Translational PKPD modeling in schizophrenia: linking receptor occupancy of antipsychotics to efficacy and safety

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. 201