BACKGROUND: Apalutamide is a next-generation androgen receptor inhibitor approved for treatment of subjects with high-risk, non-metastatic, castration-resistant prostate cancer (NM-CRPC). OBJECTIVE: The objective of this study was to characterize the population pharmacokinetics of apalutamide and its metabolite N-desmethyl-apalutamide in healthy male and castration-resistant prostate cancer subjects. METHODS: Plasma concentration data for apalutamide and N-desmethyl-apalutamide from 1092 subjects (seven clinical studies) receiving oral apalutamide (30-480 mg) once daily were pooled for a population pharmacokinetic analysis using a non-linear mixed-effect modelling approach. The impact of clinically relevant covariates was also assessed. RESULTS: Apalutamide absorption was rapid, and the apparent steady-state volume of distribution was large (276 L), reflecting a wide body distribution. Apalutamide was eliminated slowly, with its apparent clearance increasing from 1.31 L/h after the first dose to 2.04 L/h at steady state. No evidence of time-dependent disposition was observed for N-desmethyl-apalutamide, which was also widely distributed and slowly cleared (1.5 L/h). After 4 weeks of treatment, more than 95% of steady-state exposure of apalutamide and N-desmethyl-apalutamide was reached. At a dose of apalutamide 240 mg/day, apalutamide and N-desmethyl-apalutamide exposure exhibited 5.3- and 85.2-fold accumulation in plasma, respectively. Inter-individual variability in apalutamide apparent clearance is low (< 20%). Among the covariates evaluated, apalutamide and N-desmethyl-apalutamide exposure were statistically associated only with health status, body weight, and albumin concentration, and the effect was low (< 25%). CONCLUSIONS: A population pharmacokinetic modelling approach was successfully applied to describe the pharmacokinetics of apalutamide and N-desmethyl-apalutamide. No clinically relevant covariates were identified as predictors of apalutamide and N-desmethyl-apalutamide pharmacokinetics.
BACKGROUND:Apalutamide is a next-generation androgen receptor inhibitor approved for treatment of subjects with high-risk, non-metastatic, castration-resistant prostate cancer (NM-CRPC). OBJECTIVE: The objective of this study was to characterize the population pharmacokinetics of apalutamide and its metabolite N-desmethyl-apalutamide in healthy male and castration-resistant prostate cancer subjects. METHODS: Plasma concentration data for apalutamide and N-desmethyl-apalutamide from 1092 subjects (seven clinical studies) receiving oral apalutamide (30-480 mg) once daily were pooled for a population pharmacokinetic analysis using a non-linear mixed-effect modelling approach. The impact of clinically relevant covariates was also assessed. RESULTS:Apalutamide absorption was rapid, and the apparent steady-state volume of distribution was large (276 L), reflecting a wide body distribution. Apalutamide was eliminated slowly, with its apparent clearance increasing from 1.31 L/h after the first dose to 2.04 L/h at steady state. No evidence of time-dependent disposition was observed for N-desmethyl-apalutamide, which was also widely distributed and slowly cleared (1.5 L/h). After 4 weeks of treatment, more than 95% of steady-state exposure of apalutamide and N-desmethyl-apalutamide was reached. At a dose of apalutamide 240 mg/day, apalutamide and N-desmethyl-apalutamide exposure exhibited 5.3- and 85.2-fold accumulation in plasma, respectively. Inter-individual variability in apalutamide apparent clearance is low (< 20%). Among the covariates evaluated, apalutamide and N-desmethyl-apalutamide exposure were statistically associated only with health status, body weight, and albumin concentration, and the effect was low (< 25%). CONCLUSIONS: A population pharmacokinetic modelling approach was successfully applied to describe the pharmacokinetics of apalutamide and N-desmethyl-apalutamide. No clinically relevant covariates were identified as predictors of apalutamide and N-desmethyl-apalutamide pharmacokinetics.
Authors: Nicola J Clegg; John Wongvipat; James D Joseph; Chris Tran; Samedy Ouk; Anna Dilhas; Yu Chen; Kate Grillot; Eric D Bischoff; Ling Cai; Anna Aparicio; Steven Dorow; Vivek Arora; Gang Shao; Jing Qian; Hong Zhao; Guangbin Yang; Chunyan Cao; John Sensintaffar; Teresa Wasielewska; Mark R Herbert; Celine Bonnefous; Beatrice Darimont; Howard I Scher; Peter Smith-Jones; Mark Klang; Nicholas D Smith; Elisa De Stanchina; Nian Wu; Ouathek Ouerfelli; Peter J Rix; Richard A Heyman; Michael E Jung; Charles L Sawyers; Jeffrey H Hager Journal: Cancer Res Date: 2012-01-20 Impact factor: 12.701
Authors: Dana E Rathkopf; Michael J Morris; Josef J Fox; Daniel C Danila; Susan F Slovin; Jeffrey H Hager; Peter J Rix; Edna Chow Maneval; Isan Chen; Mithat Gönen; Martin Fleisher; Steven M Larson; Charles L Sawyers; Howard I Scher Journal: J Clin Oncol Date: 2013-09-03 Impact factor: 44.544
Authors: Ahmedin Jemal; Freddie Bray; Melissa M Center; Jacques Ferlay; Elizabeth Ward; David Forman Journal: CA Cancer J Clin Date: 2011-02-04 Impact factor: 508.702
Authors: T H T Nguyen; M-S Mouksassi; N Holford; N Al-Huniti; I Freedman; A C Hooker; J John; M O Karlsson; D R Mould; J J Pérez Ruixo; E L Plan; R Savic; J G C van Hasselt; B Weber; C Zhou; E Comets; F Mentré Journal: CPT Pharmacometrics Syst Pharmacol Date: 2017-02-10