Physiologically Based Pharmacokinetic Modeling for Maribavir to Inform Dosing in Drug-Drug Interaction Scenarios with CYP3A4 Inducers and Inhibitors.

Maribavir, an orally available antiviral agent, has been approved in multiple countries for the treatment of patients with refractory post-transplant cytomegalovirus (CMV) infection and/or disease. Maribavir is primarily metabolized by CYP3A4; coadministration with CYP3A4 inducers and inhibitors may significantly alter maribavir exposure, thereby affecting its efficacy and safety. The effect of CYP3A4 inducers and inhibitors on maribavir exposure was evaluated based on a drug-drug interaction (DDI) study and physiologically-based pharmacokinetic (PBPK) modeling.

Development and application of a PBPK modeling strategy to support antimalarial drug development.

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.

Using physiologically-based pharmacokinetic modeling for predicting the effects of hepatic impairment on the pharmacokinetics of olanzapine and samidorphan given as a combination tablet.

A combination of olanzapine and samidorphan (OLZ/SAM) was recently approved by the US Food and Drug Administration for treatment of patients with schizophrenia or bipolar I disorder. The effects of moderate hepatic impairment on the pharmacokinetics (PKs) of olanzapine and samidorphan after a single dose of OLZ/SAM were characterized in a clinical study. Physiologically-based pharmacokinetic (PBPK) modeling was used to extend the clinical findings to predict the effects of varying degrees of hepatic impairment on the PKs of olanzapine and samidorphan.

Differences in cytochrome p450-mediated pharmacokinetics between chinese and caucasian populations predicted by mechanistic physiologically based pharmacokinetic modelling.

Background: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines emphasize the need for better understanding of the influence of ethnicity on drug response to minimize duplication of clinical studies, thereby expediting drug approval.

Objectives: We have developed a Chinese database for the prediction of differences in the population kinetics of drugs mainly metabolized by cytochromes P450 (CYPs) relative to Caucasian populations. Such predictions should help to inform the need for duplication of in vivo pharmacokinetic studies in the two ethnic groups and the design of such studies.

Age related changes in fractional elimination pathways for drugs: assessing the impact of variable ontogeny on metabolic drug-drug interactions.

The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which statistical differences existed between each pair of specific pathways.

Application of permeability-limited physiologically-based pharmacokinetic models: part I-digoxin pharmacokinetics incorporating P-glycoprotein-mediated efflux.

A prerequisite for the prediction of the magnitude of P-glycoprotein (P-gp)-mediated drug-drug interactions between digoxin and P-gp inhibitors (e.g. verapamil and its metabolite norverapamil) or P-gp inducers (e.

Application of permeability-limited physiologically-based pharmacokinetic models: part II - prediction of P-glycoprotein mediated drug-drug interactions with digoxin.

Digoxin is the recommended substrate for assessment of P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) in vivo. The overall aim of our study was to investigate the inhibitory potential of both verapamil and norverapamil on the P-gp-mediated efflux of digoxin in both gut and liver. Therefore, a physiologically-based pharmacokinetic (PBPK) model for verapamil and its primary metabolite was developed and validated through the recovery of observed clinical plasma concentration data for both moieties and the reported interaction with midazolam, albeit a cytochrome P450 3A4-mediated DDI.

Using human recombinant UDP-glucuronosyltransferase isoforms and a relative activity factor approach to model total body clearance of laropiprant (MK-0524) in humans.

A major pathway of elimination of the prostaglandin D2 receptor 1 antagonist laropiprant in humans is by uridine diphosphate-glucuronosyltransferase (UGT)-mediated biotransformation. In this study, liver and kidney relative activity factors were developed for UGT1A1, 1A9 and 2B7 to allow for in vitro-in vivo extrapolation of intrinsic clearance data to whole organ clearance using recombinant human UGT isoforms applying this to laropiprant as a model substrate. The total body metabolic clearance of laropiprant determined using this approach (5.

Bottom-up modeling and simulation of tacrolimus clearance: prospective investigation of blood cell distribution, sex and CYP3A5 expression as covariates and assessment of study power.

The objectives were to investigate the ability of population-based in vitro-in vivo extrapolation (IVIVE) to reproduce the influence of haematocrit on the clearance of tacrolimus, observed previously, and to assess the power of clinical studies to detect the effects of covariates on the clearance of tacrolimus. A population-based pharmacokinetic simulator (Simcyp) was used to simulate tacrolimus clearance from in vitro metabolism data and demographic characteristics of Japanese liver transplant patients (JLTs). The relationship between haematocrit and dose-to-concentration (D/C) ratio was validated using seven JLTs, whose highly variable haematocrit and D/C ratio were previously analysed.

Sources of interindividual variability in IVIVE of clearance: an investigation into the prediction of benzodiazepine clearance using a mechanistic population-based pharmacokinetic model.

Prediction of metabolic clearance in extreme individuals rather than the 'average human' is becoming an attractive tool within the pharmaceutical industry. The current study involved prediction of variability in metabolic clearance for alprazolam, triazolam and midazolam with emphasis on the following factors: first, evaluation of clearance prediction accuracy using intrinsic clearance (CL(int)) data from in vitro metabolic data and back-calculation from in vivo clearance data. Second, the sensitivity of predicted in vivo variability to changes in variability for physiological parameters (e.

Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver.

Reported predictions of human in vivo hepatic clearance from in vitro data have used a variety of values for the scaling factors human microsomal protein (MPPGL) and hepatocellularity (HPGL) per gram of liver, generally with no consideration of the extent of their inter-individual variability. We have collated and analysed data from a number of sources, to provide weighted meangeo values of human MPPGL and HPGL of 32 mg g-1 (95% Confidence Interval (CI); 29-34 mg.g-1) and 99x10(6) cells.