Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer [Support Care Cancer] Journal article | | Title | Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron. | | Author(s) | Adams LM, Johnson B, Zhang K, Yue L, Kirby LC, Lebowitz P, Stoltz R | | Institution | GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA. laurel.m.adams@gsk.com | | Source | Support Care Cancer 2009 Sep; 17(9):1187-93. | | Abstract | OBJECTIVE: The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron.
MATERIALS AND METHODS: In a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100 mg once daily for 3 days) or oral granisetron (2 mg once daily for 3 days) alone (period 1) and combined with oral casopitant, 150 mg day 1, 50 mg days 2 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on days 1 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort.
RESULTS: The largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on day 1 and 30% increase in Cmax on days 1 and 3. All other changes in hydrodolasetron exposure were <20%, and granisetron exposure was not altered to any relevant extent (<11%).
CONCLUSION: None of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 19205754 |
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