5 years ago

Population pharmacokinetics of the MEK inhibitor selumetinib and its active N-desmethyl metabolite: data from ten Phase I trials

Diansong Zhou, Eleanor Howgate, Leon Aarons, Paul Martin, Parul Patel, David J. Carlile
Aims To characterise the pharmacokinetics (PK) of selumetinib (AZD6244; ARRY-142886), a MEK1/2 inhibitor in clinical development for numerous indications, and its N-desmethyl metabolite in healthy volunteers, and evaluate clinically important covariates. Methods A pooledpopulation PK analysis was performed using a non-linear mixed effects approach with plasma concentration data from 346 subjects who received single oral doses of selumetinib 20–75 mg across ten Phase I studies. Absolute bioavailability was determined using intravenous [14C] selumetinib. Results A two compartment, linear model with sequential zero-first order absorption and a lag time for the zero order process was describedselumetinib PK. N-desmethyl metabolite disposition was described by a single compartment with linear elimination without back transformation. The parent-only and joint modelsgenerally adequately described pooled data. For the median subject, not taking interacting drugs, estimates for clearance (CL) and central volume of distribution (V2) for selumetinib in the final joint model were 12.7 L/h and 35.6 L, respectively. Food effects, co-medication with itraconazole (CYP3A4 inhibitor), fluconazole (CYP2C19 inhibitor) and rifampicin (CYP3A4 inducer), and formulation effects were incorporated into the base model a priori. Race and hepatic function were also influential in the PK model. Additional covariates affecting selumetinib disposition identified from covariate analysis were age on V2, bilirubin on CL, and weight on CL and V2. Conclusions Analysis confirmed previous clinical pharmacology studyfindings of drug-drug interactions and food effects, with additional covariates that influence selumetinib and N-desmethyl selumetinib PK identified.Dose modifications based on these additional covariates are not considered necessary.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bcp.13404

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