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


METHODS
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).


RESULTS
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.


CONCLUSIONS
Casopitant is a dose- and duration-dependent weak to moderate inhibitor of CYP3A.
Zamuner
Stefano
S
GlaxoSmithKline, Verona, Italy GlaxoSmithKline, Research Triangle Park, NC, USA.
Johnson
Brendan M
BM
Pagliarusco
Sabrina
S
Fina
Paolo
P
Peroni
Michela
M
Fiore
Monica
M
Adams
Laurel M
LM
Fernandes
Sofia A
SA
D000328:Adult; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D015331:Cohort Studies; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D008875:Middle Aged; D064729:Neurokinin-1 Receptor Antagonists; D009543:Nifedipine / Q000493:pharmacokinetics*; D010879:Piperazines / Q000493:pharmacokinetics*; D010880:Piperidines / Q000493:pharmacokinetics*; D055815:Young Adult; D014508:Urea
D002121:Calcium Channel Blockers; D003577:Cytochrome P-450 Enzyme System; D006993:Hypnotics and Sedatives; D008874:Midazolam; D064729:Neurokinin-1 Receptor Antagonists; D009543:Nifedipine; D010879:Piperazines; D010880:Piperidines; C531951:casopitant; D014508:Urea