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Maraviroc modelling strategy: use of early phase 1 data to support a semi‐mechanistic population pharmacokinetic model
Author(s) -
Weatherley Barry,
McFadyen Lynn
Publication year - 2009
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2009.03455.x
Subject(s) - maraviroc , pharmacokinetics , physiologically based pharmacokinetic modelling , population , dosing , pharmacology , medicine , chemistry , immunology , environmental health , human immunodeficiency virus (hiv)
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The non‐compartmental pharmacokinetics of maraviroc have been published for a number of phase 1 studies (including mass balance) but there has been no previous attempt to integrate the results into a model that is of utility beyond phase 1. WHAT THIS STUDY ADDS • This study provides a novel approach for pooling phase 1 non‐compartmental data (normalized AUC) and assessing the influence of key covariates for drugs with non‐linear/complex absorption patterns. We show a detailed example of how data may be integrated from a number of studies/sources in early drug development to construct semi‐mechanistic pharmacokinetic models (partitioning absorption and extraction components) for later phase applications (population pharmacokinetics and pharmacokinetics/pharmacodynamics). AIMS To model the basic pharmacokinetic (PK) characteristics of maraviroc to construct an integrated semi‐mechanistic PK model for use in later population PK analyses. METHODS Three analyses were performed utilizing intravenous, oral and radiolabel data. Firstly, a PK disposition model was developed from data from 20 healthy males who received 3, 10 or 30 mg of intravenous maraviroc. Secondly, a sigmoid E max vs dose model of dose‐normalized non‐compartmental AUC from oral dosing in 134 healthy young males and females across five phase 1 studies was constructed. This described absorption dose non‐linearities and tested for the influence of food, formulation and dose frequency on model parameters. The third analysis developed a mass balance model for both absorption and disposition of maraviroc with 300 mg solution and predicted the mass balance after administration of 100 mg tablet formulation. RESULTS A four‐compartment PK model best described the intravenous data and no influence of dose was found on clearance. Total clearance was 48 l h −1 (2.2% SE). The main covariate effect in the non‐compartmental analysis reproduced the dose‐dependency of food through a five‐fold increase in the ED 50 of the sigmoid E max model. The mass balance models calculated that 33.3% and 22.9% of 300 mg solution and 100 mg tablet doses, respectively, are systemically available, and first‐pass metabolism extracts 62% of an absorbed dose, estimating a hepatic blood flow of 101 l h −1 . CONCLUSIONS The analysis demonstrates a novel integration approach to build a maraviroc semi‐mechanistic population PK model for further use in volunteers and patients.