Effect of single and repeat doses of casopitant on the pharmacokinetics of CYP450 3A4 substrates midazolam and nifedipine

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Casopitant is an NK-1 receptor antagonist which has been evaluated for the prevention of chemotherapy-induced and post-operative nausea and vomiting.• Data from in vitro systems suggested that casopitant both inhibits and induces CYP3A. Therefore, a risk of an interaction between casopitant and CYP3A4 substrates is likely. WHAT THIS STUDY ADDS• Casopitant showed a dose and time dependent interaction with CYP3A, resulting in weak inhibition after a single dose, and weak to moderate inhibition after repeated dose administration.• The interaction with nifedipine could be predicted from the midazolam data for acute casopitant administration, but not after 14 days repeated dose casopitant administration, suggesting an induction effect complicating the interaction with nifedipine.• These results suggest that the use of in vitro or in vivo data to predict the interaction potential of other concomitant medications needs to account properly for any potential induction effect. AIMTo evaluate the impact of single and repeated doses casopitant on the pharmacokinetics of single dose midazolam and nifedipine (CYP3A substrates) in healthy subjects. The effect on debrisoquine metabolism (CYP2D6 substrate) was also assessed.

Casopitant: In Vitro Data and SimCyp Simulation to Predict In Vivo Metabolic Interactions Involving Cytochrome P450 3A4

“…Measurements of casopitant, its metabolite GSK525060, MID, NIF, KET, and RIF in plasma were performed with validated and specific HPLC-MS/MS assays by or on behalf of the Drug Metabolism and Pharmacokinetics Department, GlaxoSmithKline. All the details of the bioanalytical methods and their specific performances are reported in Zamuner et al (2010) and Johnson et al (2010).…”

“…The time of administration was chosen to match the maximal plasma concentrations of the two drugs and, thus, maximize the potential pharmacokinetic interaction. This allowed a comparison of the pharmacokinetics of MID when this drug was given on its own or after 3 and 14 days of daily treatment with casopitant (Zamuner et al, 2010).…”

“…Pharmacokinetic analysis applied to the concentration-time profiles concerning casopitant, GSK525060, MID, and NIF, is reported in Zamuner et al (2010) and Johnson et al (2010).…”

“…On days 10 and 21, all subjects also received a single 10-mg oral dose of NIF. This administration allowed a comparison of the pharmacokinetics of NIF when this drug was given on its own or after 3 and 14 days of daily treatment with casopitant (Zamuner et al, 2010). In both studies, blood samples for determination of plasma concentration of MID or NIF, casopitant, and its metabolite GSK525060 were collected at selected days and time points and analyzed by HPLC-MS/MS (Zamuner et al, 2010).…”

“…GSK525060 ( Fig. 1), the major circulating metabolite in man, is present at concentrations comparable to those of the parent drug, both after single (Pellegatti et al, 2009) and repeated (Zamuner et al, 2010) oral administration of casopitant.…”