Characterizing exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, in healthy and castration-resistant prostate cancer subjects
Carlos Pérez-Ruixo (1)*, Jonás Samuel Pérez-Blanco (1)*, Caly Chien (2), Margaret Yu (3), Daniele Ouellet (2), Juan-José Pérez-Ruixo (2), Oliver Ackaert (1)#
(1) Janssen Research & Development, Antwerp, Belgium; (2) Janssen Research & Development, Spring House, PA, USA; (3) Janssen Research & Development, Los Angeles, CA, USA *Contributed equally as first author #Corresponding author
Objectives: Apalutamide is an androgen receptor inhibitor approved for treatment of high-risk non-metastatic castration-resistant prostate cancer (NM-CRPC) subjects [1,2]. The objective of this population pharmacokinetics (PK) analysis was to characterize the time course of plasma concentrations of apalutamide and its active metabolite N-desmethyl apalutamide following single and repeat oral dosing.
Methods: Plasma concentration data of apalutamide and N-desmethyl-apalutamide from 1092 subjects (3 single-dose studies in healthy male subjects and 4 multiple-dose once daily studies in CRPC and NM-CRPC subjects) were pooled for a population PK analysis using a non-linear mixed effect modelling approach. A covariate analysis was conducted to quantify the impact of intrinsic and extrinsic factors on the PK of apalutamide and N-desmethyl apalutamide.
Results: Apalutamide pharmacokinetics were adequately described with an open linear two-compartment disposition model with a time-dependent apparent clearance and lagged first-order absorption. The apparent total clearance of apalutamide was composed of a constant, not inducible, clearance and an inducible clearance that increased over time until achieving steady-state after the continuous once daily dosing of apalutamide. The apparent total clearance of apalutamide increased according to a first order process with an induction half-life of 18 days from 1.31 L/h after first dose to 2.04 L/h at steady-state, consistent with auto-induction of apalutamide’s own metabolism. The formation of the metabolite N-desmethyl apalutamide was assumed to be equal to apalutamide elimination. N-desmethyl apalutamide pharmacokinetics were described with an open linear two-compartment disposition model with the assumption of linear elimination from the central compartment. After 4 weeks of treatment, more than 95% of steady state exposure of apalutamide and N-desmethyl-apalutamide is reached. At steady-state, the elimination half-life of apalutamide and its metabolite was 4.2 and 4.6 days, respectively. At 240 mg of apalutamide per day, apalutamide and N-desmethyl-apalutamide exposure exhibited a 5.3 and 85.2-fold accumulation in plasma, respectively. In addition, apalutamide administration once daily results in relative constant steady state apalutamide and N-desmethyl apalutamide plasma concentration with 1.4- fold and negligible fluctuation over the dosing interval, respectively. Within the range of covariate values evaluated using a stepwise covariate modeling approach, only health status (healthy vs. patients), body weight and albumin concentration were statistically associated with the exposure of apalutamide or N-desmethyl-apalutamide and the effect was small (<25%).
Conclusions: The PK of apalutamide and N-desmethyl-apalutamide was adequately described simultaneously using one combined model. None of the investigated covariates has a discernible and or clinically relevant impact on the apalutamide or N-desmethyl-apalutamide PK.
References:
[1] Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012;72(6): 1494-503.
[2] ERLEADATM (apalutamide) prescribing information. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210951s000lbl.pdf. Accessed 11 January 2019.
