Population Pharmacokinetics/Pharmacodynamics of Antidepressant R,R(-) and S,S(+) Reboxetine (RBX)

Conference: AAPS
Division: Cognigen


Purpose: To develop a population pharmacokinetic model describing the disposition of each enantiomer of antidepressant reboxetine and a pharmacodynamic model relating plasma concentrations and adverse effects.

Methods: Data for analysis were from a double-blind, placebo-controlled, multi-center trial. 198 patients received oral doses of 1, 2, or 4 mg b.i.d. reboxetine and 80 patients received placebo. Population PK models for R,R(-) and S,S(+) reboxetine were developed separately in NONMEM®. A PD model on pulse variation was also developed using NONMEM® and a logistic regression analysis was performed on the risk of selected adverse events during treatment with reboxetine using SAS® software.

Results: One-compartment models with first-order absorption best described the PK of both R,R(-) and S,S(+) reboxetine. Clearance and steady-state volume of distribution of R,R(-) and S,S(+) reboxetine were estimated as 2.36 L/hr, 59.2 L, 4.45 L/hr and 102 L, respectively. Gender and weight were observed to affect clearance of R,R(+) reboxetine, with a 24.3% reduction for females and about 0.012 L/hr reduction for every 1 kg gain in weight. None of the concomitant medications explored was found to significantly influence R,R(-) reboxetine PK. Neither demographic characteristics nor concomitant medications were found to significantly affect S,S(+) reboxetine PK. Reboxetine doses were found to be significantly related to the risk of the combined adverse events with an odds ratio (95% CI) of 1.52 (1.26, 1.83). The time course of change in pulse rate from baseline is best represented by a sigmoid model. Reboxetine treatment was observed to increase pulse rate by about 8 beats/minute on average, not significantly varying with doses, demographics, or concomitant medications.

Conclusions: No demographic factors were identified in this analysis which affect the pharmacokinetics of reboxetine enantiomers to a clinically significant degree. No clear relationship between reboxetine exposure and specific adverse events was observed.

American Association of Pharmaceutical Scientists (AAPS); Denver, Colorado; October 2001

By A.J. Xiao, Jill Fiedler-Kelly, M. Redman, J.C. Fleishaker