Venkatesh Pilla Reddy*(1), Magdalena Kozielska(1), Martin Johnson (1), An Vermeulen(2), Jing Liu(3), Rik de Greef (4), Geny M.M Groothuis(5), Meindert Danhof (6) and Johannes H. Proost (1)
(1) Dept of Pharmacokinetics, Toxicology and Targeting, University of Groningen, The Netherlands, (2) Advanced PK-PD Modeling & Simulation, Janssen Research & Development, Beerse, Belgium, (3) Pfizer Global Research & Development, Groton, CT 06340, USA, (4) Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3), Merck Sharp & Dohme, Oss, The Netherlands, (5) Leiden/Amsterdam Center For Drug Research, Dept of Pharmacology, Leiden, The Netherlands
Objectives: To link the brain dopamine D2 receptor occupancy (D2RO) of antipsychotic drugs with clinical endpoints of efficacy and safety to assess the therapeutic window of D2RO.
Methods: Pharmacokinetic-Pharmacodynamic (PK-PD) models were developed to predict the D2 receptor occupancy of antipsychotics. We consider the following currently available atypical antipsychotic drugs: risperidone, olanzapine, ziprasidone, paliperidone, and a recent Phase II test compound (JNJ-37822681). Haloperidol (typical antipsychotic drug) was used as a reference drug to compare the efficacy and safety profiles. Step 1: Patient-specific steady-state concentration was calculated using the post-hoc empirical Bayesian estimate of clearance. Step 2: D2RO was predicted for each patient with empirical and mechanistic-based models using observed D2RO or in vitro (ki values, plasma/brain protein binding) data. Step 3: D2RO was linked to the clinical endpoints of efficacy (Positive and Negative Syndrome Scale, PANSS) and safety (extrapyramidal side effects, EPS). Step 4: Effective D2RO for good clinical efficacy (30% reduction in PANSS score) and minimal EPS events were computed using the model parameters.
Results: Predicted D2RO was in agreement with clinically observed D2RO at relevant antipsychotic doses. The effective D2RO required to achieve 30% reduction in PANSS from baseline score was in the range of 50-70%. Above 80% D2RO, incidence rates of EPS increased sharply.
Conclusions: This modeling framework provides a valuable tool to characterize the relationship between D2RO and clinical effects of antipsychotic drugs and to predict the optimal human dose for new antipsychotic drugs.
References: Modelling and Simulation of the Positive and Negative Syndrome Scale (PANSS) Time Course and Dropout Hazard in Placebo Arms of Schizophrenia Clinical Trials. Clinical Pharmacokinetics: 51, 4, 261-275. 2012
Reference: PAGE 21 () Abstr 2368 [www.page-meeting.org/?abstract=2368]
Poster: CNS