Presented as an invited lecture at the Supportive Care in Cancer MASCC/ISOO 2008 International Symposium in Houston, TX, USA on June 26–28, 2008
This work was sponsored by GlaxoSmithKline. R Stoltz received funding from GlaxoSmithKline to conduct this study. All other authors were employees of GlaxoSmithKline.
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.
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.
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%).
None of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated.
Aventis (2006) Anzemet prescribing information. June
Bloomer JC, Baldwin SJ, Smith GJ et al (1994) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron. Br J Clin Pharmacol 38:557–566 PubMed
De Mulder PH, Seynaeve C, Vermorken JB et al (1990) Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double-blind, crossover study. Ann Intern Med 113:834–840 PubMed
Diemunsch P, Schoeffler P, Bryssine B et al (1999) Antiemetic activity of the NK1 receptor antagonist GR205171 in the treatment of established postoperative nausea and vomiting after major gynaecological surgery. Br J Anaesthesia 82:274–276.1
Gan TJ, Apfel CC, Kovac A (2007) A randomized, double-blind comparison of the NK 1 antagonist, aprepitant. Ondansetron Prev Postoperative Nausea Vomiting Anesth Analg 104(5):1082–1089
Grunberg S (2008) Phase III results of a novel neurokinin-1 (NK-1) receptor antagonist, casopitant: single oral and 3-day oral dosing regimens for chemotherapy-induced nausea and vomiting (CINV) in patients (Pts) receiving moderately emetogenic chemotherapy (MEC). J Clin Oncol 26:9540. doi: 10.1200/JCO.2008.18.7559 CrossRef
Herrstedt J (2008) Phase III results for the novel neurokinin-1 (NK-1) receptor antagonist, casopitant: single oral dosing regimen for chemotherapy-induced nausea and vomiting (CINV) in patients (Pts) receiving highly emetogenic chemotherapy (HEC). J Clin Oncol 26:9549
Hesketh PJ (2004) Management of nausea and vomiting in cancer and cancer treatment. Jones & Bartlett, Sudbury
Johnson B, Adams L, Lu E et al (2008) Minimal impact of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of ondansetron and dexamethasone. J Support Care Cancer, companion paper. doi: 10.1007/s00520-008-0572-5
Johnson B, Zhang K, Fang L et al (2008) Use of modeling and simulation in the QTC assessment of casopitant. J Clin Pharmacol 48:1114. doi: 10.1177/0091270008321940. Abstract 67
Keung ACF, Landriault H, LeFebvre M et al (1997) Pharmacokinetics and safety of single intravenous and oral doses of dolasetron mesylate in healthy women. Biopharm Drug Dispos 18(4):361–369 doi: 10.1002/(SICI)1099-081X(199705)18:4<361::AID-BDD25>3.0.CO;2-I PubMedCrossRef
Marty M, Pouillart P, Scholl S et al (1990) Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 322:816–821 PubMed
MGI Pharma (2007) Aloxi prescribing information. September
Multinational Association of Supportive Care in Cancer (2008) Antiemetic subcommittee guidelines. http://www.mascc.org
Sanwald P, David M, Dow J (1996) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron. Drug Metab Dispos 24(5):602–609 PubMed
Singla N, Chung F, Singla S, Grenier A, Kutsogiannis D, Kett A, Pergolizzi J, Russo M (2006) Efficacy of oral casopitant mesylate, a novel neurokinin-1 receptor antagonist, with intravenous ondansetron HCl in the prevention of postoperative nausea and vomiting (PONV) in high-risk patients. Eur J Anaesthesiol 23(S37):A614
- Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron
Laurel M. Adams
Lyndon C. Kirby
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