Population pharmacokinetics of abiraterone in patients with metastatic castration resistant prostate cancer
Mourad Mseddi (1), Jean-Stephane Giraud (2), David Balakirouchenane (1), Stephane Oudard (3), Luca Campedel (4), Sylvain Ladoire (5), Ahmed Khalil (6), Denis Maillet (7), Christophe Tournigand (8), Charles Dariane (9), Florence Joly (10), Evanguelos Xylinas (11), Olivier Huillard (12), Jérôme Alexandre (12), Benoit Blanchet (1), Alicja Puszkiel (1,13)
(1) Biologie du Médicament – Toxicologie, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France (2) Department of Pharmacy, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France (3) Departement of Medical Oncology, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France (4) Departement of Medical Oncology, Hôpital La Pitié Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France (5) Departement of Medical Oncology, Centre Georges-François Leclerc, Dijon, France (6) Departement of Medical Oncology, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Paris (7) Departement of Medical Oncology, Centre Hospitalier Lyon Sud, Pierre-Bénite, France (8) Departement of Medical Oncology, Hôpital Mondor, Assistance Publique Hôpitaux de Paris, Créteil, France (9) Departement of Urology, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France (10) Departement of Medical Oncology, F Baclesse, Caen, France (11) Departement of Urology, Hôpital Bichat, Assistance Publique Hôpitaux de Paris, Paris, France (12) Departement of Medical Oncology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France (13) Université Paris Cité, Inserm UMR1144, Paris, France
Introduction/Objectives:
Abiraterone acetate is approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) [1,2]. After oral administration, abiraterone acetate is rapidly hydrolyzed in the intestinal fluids into abiraterone [3] which is a selective and irreversible inhibitor of CYP17, a key enzyme for testosterone synthesis [4]. Abiraterone steady-state trough concentration (Cmin,ss) > 8.5 ng/mL was previously associated with better clinical efficacy in mCRPC patients [5,6]. Since abiraterone exhibits large interindividual variability (IIV) in pharmacokinetics (PK) [5,7], monitoring of its plasma concentrations could help to optimize treatment efficacy [8]. The objective of this study was to develop a population PK model of abiraterone in a large cohort of patients, to identify determinants of abiraterone IIV in PK and to evaluate the number of under-exposed patients at the standard dose and simulate alternative doses for these patients allowing to reach target exposure (Cmin,ss > 8.5 ng/mL).
Methods:
Steady-state plasma abiraterone concentrations were obtained from mCRPC patients treated with abiraterone acetate between January 2013 and December 2021. In addition, a subset of patients enrolled in phase 2 OPTIMABI study (NCT03458247) was included in the modelling analysis. Plasma concentrations of abiraterone were measured using a fully validated high-performance liquid chromatography (HPLC) method coupled with fluorescence detection [9]. Population PK analysis was based on FDA & EMA guidelines using non-linear mixed effects modelling with the stochastic approximation expectation–maximization (SAEM) algorithm implemented in the Monolix Suite version 2021R2 (Lixoft®, Anthony, France). One and two-compartment models were tested with linear or zero-order absorption and linear elimination. The following baseline covariates were tested on apparent clearance (CL/F): age, body mass index (BMI), serum albumin, total bilirubin, aspartate (AST) and alanine (ALT) aminotransferase and estimated glomerular filtration rate (eGFR). Model selection was based on corrected version of Bayesian information criteria (BICc), precision of estimated parameters, decrease in residual error variance and goodness-of-fit (GOF) plots. Selection of covariates was based on log-likelihood ratio test (LRT) using objective function value (OFV). The model was validated using non-parametric bootstrap and prediction corrected visual predictive check (pcVPC). The final PK model was used to simulate 1000 patients treated with 1000 mg once daily (qd) abiraterone acetate dose in Simulx and the number of patients below Cmin,ss threshold (8.5 ng/mL) was calculated. Simulations of alternative dose (500 mg twice daily, bid) were performed for under-exposed patients.
Results:
A total of 321 patients (including 64 patients from OPTIMABI trial) were enrolled in this study. The median age was 74.5 years old and the median daily dose of abiraterone acetate was 1000 mg (range: 250 – 2000 mg). PK dataset consisted of 663 abiraterone concentrations (including 143 from OPTIMABI trial). Data were described using a two-compartment model with first-order absorption and elimination. The proportional residual error was 36%. The mean estimates of the final PK model for apparent clearance (CL/F), central volume of distribution (V1/F), peripheral volume of distribution (V2/F) and apparent intercompartmental clearance (Q/F) were 801 L/h, 1859 L, 6144 L and 314 L/h, respectively. Age was significantly associated with CL/F. The typical CL/F estimated for a 50 years old patient was 25% lower than that for a 80 years old patient. At 1000 mg qd dose, the median simulated abiraterone Cmin,ss was 9.7 ng/mL (IQR 5.6 – 17.0). Simulations showed that 68.6% of patients were above efficacy threshold (Cmin,ss> 8.5 ng/mL). Splitting daily 1000 mg dose into 500 mg bid in under-exposed patients resulted in an increase in their median abiraterone Cmin,ss from 6.3 (IQR 5.2 – 7.5) to 9.4 ng/mL (IQR 7.6 – 11.1). Dose splitting allowed reaching the efficacy threshold in 61.8% of patients.
Conclusions:
This model could be used in routine practice to predict individual Cmin,ss based on plasma concentration drawn at any time after drug intake and to guide individual dose adaptations.
References:
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