Exposure-Response Relationship of Typical and Atypical Antipsychotics Assessed by the Positive and Negative Syndrome Scale (PANSS) and its Subscales
Venkatesh Pilla Reddy*(1), Ahmed Abbas Suleiman (1), Magdalena Kozielska(1), Martin Johnson(1), An Vermeulen(2), Jing Liu(3), Rik de Greef(4), Geny M.M Groothuis(1), Meindert Danhof(5) and Johannes H. Proost(1)
(1) Division of Pharmacokinetics, Toxicology and Targeting, Dept of Pharmacy, (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: It has been suggested that atypical antipsychotics (ATAPs), are more effective towards negative symptoms than typical antipsychotics (TAPs) in schizophrenic patients.[1,2] To quantify the above statement, we aimed i) to develop a PK-PD model that characterizes the time course of PANSS score- total and its subscales in patients treated with TAPs and ATAPs; ii) to compare the effect of ATAPs vs. TAPs across the different symptom domains of schizophrenia.
Methods: Data from clinical studies with the ATAPs olanzapine (10&15mg/day), risperidone (1-16mg/day), paliperidone (3-15mg/day) and ziprasidone (40-200mg/day) and the TAP haloperidol (10-20mg/day) were used. 3 approaches were used in the analysis of drug effect, on top of the placebo effect (PE): i) overall efficacy (OE), ii) dose-response (DR), and iii) concentration-response (CR). The first two approaches utilized simultaneous analysis of all drugs together, while the CR analysis was performed separately. Sparse PK data & the time course of PANSS were available from the patients of olanzapine, risperidone, paliperidone and ziprasidone treated groups, while only PANSS data were available for haloperidol. A PK model for haloperidol was developed using data extracted from the literature. The predicted concentration was used as an input for the Emax model. The Weibull model was used to account for the PE. The delay in the drug effect was also modeled.
Results: Based on OE analysis, all ATAPs except ziprasidone were more effective against the negative symptoms of schizophrenia than haloperidol. The estimated ED50 values from DR analysis were in line with those reported in literature. A one-compartment model described the olanzapine & paliperidone PK adequately, while a two-compartment model was adequate for risperidone (parent + active metabolite) & haloperidol. The estimated EC50 values for each of antipsychotic were in line with those reported in literature.[4,5] Based on CR analysis, the effect size was highest for olanzapine whilst it was lowest for ziprasidone.
Conclusions: The effect size (Emax) of ATAPs across the different symptom domains of schizophrenia was in the same range as that for TAP (haloperidol). Based on concentration-response analysis, the efficacy was highest for olanzapine whilst it was lowest for ziprasidone. This integrated modeling approach allows a comparison of the treatment effects of antipsychotics taking variable placebo effect into account. .
 Leucht S, Arbter D, Engel RR, et al. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 2009; 14(4):429-447.
 Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373(9657):31-41.
[3 ]Davis JM, Chen N. Dose response and dose equivalence of antipsychotics. Journal of clinical psychopharmacology. 2004; 24:192-208.
[4 ]Mauri MC, Volonteri LS, Colasanti A, et al. Clinical pharmacokinetics of atypical antipsychotics - A critical review of the relationship between plasma concentrations and clinical response. Clinical Pharmacokinetics 2007; 46(5):359-388.
 Giegling I, Drago A, Schafer M, et al. Interaction of haloperidol plasma level and antipsychotic effect in early phases of acute psychosis treatment. Journal of Psychiatric Research 2010; 44(8):487-492.