Impact of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of ondansetron and dexamethasone.
BACKGROUND
Pharmacokinetic interactions between casopitant (a substrate and weak to moderate inhibitor of CYP3A), dexamethasone (a substrate and weak inducer of CYP3A), and ondansetron (a mixed CYP substrate) were evaluated in a two-part, three-period, single-sequence study in two groups of healthy subjects.


METHODS
Part 1: subjects received oral casopitant (regimen A); oral dexamethasone and IV ondansetron (regimen B); and oral casopitant, a reduced dose of oral dexamethasone, and IV ondansetron (regimen C). Part 2: subjects received oral casopitant (regimen D); IV dexamethasone and oral ondansetron (regimen E); and oral casopitant, IV dexamethasone, and oral ondansetron (regimen F). Each regimen was separated by 14 days.


RESULTS
Casopitant AUC in regimen C was increased 28% on day 1 but decreased 34% on day 3 compared to casopitant alone in regimen A. When given with casopitant and ondansetron in regimen C, dexamethasone AUC was 17% lower on day 1, but similar on day 3, compared to regimen B (representing dose-normalized increases in exposure of 39% and 108%, respectively). Ondansetron exposure was equivalent in regimens B and C. Casopitant AUC in regimen F was similar to regimen D on days 1 and 3. Dexamethasone AUC increased 21% when given with oral casopitant and oral ondansetron (regimen F compared to regimen E). Ondansetron exposure was equivalent in regimens E and F.


CONCLUSIONS
When repeat-dose oral dexamethasone is to be coadministered with oral casopitant, a reduction in dexamethasone dose may be considered; however, no change in casopitant dose is required. Ondansetron exposure was not affected by coadministration with casopitant.
Johnson
Brendan
B
GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, Durham, NC 27709, USA.
Adams
Laurel
L
Lu
Emily
E
Zhang
Ke
K
Lebowitz
Peter
P
Lates
Christian
C
Blum
Robert
R
D000293:Adolescent; D000328:Adult; D000932:Antiemetics / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control; D064729:Neurokinin-1 Receptor Antagonists; D017294:Ondansetron / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control; D055815:Young Adult; D014508:Urea
D000932:Antiemetics; D003907:Dexamethasone; D064729:Neurokinin-1 Receptor Antagonists; D017294:Ondansetron; D010879:Piperazines; D010880:Piperidines; C531951:casopitant; D014508:Urea