title: Inhibitory effect of ketoconazole on the pharmacokinetics of a multireceptor tyrosine kinase inhibitor BMS-690514 in healthy participants: assessing the mechanism of the interaction with physiologically-based pharmacokinetic simulations.
abstract: BMS-690514, a selective inhibitor of the ErbB and vascular endothelial growth factor receptors, has shown antitumor activity in early clinical development. The compound is metabolized by multiple enzymes, with CYP3A4 responsible for the largest fraction (34%) of metabolism. It is also a substrate of P-glycoprotein (P-gp) in vitro. To assess the effect of ketoconazole on BMS-690514 pharmacokinetics, 17 healthy volunteers received 200 mg BMS-690514 alone followed by 100 mg BMS-690514 with ketoconazole (400 mg once daily for 4 days). The AUC(∞)  of 100 mg BMS-690514 concomitantly administered with ketoconazole was similar to that of 200 mg BMS-690514 alone. The dose-normalized C(max)  and AUC(∞)  of BMS-690514 from the 100-mg BMS-690514/400-mg ketoconazole treatment increased by 55% and 127%, respectively, relative to those from 200 mg BMS-690514 alone. Prediction of the drug-drug interaction (DDI) using a population-based simulator (Simcyp) indicated that, in addition to CYP3A4 inhibition, the inhibition of P-gp by ketoconazole in the intestine, liver, and kidneys must be invoked to fully account for the DDI observed. This finding suggests that the inhibition of P-gp by ketoconazole, along with its effect on CYP3A4, needs to be considered when designing a DDI study of ketoconazole with a victim drug that is a dual substrate.
authors: Bristol-Bristol Squibb, Princeton, NJ 08543-4000, USA.
authors: Zheng
authors: Z
authors: Yang
authors: Blisse
authors: B
authors: Vakkalagadda
authors: Guoxiang
authors: G
authors: Shen
authors: Christoph M
authors: CM
authors: Ahlers
authors: Teresa
authors: T
authors: Has
authors: Lisa J
authors: LJ
authors: Christopher
authors: John F
authors: JF
authors: Kurland
authors: Vikram
authors: V
authors: Roongta
authors: Eric
authors: E
authors: Masson
authors: Steven
authors: S
authors: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D003198:Computer Simulation; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005838:Genotype; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014227:Triazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D000970:Antineoplastic Agents; C552150:BMS-690514; D065692:Cytochrome P-450 CYP3A Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014227:Triazines; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011505:Protein-Tyrosine Kinases; D007654:Ketoconazole