NDLI: Ascending single-dose study of the safety profile, tolerability, and pharmacokinetics of bosutinib coadministered with ketoconazole to healthy adult subjects.

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Ascending single-dose study of the safety profile, tolerability, and pharmacokinetics of bosutinib coadministered with ketoconazole to healthy adult subjects.

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Ascending single-dose study of the safety profile, tolerability, and pharmacokinetics of bosutinib coadministered with ketoconazole to healthy adult subjects.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Abbas, Richat Leister, Cathie El Gaaloul, Myriam Chalon, Stephan Sonnichsen, Daryl
Description	Country affiliation: United States Author Affiliation: Abbas R ( Department of Clinical Pharmacology, Pfizer Inc, Collegeville, Pennsylvania 19426, USA. richat.abbas-borhan@pfizer.com)
Abstract	BACKGROUND: Bosutinib (SKI-606) is an orally bioavailable, competitive tyrosine kinase inhibitor that selectively targets both Src and Abl tyrosine kinases. Bosutinib is metabolized primarily through the cytochrome P450 3A4 pathway. Inhibition of bosutinib metabolism by coadministration with the potent cytochrome P450 3A4 inhibitor ketoconazole could potentially increase plasma concentrations of bosutinib, allowing for the study of bosutinib tolerability at supratherapeutic concentrations in a healthy subject population. OBJECTIVE: This study assessed the safety profile, tolerability, and pharmacokinetics of different dose combinations of bosutinib coadministered with ketoconazole in healthy adults, and determined whether supratherapeutic concentrations of bosutinib can be achieved with ketoconazole. METHODS: This was a randomized, Phase I, double-blind, placebo-controlled, sequential-group study conducted in healthy adults. Single oral doses of bosutinib 100, 200, 300, 400, 500, and 600 mg or placebo were administered with ketoconazole and food on day 1; daily single oral doses of ketoconazole 400 mg were administered on days -1 and 1 through 4. RESULTS: Forty-eight subjects were enrolled. Their mean (SD) age was 32.0 (10.7) years (range, 18-50 years). The majority of the subjects (n = 44 [92%]) were white, 2 (4%) were black or African American, and 2 (4%) were of other races. Bosutinib was associated with acceptable tolerability at doses from 100 to 600 mg, with adverse events either mild (n = 30 [63%]) or moderate (n = 12 [25%]) in severity; no subject discontinued treatment due to adverse events, and no serious events were reported. Mean (SD) values for bosutinib 100 to 600 mg ranged from 58.4 (13.3) to 426 (100) ng/mL for C(max) and 2980 (802) to 23,000 (4020) ng·h/mL for AUC(0-∞); mean AUC(0-24) and AUC(0-last) ranged from 876 (234) to 7080 (1640) ng· h/mL and from 2740 (854) to 22,200 (3630) ng · h/mL, respectively. C(max) and AUC were linear and dose proportional. Mean C(max) at 600 mg was 2.1-fold higher than the steady-state C(max) previously observed for patients with chronic myelogenous leukemia who received bosutinib 500 mg once daily with food. CONCLUSIONS: Single doses of bosutinib up to 600 mg coadministered with multiple doses of ketoconazole were acceptably well tolerated in this small, selected group of healthy male volunteers. In addition, supratherapeutic exposure was achieved within this range for bosutinib when coadministered with ketoconazole. ClinicalTrials.gov identifier: NCT00777530.
File Format	HTM / HTML
ISSN	01492918
Issue Number	9
Volume Number	34
e-ISSN	1879114X
Journal	Clinical Therapeutics
Language	English
Publisher	Elsevier
Publisher Date	2012-09-01
Publisher Place	United States
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Discipline Pharmacology Aniline Compounds Pharmacokinetics Cytochrome P-450 Cyp3a Inhibitors Ketoconazole Pharmacology Nitriles Quinolines Administration, Oral Adolescent Adult Administration & Dosage Adverse Effects Antifungal Agents Area Under Curve Cytochrome P-450 Cyp3a Dose-response Relationship, Drug Double-blind Method Drug Interactions Humans Male Middle Aged Protein Kinase Inhibitors Young Adult Clinical Trial, Phase I Comparative Study Journal Article Randomized Controlled Trial Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmacology (medical)

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