Effects of Orlistat, a Lipase Inhibitor, on the Pharmacokinetics of Three Highly Lipophilic Drugs (Amiodarone, Fluoxetine, and Simvastatin) in Healthy Volunteers

Abstract

To investigate the effect of orlistat on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin), the authors performed double-blind, placebo-controlled, randomized two-period crossover (for fluoxetine and simvastatin) or parallel (for amiodarone) studies in healthy volunteers ages 18 to 65 years of a body mass index between 18 and 30 kg/m2. During treatment with orlistat or matching placebo for 5 to 13 1/3 days, a single oral dose of highly lipophilic drug was administered, followed by obtaining serial blood samples for measuring plasma (for fluoxetine and simvastatin) or serum (for amiodarone) concentrations of the lipophilic drug and its active metabolite. Treatments were compared for the pharmacokinetic parameters AUC0-infinity, Cmax, tmax, and t 1/2 of highly lipophilic drugs and active metabolites. Analysis of variance was performed to assess the significance of the sequence effect and provide the variance estimate for the 90% confidence intervals. Subjects were also evaluated for adverse events, vital signs, and clinical and laboratory safety. The absorption of amiodarone (and active metabolite) was significantly reduced by approximately one-quarter using parameters of Cmax and AUC, while no inhibition of absorption was observed for fluoxetine and simvastatin as well as their active metabolites. There were no clinically significant differences in t 1/2 and tmax for all three drugs tested. Due to expected gastrointestinal adverse events known to occur with orlistat, there was a higher incidence of adverse events under regimen B (highly lipophilic drugs and orlistat) than under regimen A (highly lipophilic drugs and placebo). Other adverse events were sporadic and unremarkable. There were no clinically relevant changes in vital signs or laboratory values. In conclusion, except for amiodarone, there was no effect of orlistat on the pharmacokinetics of highly lipophilic drugs when these drugs were taken concomitantly with orlistat.

Obesity: Pathophysiology and Clinical Management

“…As vitamin K a bsorption may be decreased, warfarin anticoagulation may be potentiated during orlistat therapy [87]. Therefore, patients receiving warfarin who start Orlistat need close monitoring of t heir IN R. Re duction i n t he a bsorption of amiodarone and cyclosporine is another potential drug interaction of or listat [88,89]. A lthough absolute concentrations of vi tamins D, E, a nd -carotene de creased duri ng orl istat treatment, th e co ncentrations r emained w ithin the n ormal range a nd on ly fe w i ndividuals w ith l ow v alues n eed s upplementation [83].…”

Current pharmacotherapeutic concepts for the treatment of obesity in adults

“…Caution is required when these two drugs are used concurrently. Orlistat can also reduce the absorption of cyclosporine [Zhi et al 2002] and amiodarone [Zhi et al 2003]. …”

Obesity: Which drug and when?

“…It can reduce absorption of both cyclosporine (23) and amiodarone (24), and extra anticoagulant monitoring is suggested because of a potential increased anticoagulant effect with warfarin (25); these potential problems would very rarely preclude its use. Concomitant use with acarbose is not advised.…”