Maraviroc modelling strategy: use of early phase 1 data to support a semi-mechanistic population pharmacokinetic model

center dot 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 center dot 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.