Concentration-QTC modeling in healthy volunteers (HV) and in subjects with major depressive disorder (MDD) for a novel antidepressant candidate

Abstract

Purpose Evaluation of QTc vs. concentration relationship was undertaken to assess QTc prolongation early in drug development for a novel antidepressant. Objective To evaluate the QTc to concentration relationship in HV and MDD subjects at high concentrations and to predict QTc prolongation in MDD subjects for various sources of pharmacokinetic variability. Methods 28 healthy subjects and 31 subjects with MDD were studied. All subjects received 10 mg QD on Day 1 followed by 30 mg on days 2-6 of the antidepressant candidate. In addition, healthy volunteers received 60 mg QD on days 7–9. Triplicate time-matched baseline ECG data on two baseline days were collected. Triplicate and singlet ECG measurements were collected during treatment arms. Delta QTcF (Fridericia) was modeled using NONMEM v.5. Intercept vs. slope/intercept models were employed. Influence of disease state was also tested. Nonparametric bootstrap was used to construct 95% confidence intervals. Results Concentrations were similar in HV and MDD subjects. A linear QtcF vs. concentration relationship best described the data. HV and MDD subjects had similar slope estimates. Slope for HV: 0.0375 (0.0206, 0.0555) and for MDD: 0.03501 (0.0203, 0.0508). Conclusions Due to the similarity of slope in HV and MDD subjects, use of a population PK/PD model based on phase I data allows for the projection of QTcF in such cases as overdose and drug-drug interaction. Clinical Pharmacology & Therapeutics (2004) 75, P88–P88; doi: 10.1016/j.clpt.2003.11.336