Pharmacokinetic-pharmacodynamic modelling of antipsychotic drugs in patients with schizophrenia: Part II: The use of subscales of the PANSS score

SCHIZOPHRENIA RESEARCH

卷:146

Article

Reddy, Venkatesh Pilla¹  Kozielska, Magdalena¹  Suleiman, Ahmed Abbas¹  Johnson, Martin¹  Vermeulen, An²  Liu, Jing³  de Greef, Rik⁴  Groothuis, Geny M. M.¹  Danhof, Meindert⁵  Proost, Johannes H.¹ 

[1] Univ Groningen, Div Pharmacokinet Toxicol & Targeting, Univ Ctr Pharm, NL-9713 AV Groningen, Netherlands

[2] Janssen Res & Dev, Adv PKPD Modelling & Simulat, Beerse, Belgium

[3] Pfizer Global Res & Dev, Clin Pharmacol, Groton, CT 06340 USA

[4] Merck Sharp & Dohme Ltd, Merck Res Labs, Pharmacokinet Pharmacodynam & Drug Metab, Clin PKPD, Oss, Netherlands

[5] Leiden Amsterdam Ctr Drug Res, Div Pharmacol, Leiden, Netherlands

关键词: Antipsychotic drugs;    Population pharmacokinetic-pharmacodynamic modelling;    PANSS subscales;    Placebo effect;    Dropout model;   

DOI  :  10.1016/j.schres.2013.02.010

来源: Elsevier

【 摘 要 】

Background and objectives: The superiority of atypical antipsychotics (also known as second-generation antipsychotics (SGAs)) over typical antipsychotics (first generation antipsychotics (FGAs)) for negative symptom control in schizophrenic patients is widely debated. The objective of this study was to characterize the time course of the scores of the 3 subscales (positive, negative, general) of the Positive and Negative Syndrome Scale (PANSS) after treatment of patients with antipsychotics, and to compare the control of negative symptom by SGAs versus a FGA (haloperidol) using pharmacokinetic and pharmacodynamic (PKPD) modelling. In addition, to obtain insight in the relationship between the clinical efficacy and the in vitro and in vivo receptor pharmacology profiles, the D-2 and 5-HT2A receptor occupancy levels of antipsychotics were related to the effective concentrations. Methods: The PKPD model structure developed earlier (part I) was used to quantify the drug effect using the 3 PANSS subscales. The maximum drug effect sizes (E-max) of oral SGAs (risperidone, olanzapine, ziprasidone, and paliperidone) across PANSS subscales were compared with that of haloperidol, while accounting for the placebo effect. Using the estimates of PKPD model parameters, the effective concentrations (C-eff) needed to achieve 30% reduction in the PANSS subscales were computed. Calculated effective concentrations were then correlated with receptor pharmacology profiles. Results: Positive symptoms of schizophrenia responded well to all antipsychotics. Olanzapine showed a better effect towards negative symptoms than the other SGAs and haloperidol. Dropout modelling results showed that the probability of a patient dropping out from a trial was associated with all subscales, but was more strongly correlated with the positive subscale than with the negative or the general subscales. Our results suggest that different levels of D-2 or 5-HT2A receptor occupancy are required to achieve improvement in PANSS subscales. Conclusions: This PKPD modelling approach can be helpful to differentiate the effect of antipsychotics across the different symptom domains of schizophrenia. Our analysis revealed that olanzapine seems to be superior in treating the negative symptoms compared to other non-clozapine SGAs. The relationship between receptor pharmacology profiles of the antipsychotics and their clinical efficacy is not yet fully understood. (C) 2013 Elsevier B.V. All rights reserved.

【 授权许可】

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