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Medientyp:
E-Artikel
Titel:
Effect of single and repeat doses of casopitant on the pharmacokinetics of CYP450 3A4 substrates midazolam and nifedipine
Beteiligte:
Zamuner, Stefano;
Johnson, Brendan M.;
Pagliarusco, Sabrina;
Fina, Paolo;
Peroni, Michela;
Fiore, Monica;
Adams, Laurel M.;
Fernandes, Sofia A.
Erschienen:
Wiley, 2010
Erschienen in:British Journal of Clinical Pharmacology
Beschreibung:
<jats:sec><jats:label /><jats:p> <jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT</jats:bold> </jats:p><jats:p>• Casopitant is an NK‐1 receptor antagonist which has been evaluated for the prevention of chemotherapy‐induced and post‐operative nausea and vomiting.</jats:p><jats:p>• Data from <jats:italic>in vitro</jats:italic> systems suggested that casopitant both inhibits and induces CYP3A. Therefore, a risk of an interaction between casopitant and CYP3A4 substrates is likely.</jats:p><jats:p> <jats:bold>WHAT THIS STUDY ADDS</jats:bold> </jats:p><jats:p>• 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.</jats:p><jats:p>• 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.</jats:p><jats:p>• These results suggest that the use of <jats:italic>in vitro</jats:italic> or <jats:italic>in vivo</jats:italic> data to predict the interaction potential of other concomitant medications needs to account properly for any potential induction effect.</jats:p></jats:sec><jats:sec><jats:title>AIM</jats:title><jats:p>To 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.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>Three open‐label studies were conducted in healthy subjects. In the first study subjects received single dose 50 or 100 mg oral casopitant, single dose 5 mg oral midazolam and single dose 10 mg oral debrisoquine. In the other two studies subjects received repeated doses of 10 mg (study 2), 30, or 120 mg oral casopitant and single doses of 5 mg oral midazolam (study 2) and single doses of 10 mg oral nifedipine (study 3). Plasma concentration–time data were analyzed using standard non‐compartmental methods. The effect of casopitant on all probes was assessed using geometric means ratios and corresponding 90% confidence intervals (CIs).</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>The AUC(0,∞) of midazolam was increased 1.44‐fold (90% CI 1.35, 1.54) and 1.52‐fold (90% CI 1.41, 1.65) after co‐administration with a single dose of 50 or 100 mg casopitant, respectively. Debrisoquine metabolism was unchanged. After 3 days of casopitant administration, midazolam AUC(0,∞) was increased 1.45‐ (90% CI 1.32, 1.59), 2.02‐ (90% CI 1.75, 2.32), and 2.67‐fold (90% CI 2.18, 3.27) after co‐administration with 10, 30 or 120 mg casopitant, respectively. After 14 days of casopitant administration, midazolam AUC(0,∞) was increased 1.51‐ (90% CI 1.40, 1.63) to 3.49‐fold (90% CI 2.98, 4.08). After 3 days of casopitant administration, nifedipine AUC(0,∞) was increased 1.56‐ (90% CI 1.37, 1.78) and 1.77‐fold (90% CI 1.54, 2.04) after co‐administration with 30 or 120 mg casopitant, respectively. Similar increases in nifedipine exposure were observed after 14 days of casopitant administration.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>Casopitant is a dose‐ and duration‐dependent weak to moderate inhibitor of CYP3A.</jats:p></jats:sec>