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01.09.2009 | Original Article | Ausgabe 9/2009 Open Access

Supportive Care in Cancer 9/2009

Impact of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of ondansetron and dexamethasone

Zeitschrift:
Supportive Care in Cancer > Ausgabe 9/2009
Autoren:
Brendan Johnson, Laurel Adams, Emily Lu, Ke Zhang, Peter Lebowitz, Christian Lates, Robert Blum
Wichtige Hinweise
Presented as an invited lecture at the Supportive Care in Cancer MASCC/ISOO 2008 International Symposium in Houston, Texas on June 26–28, 2008.
This work was sponsored by GlaxoSmithKline. C Lates and R Blum received funding from GlaxoSmithKline to conduct this study. All other authors were employees of GlaxoSmithKline.

Abstract

Introduction

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.

Materials and 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.

Conclusion

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.

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