Pharmacokinetic-Pharmacodynamic Modeling of Dopamine D2 Receptor Occupancy in humans using Bayesian modeling tools
Martin Johnson* (1), Nyashadzaishe Mafirakureva (1), Magdalena Kozielska (1), Venkatesh Pilla Reddy (1), An Vermeulen (2), Jing Liu (3), Rik de Greef (4), Geny M.M. Groothuis (1), Meindert Danhof (5), & Johannes H. Proost (1)
(1) Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, The Netherlands; (2) Advanced PK-PD Modeling & Simulation, Janssen Research & Development, Beerse, Belgium; (3) Worldwide Research & Development, Pfizer, Inc., Groton, CT, USA; (4) Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3), Merck Sharp & Dohme, Oss, The Netherlands; (5) Division of Pharmacology, Leiden/Amsterdam Center For Drug Research, Leiden, The Netherlands
Objectives: Blockade of dopamine-2 receptors is the key pharmacological component to the antipsychotic efficacy of both the typical and atypical antipsychotics (1). A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to describe the relationship between the plasma concentration of antipsychotics (AP) and their D2 receptor occupancy (D2RO) in humans. Bayesian tools were utilized to estimate the PK-PD parameters from the limited data available in the literature.
Methods: Plasma levels and D2RO of four antipsychotics (risperidone, paliperidone, olanzapine, haloperidol) from 82 schizophrenic patients and 34 healthy volunteers were collected from literature(2). D2RO was measured using a PET or a SPECT scan at one or two time points per individual. PK-PD parameters were estimated using nonlinear mixed effect modeling by the Bayesian method with interaction option as implemented in NONMEM VII. Priors and uncertainty on priors were taken from in-house model estimates, when available, or non-informative priors were used. Moreover, the influence of ligand selection on the dissociation constant (Kd) estimates of paliperidone was checked.
Results: A one-compartment pharmacokinetic (PK) model explained the plasma PK profile for olanzapine and paliperidone, whereas a two-compartment PK model was used for risperidone and haloperidol. An Emax model linked with an effect compartment described the relationship between drug exposure and D2RO. Ke0 (equilibration rate to the effect compartment) was allometrically scaled from preclinical literature information and used as prior in this analysis. The estimated Kd was close to the values in the literature (reported as EC50) for risperidone, paliperidone, olanzapine and haloperidol (3). No significant influence of ligand selection was observed in the Kd estimates of paliperidone.
Conclusions: An Emax model linked with an effect compartment adequately described the relationship between the drug exposure and D2RO, using a Bayesian method to estimate PK-PD parameters from limited information. The model-estimated Kd values were close to the values reported in the literature for risperidone, paliperidone, olanzapine and haloperidol.
References:
[1] Nordstrom AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C, et al. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry 1993 Feb 15;33(4):227-235.
[2] Ahadieh S, Corrigan B, Riley S, Lalonde R. Meta-analysis of D2 receptor occupancy-plasma concentration for antipsychotics, ASCPT Annual Meeting, National Harbor, MD, March 18-21,2009.
[3] Nucci G, Gomeni R, Poggesi I. Model-based approaches to increase efficiency of drug development in schizophrenia: a can't miss opportunity. Expert Opinion on Drug Discovery 2009;4(8):837-856.