Exposure-response analysis in patients with schizophrenia to assess the effect of asenapine on QTc prolongation.
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 C(max) 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.
Chapel
Sunny
S
Department of Clinical Pharmacology, Pfizer Global Research & Development, Ann Arbor, Michigan, USA. sunny.chapel@a2pg.com
Hutmacher
Matt M
MM
Haig
George
G
Bockbrader
Howard
H
de Greef
Rik
R
Preskorn
Sheldon H
SH
Lalonde
Richard L
RL
D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003986:Dibenzocycloheptenes; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000188:drug therapy*; D013997:Time Factors
D014150:Antipsychotic Agents; D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings; C522667:asenapine