasis causes significant morbidity and mortality in high risk infants. The micafungin dosage regimen of 10 mg/kg established for the treatment of neonatal candidiasis is based on a laboratory animal model of neonatal hematogenous Candida meningoencephalitis and pharmacokinetic (PK)-pharmacodynamic (PD) bridging studies....

Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and other...

The current method to analyze concentration-QT interval data, which is based on predictions conditional on a best model, fails to take into account the uncertainty of the model. Previous studies have suggested that failure to take into account model uncertainty using a best model approach can result in confidence intervals that are overly optimisti...

Quantitative systems pharmacology (QSP) is the design and application of mathematical models to explain how drugs function at a systems level. Whereas traditional pharmacokinetic-pharmacodynamic modeling takes an empirical or mechanistic approach to modeling, QSP takes a holistic approach exploring whole biochemical and metabolic pathways and how d...

To find the right dose and regimen is crucial for the therapeutic effectiveness of oncolytics. Prior to the 1960s, early oncologists dosed their patients at the maximum tolerated dose (MTD) using either fixed doses (sometimes called flat doses) or doses standardized to total body weight (TBW). In the 1960s, this changed as oncology dosing switched...

The effect of correlation among covariates on covariate selection was examined with linear and nonlinear mixed effect models. Demographic covariates were extracted from the National Health and Nutrition Examination Survey III database. Concentration-time profiles were Monte Carlo simulated where only one covariate affected apparent oral clearance (...

Isavuconazole, the active moiety of water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model to identify covariates that affect isavuconazole pharmacokinetics and determine the probability of t...

Isavuconazonium sulfate, a water-soluble prodrug of the triazole antifungal agent, isavuconazole, is available for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (Astellas Pharma Inc, Cresemba® [isavuconazonium sulfate] 2015, http://www.astellas.us/docs/cresemba.pdf). A population pharmacokinetic (PPK) model was constructed...

Objectives: Isavuconazole, a novel triazole antifungal agent, has broad-spectrum activity against Aspergillus spp. and other pathogenic fungi. The isavuconazole exposure-response relationship in experimental invasive pulmonary aspergillosis using galactomannan index (GMI) suppression as a marker of disease clearance was explored. Methods: The im...

The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working g...

The effect of extrapolated area (%AUCextrap) on estimating mean AUCinf in a simulated single-dose clinical trial was examined. Concentration–time (C–t) profiles from 12 to 36 subjects for 1- and 2-compartment models after single dose administration were simulated with increasing right-tailed censoring. Each subject’s %AUCextrap and AUCinf was calcu...

Purpose: The purpose of this study is to characterize tumor growth kinetics in patients with renal cell carcinoma (RCC) after treatment with pazopanib or placebo and to identify predictive patient-specific covariates. Methods: Different tumor growth models that included patient-specific covariates were fit to tumor growth data from Phase 2 (n =...

Linear mixed-effects models (LMEMs) of concentration-double-delta QTc intervals (QTc intervals corrected for placebo and baseline effects) assume that the concentration measurement error is negligible, which is an incorrect assumption. Previous studies have shown in linear models that independent variable error can attenuate the slope estimate with...

Tumor growth profiles were simulated for 2 years using the Wang and Claret models under a phase 3 clinical trial design. Profiles were censored when tumor size increased >20% from nadir similar to clinical practice. The percent of patients censored varied from 0% (perfect case) to 100% (real-life case). The model used to generate the data was then...

The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively) are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastr...

Trial Protocol. (PDF)

CONSORT Checklist. (DOC)

Trial Laboratory Manual. (PDF)

These are the study sites and the approving ethical review boards for participating sites. (DOCX)

This file contains: Table S1. Drug-related modulation of median plasma HGF, sVEGFR2, sMET and VEGF-A concentrations observed over the first dosing interval in the intermittent 5/9 dosing group. Figure S1. Foretinib inhibits gastric tumor xenograft growth and MET activation in mice xenografts. (A) Mice bearing MKN-45 gastric tumors (n = 10 per group...

Monte Carlo simulation was used to assess the performance of linear mixed effect models (LMEMs) to characterize the concentration–effect relationship when both parent and metabolite concentrations were available. Parent and metabolite concentrations were simulated under an experimental design that mimicked a thorough QT study. Simulations were done...

Quality population modeling and simulation analyses and reports are something every modeler desires. However, little attention in the literature has been paid to what constitutes quality regarding population analyses. Very rarely do published manuscripts contain any statement about quality assurance of the modeling results contained therein. The pu...

This phase I, open-label, randomized, 2-part crossover study assessed the safety, pharmacokinetics and relative bioavailability of single doses of the anticancer MET inhibitor foretinib (formerly known as GSK1363089, EXEL-2880 and XL-880) free base tablet formulation compared to a bisphosphate salt capsule formulation (Part 1), and assessed the saf...

The components of a clinical trial simulation consist of the input–output model, the covariate distribution model, and the trial execution model. The input–output model consists of submodels that incorporate the drug’s pharmacokinetics and pharmacodynamics, the disease progression during the trial, the trial endpoints, and the residual variability....

Pharmacokinetics is the study of the absorption, distribution, metabolism, and excretion of drugs. Simply put, pharmacokinetics is what the body does to the drug, which is opposed to pharmacodynamics, which is what the drug does to the body. This review will introduce pharmacokinetics as a science showing how biochemistry, biology, pharmacology, an...

This chapter provides practical advice in the development of nonlinear mixed effects models. Topics that are discussed include how to choose an estimation method, how to incorporate various covariates in the model (concomitant medications, weight, age, smoking, pregnancy, pharmacogenomics, food, formulation, race, renal function, and laboratory val...

Modeling is a useful way to summarize and characterize data, but modeling truly becomes powerful when it is used to answer questions that could not be answered without otherwise having to perform an experiment or to answer questions for which there is no means to answer the question experimentally. This is the realm of simulation, which can be thou...

This chapter introduces a series of case studies that use linear and nonlinear regression techniques. Allometric scaling and dose proportionality are examined using simple linear regression techniques. Limited sampling and development of a dosing formula for carboplatin are developed using multiple linear regression. The pharmacokinetics of cocaine...

There is more to modeling than the act of modeling. To be an effective modeler requires understanding the different types of models and when one type of model is more appropriate than another, how to select a model from a family of similar models, how to evaluate a model’s goodness of fit, how to present modeling results both verbally and graphical...

This chapter introduces the theory behind nonlinear mixed effects models through the concept of a structural model or covariate model coupled to both fixed and random effects in a nonlinear manner. Modeling and estimation of model parameters in the face of different sources of variability (between-subject, inter-occasion, inter-study, and residual...

This chapter introduces how to analyze nonstandard data types, like binary, categorical, ordinal, and time to event data through generalized linear models (GLMs) and their extension. Logistic regression of binary or ordinal data, Poisson regression of count data, beta regression of proportions, and parametric modeling of survival data are discussed...

A model is said to be linear if the partial derivatives with respect to any of the model parameters are independent of the other parameters. This chapter introduces linear models and regression, both simple linear and multiple regression, within the framework of ordinary least squares and maximum likelihood. Influence diagnostics, conditional model...

A model is nonlinear if any of the partial derivatives with respect to any of the model parameters are dependent on any other model parameter or if any of the derivatives do not exist or are discontinuous. This chapter expands on the previous chapter and introduces nonlinear regression within a least squares (NLS) and maximum likelihood framework....

The previous chapters assumed that every observation carried equal weight in the estimation of the model parameters and that the assumptions of the model, e.g., normality of the residuals, were met. When the observations have nonconstant variance this is referred to as heteroscedasticity. This chapter introduces weighted least-squares (WLS) and var...

Sometimes a scientist has prior information regarding the parameters in a model. Previous studies may have already reported a drug’s clearance or an expert may have an estimate for some pharmacodynamic parameter. Bayesian models take into account this prior information to provide new estimates that balance the prior information and the likelihood o...

Two case studies in nonlinear mixed effects modeling are presented. The first case is development of a pharmacodynamic model with the acetylcholinesterase inhibitor zifrosilone. The second case study is the development and validation of a pharmacokinetic model for tobramycin in patients with varying degrees of renal function. All aspects of modelin...

Three phase 1 studies of eliglustat tartrate (Genz-112638), an oral inhibitor of glucosylceramide synthase under development for treating Gaucher disease type 1 (GD1), evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after escalating single doses (n = 99), escalating multiple doses (n = 36), and food (n = 24). Eliglust...

Clofarabine for injection is a second-generation nucleoside analog approved in the United States (Clolar(®)) and Europe (Evoltra(®)) for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. This report describes the population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric pati...

The literature was reviewed for pharmacokinetic studies of cocaine in any species from 1966 to 1994.Fourteen studies were identified as either presenting pharmacokinetic parameters or having sufficient data to calculate the pharmacokinetic parameters using model-independent techniques. Clearance and volume of distribution were successfully scaled u...

In cancer drug development, measurement of tumor growth is necessary for preclinical assessment of anticancer activity and clinical assessment of efficacy. This chapter reviews mathematical models of preclinical and clinical tumor growth. Issues and models with regards to mouse xenograft data will be highlighted.

* Provides practical guidance on the application of pharmacokinetics as a drug development science * Includes characterization of drug disposition in pregnant subjects, for measuring arrhythmic potential, for analysis tumor growth modeling, and for disease progression modeling * Introduces important technologies. © American Association of Pharmaceu...

Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1). A multinational, open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of...

Tasidotin (ILX651) is a dolastatin analog active against several solid tumors. It is converted in vivo into two metabolites: M1, which lacks the carboxyl-terminal tert-butylamide group and is more active pharmacologically, and M2, which lacks this group and an adjacent proline residue. Both tasidotin and metabolite M1 were found to be competitive i...

The renal excretion of clofarabine was studied in vitro in the isolated perfused rat kidney (IPK) model and in vivo in rats. Clofarabine excretion was studied at four doses (160, 800, 2000 and 4000microg) in the IPK, targeting perfusate levels of 2, 10, 25, 50microg/mL, respectively. Clofarabine (2microg/mL) was also co-perfused with known inhibito...

Patients that are exposed to biotechnology-derived therapeutics often develop antibodies to the therapeutic, the magnitude of which is assessed by measuring antibody titers. A statistical approach for analyzing antibody titer data conditional on seroconversion is presented. The proposed method is to first transform the antibody titer data based on...

To evaluate the plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of tasidotin and metabolites in a nonhuman primate model. Tasidotin 0.75 mg/kg was administered intravenously. The plasma and CSF concentrations of tasidotin and its metabolites were determined. Pharmacokinetic parameters were estimated using model-independent...

Tasidotin, an oncolytic drug in phase II clinical trials, is a peptide analog of the antimitotic depsipeptide dolastatin 15. In tasidotin, the carboxyl-terminal ester group of dolastatin 15 has been replaced by a carboxy-terminal tert-butyl amide. As expected from studies with cemadotin, [(3)H]tasidotin, with the radiolabel in the second proline re...

The pharmacokinetics of tasidotin (ILX651), a depsipeptide currently in phase II for the treatment of advanced solid tumors, and tasidotin-C-carboxylate, the main metabolite, were characterized in male nude mice implanted with LOX tumors, which are sensitive to tasidotin, or H460 tumors, which are resistant to tasidotin. The pharmacokinetics of tas...

To characterize alemtuzumab pharmacokinetics and its exposure-response relationship with white blood cell (WBC) count in patients with B-cell chronic lymphocytic leukaemia (CLL). Nonlinear mixed effects models were used to characterize plasma concentration-time data and WBC count-time data from 67 patients. Logistic regression was used to relate su...

The American Association of Pharmaceutical Scientists (AAPS) covers the full range of areas of expertise associated with the resolution of concerns pertaining to drugs and drug products. This editorial highlights the initiatives, issues, and challenges that are the forefront of the pharmaceutical sciences in 2007. It also provides an overview of ho...

The American Association of Pharmaceutical Scientists (AAPS) covers the full range of areas of expertise associated with the resolution of concerns pertaining to drugs and drug products. This editorial highlights the initiatives, issues, and challenges that are the forefront of the pharmaceutical sciences in 2007. It also provides an overview of ho...

IntroductionThe DolastatinsDiscovery and Preclinical Pharmacokinetics of TasidotinPreclinical Pharmacology of Tasidotin and ILX651-C-CarboxylateToxicology of TasidotinClinical Pharmacology and Studies of Tasidotin in Patients with Solid TumorsClinical Pharmacology of ILX651-C-CarboxylateExposure–Response RelationshipsDiscussionSummaryReferences

The treatment of acute leukaemias, which are the most common paediatric cancers, has improved considerably in recent decades, with complete response rates approaching approximately 90% in some cases. However, there remains a major need for treatments for patients who do not achieve or maintain complete remission, for whom the prognosis is very poor...

To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks. Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels rang...

Based on its mechanistic similarity to fludarabine and cladribine and the success of these analogues for treatment of chronic lymphocytic leukemia (CLL), we hypothesized that clofarabine would be effective for indolent leukemias. The present study was conducted to determine the efficacy and cellular pharmacology during clinical trials of single-age...

Clinical Trial Simulation (CTS) sounds daunting. To think that you can simulate a process as complicated as a clinical trial simply sounds crazy. I personally believe that CTS has suffered because of the use of this phrase. But, simulation is nothing more than applied modeling. The principles involved are the same principles that have guided Monte...

Aims to present through theory and example how to develop pharmacokinetic models, both at an individual and population level. In order to do so, one must first understand linear models and then build to nonlinear models followed by linear mixed effects models and then ultimately nonlinear mixed effects models. This book develops in that manner. © 2...

This chapter presented many case studies in the application of linear and nonlinear modeling to real-life data sets. Some of the examples were relatively simple, whereas some were quite complex As might be apparent, there is no right approach to any problem and that the more complex the problem, the more approaches there are to solving a problem, n...

To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of the dolastatin-15 analogue, tasidotin (ILX651), when administered i.v. daily for 5 days every 3 weeks. Thirty-six patients with advanced solid tumors received a total of 114 courses through eight dose levels ranging from 2.3 to 36.3 mg/m(2). Pharmacokinetic sam...

To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of tasidotin (ILX651), a dolastatin-15 analogue, when administered on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors. Thirty-two patients were treated with 92 courses of tasidotin through seven dose levels determined by a modifie...

Alemtuzumab (Campath®, MabCampath®) is a humanized IgG monoclonal antibody targeting the CD52 antigen and is approved for treatment of B-cell chronic lymphocytic leukemia (B-CLL) following treatment with alkylating agents and failing fludarabine treatment. Nonlinear mixed effects modeling was used to characterize the population pharmacokinetics in...

Clofarabine (2-chloro-2'fluoro-2'-deoxy-9-beta-d-arabinofuranosyladenine) is a purine nucleoside analogue that is active in the treatment of acute leukemia. We studied the pharmacokinetics and cerebrospinal fluid penetration of clofarabine in a nonhuman primate model. A dose of 2.3 mg/kg of clofarabine was given i.v. over 2 hours to each of four an...

The distribution, metabolism, and elimination of intravenous [14C]clofarabine was studied in Fischer 344 male rats under a once daily for 5 days dosing schedule of 25 or 50 mg/kg/day. Also, the in vitro metabolism in rat, dog, and human hepatocytes was studied. Plasma radioactivity (of which clofarabine accounted for 63% to 93%) exhibited three pha...

To introduce partially linear mixed effects models (PLMEMs), to illustrate their use, and to compare the power and Type I error rate in detecting a covariate effect with nonlinear mixed effects modeling using NONMEM. Sparse concentration-time data from males and females (1:1) were simulated under a 1-compartment oral model where clearance was sex-d...

Clofarabine (2-chloro-2'-fluoro-deoxy-9-beta-D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine...

Developing the skills or expertise to create useful population pharmacokinetic-pharmacodynamic models can be a daunting task-the level of mathematical and statistical complexity is such that newcomers to the field are frequently overwhelmed. A good place to start in learning the field is to read articles in the literature. However, the number of ar...

The population pharmacokinetics of plasma clofarabine and intracellular clofarabine triphosphate were characterized in pediatric patients with acute leukemias. Traditional model-building techniques with NONMEM were used. Covariates were entered into the base model using a forward selection significance level of .05 and a backwards deletion criterio...