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PHARMACOKINETICS AND PHARMACODYNAMICS

Exposure-Response Analysis in Patients With Schizophrenia to Assess the Effect of Asenapine on QTc Prolongation

Sunny Chapel, PhD, Matt M. Hutmacher, MS, George Haig, PharmD, Howard Bockbrader, PhD, Rik de Greef, MSc, Sheldon H. Preskorn, MD and Richard L. Lalonde, PharmD

From the Department of Clinical Pharmacology, Pfizer Global Research & Development, Ann Arbor, Michigan (Dr Chapel, Dr Hutmacher, Dr Bockbrader, Dr Lalonde); CNS Clinical, Pfizer Global Medical & Development Sciences, Ann Arbor, Michigan (Dr Haig); Pharmacokinetics, Pharmacodynamics, and Pharmacometrics, Schering-Plough, Oss, the Netherlands (Dr de Greef); and Clinical Research Institute and Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine, Wichita (Dr Preskorn).

An exposure-response (E-R) analysis using linear mixed effects modeling was conducted on data from a thorough QTc trial for asenapine in 148 patients with schizophrenia. In a parallel design, patients received asenapine 5 mg twice daily (BID) for 10 days (10d) followed by 10 mg BID (6d), asenapine 15 mg BID (10d) followed by 20 mg BID (6d), quetiapine 375 mg BID (for assay sensitivity; 16d) or placebo (16d). Triplicate 12-lead electrocardiograms and concentration measurements were obtained on day -1 (baseline), 1, 10, and 16 at 8 scheduled times on each day. At mean Cmax for all asenapine doses, the E-R model predicted that the mean QTcF increase was less than 5 milliseconds, the International Conference on Harmonisation-established threshold for clinical concern. The model predicted a mean increase of 7 to 8 milliseconds for quetiapine. The corresponding upper bounds of the 95% confidence intervals were 7.5 milliseconds and 11.2 milliseconds for asenapine and quetiapine, respectively.

Key Words: Schizophrenia • asenapine • QTc prolongation • E-R analysis

Address for reprints: Sunny Chapel, PhD, Ann Arbor Pharmacometrics Group (A2PG), 110 E Miller Ave, Garden Suite, Ann Arbor, MI 48104; e-mail: sunny.chapel{at}a2pg.com.


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