Population pharmacokinetic analysis of JNJ-37822681, a specific and fast-dissociating D2 antagonist for the treatment of schizophrenia
Eef Hoeben (1), Martine Neyens (1), Erik Mannaert(1), Peter De Boer (2), Mark Schmidt (2), An Vermeulen (1)
(1) Janssen Research and Development, Clinical Pharmacology and (2) Janssen Research and Development Experimental Medicine Europe, Turnhoutseweg 30, B-2340 Beerse Belgium
Objectives: A population PK model of JNJ-37822681 was developed with the aim to describe the PK of JNJ-37822681 in healthy volunteers and in patients with schizophrenia. Objectives were to obtain estimates for PK parameters and associated variability, to evaluate the effects of covariates and to provide exposure parameter estimates derived from sparse samples of subjects participating in a Phase 2b study. Exposure parameters were used to simulate D2 occupancy and to guide dose selection for subsequent studies.
Methods: Data were obtained from 378 subjects enrolled in 3 Phase 1 and 2 Phase 2 trials. Nonlinear mixed effects modeling of pooled data was conducted using NONMEM® (1,2). Between-subject variability for PK parameters was evaluated using an exponential error model and the residual error was described using an additive model in the log domain. The FOCE method was applied throughout the analysis. Screening for covariate relationships was based on a graphical analysis of individual posterior estimates of random effects vs. covariates. The model was validated on a subset of data that were not used to build the model and was subsequently used to predict steady-state exposure for each subject in the Phase 2b study. D2 occupancy in striatum was simulated using predicted exposure combined with the PD parameters from a sigmoid Emax model established on former 11C-raclopride PET data.
Results: A two-compartment disposition model with zero-order input in a depot compartment followed by first-order absorption into and first-order elimination from the central compartment combined with a transit compartment provided the best fit to the data. Sex was a significant covariate on oral clearance and food a significant covariate on the absorption rate constant and oral bioavailability. The exposure was somewhat higher in females compared to males. The model passed external validation and allowed determination of individual exposure parameters which were similar to those calculated in a Phase 2a study. PK/PD evaluation demonstrated that simulated D2 occupancy was in the 65-80% range or partially above the 80% threshold at doses of 10, 20 and 30 mg bid. This 65-80% range has been shown to be linked to efficacy (3).
Conclusions: The developed population PK model successfully described the PK of JNJ-37822681 and allowed the determination of individual exposure parameters in a Phase 2b study. Simulated D2 occupancy based on predicted exposure and former PET-study data guided dose selection for subsequent studies.
References:
[1] Beal SL, Sheiner LB (1989-2009). NONMEM Users Guides. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] Guidance for Industry. Population Pharmacokinetics, U.S. Food and Drug Administration. 1999.
[3] Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000:157:514-520.
