Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron

Laurel M Adams, Brendan Johnson, Ke Zhang, Lin Yue, Lyndon C Kirby, Peter Lebowitz, Randall Stoltz, Laurel M Adams, Brendan Johnson, Ke Zhang, Lin Yue, Lyndon C Kirby, Peter Lebowitz, Randall Stoltz

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.

Figures

Fig. 1
Fig. 1
Day 1 and day 3 hydrodolasetron AUC(0-τ) and Cmax when a 3-day regimen of 100 mg oral dolasetron is given alone and in combination with a 3-day oral regimen of casopitant in CYP2D6 EMs (circles) and CYP2D6 PMs (triangles)
Fig. 2
Fig. 2
Day 1 and day 3 granisetron AUC(0-τ) and Cmax when a 3-day regimen of 2 mg oral granisetron is given alone and in combination with a 3-day oral regimen of casopitant

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