title: Ketoconazole and rifampin significantly affect the pharmacokinetics, but not the safety or QTc interval, of casopitant, a neurokinin-1 receptor antagonist.
abstract: Casopitant, an antiemetic, is a neurokinin-1 receptor antagonist metabolized primarily by cytochrome P450 3A4 (CYP3A4). Three phase 1 studies with 131 healthy subjects examined the impact of a strong CYP3A inhibitor (ketoconazole) and inducer (rifampin) on the pharmacokinetics and safety of casopitant. Oral casopitant was administered alone (study 1, 100-mg single dose; study 2, 150 mg on day 1, 50 mg on days 2 and 3; study 3, 150-mg single dose) with either 400 mg daily of oral ketoconazole or 600 mg daily of oral rifampin. Ketoconazole increased the maximum observed plasma concentration (C(max)) and area under the plasma concentration time curve to the last sampling time, t (AUC(0-t)) of single-dose casopitant 2.7-fold and 12-fold and increased the C(max) of 3-day casopitant 2.5-fold on day 1 and 2.9-fold on day 3, whereas AUC((0-tau)) increased 4.3-fold on day 1 and 5.8-fold on day 3. Neither safety signals nor prolongation of Fredericia-corrected QT was observed at these increased exposures in study 2. Repeat-dose rifampin reduced the C(max) and AUC((0-t)) of casopitant 96% and 90%, respectively. These clinical studies confirmed the role of CYP3A in the metabolism and disposition of casopitant. Coadministration of casopitant with strong inhibitors of CYP3A is likely to increase plasma exposure of casopitant, whereas coadministration with strong inducers of CYP3A is likely to decrease casopitant exposure and compromise efficacy.
authors.affiliation: PhD 5 Moore Drive, Research Triangle Park, NC 27709, USA. Brendan.M.Johnson@GSK.com
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Johnson
authors.forename: Laurel M
authors.initials: LM
authors.lastname: Adams
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Shelby D
authors.initials: SD
authors.lastname: Gainer
authors.forename: Lyndon C
authors.initials: LC
authors.lastname: Kirby
authors.forename: Robert A
authors.initials: RA
authors.lastname: Blum
authors.forename: Glen
authors.initials: G
authors.lastname: Apseloff
authors.forename: Royce A
authors.initials: RA
authors.lastname: Morrison
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Schutz
authors.forename: Peter F
authors.initials: PF
authors.lastname: Lebowitz
mesh_terms: D000293:Adolescent; D000328:Adult; D000932:Antiemetics / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D065692:Cytochrome P-450 CYP3A Inhibitors; D004562:Electrocardiography; D004790:Enzyme Induction; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008875:Middle Aged; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*; D055815:Young Adult; D014508:Urea
chemical_list: D000932:Antiemetics; D065692:Cytochrome P-450 CYP3A Inhibitors; D007654:Ketoconazole; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D010880:Piperidines; D012293:Rifampin; C531951:casopitant; D014508:Urea