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Population Pharmacokinetics of Apalutamide and its Active Metabolite N-Desmethyl-Apalutamide in Healthy and Castration-Resistant Prostate Cancer Subjects



Apalutamide is a next-generation androgen receptor inhibitor approved for treatment of subjects with high-risk, non-metastatic, castration-resistant prostate cancer (NM-CRPC).


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.


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.


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%).


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.

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The authors would like to thank the patients, investigators, and the medical, nursing, and laboratory staff who participated in the clinical studies included in the present work.

Author information

Correspondence to Oliver Ackaert.

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Conflicts of interest

Caly Chien, Margaret Yu, Daniele Ouellet, and Juan-José Pérez-Ruixo were employees and shareholders of Janssen Pharmaceutical Companies at the time this analysis was conducted. Carlos Pérez-Ruixo, Jonás Samuel Pérez-Blanco, and Oliver Ackaert were employees of Janssen Pharmaceutical Companies at the time this analysis was conducted.


The clinical studies were supported by research funding from Janssen Research & Development, and the analyses presented here were supported by Janssen Research & Development.

Ethical approval and informed consent

All studies were conducted in accordance with principles for human experimentation as defined in the Declaration of Helsinki and were approved by the Human Investigational Review Board of each study center and by the Competent Authority of each country. Informed consent was obtained from each subject before enrollment in the studies after being advised of the potential risks and benefits of the study, as well as the investigational nature of the study.

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Pérez-Ruixo, C., Pérez-Blanco, J.S., Chien, C. et al. Population Pharmacokinetics of Apalutamide and its Active Metabolite N-Desmethyl-Apalutamide in Healthy and Castration-Resistant Prostate Cancer Subjects. Clin Pharmacokinet 59, 229–244 (2020).

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