Ascending Single-Dose Study of the Safety Profile, Tolerability, and Pharmacokinetics of Bosutinib Coadministered With Ketoconazole to Healthy Adult Subjects

• Published in: Clinical therapeutics Vol. 34; no. 9; pp. 2011 - 2019.e1
• Main Authors: Abbas, Richat, Leister, Cathie, Gaaloul, Myriam El, Chalon, Stephan, Sonnichsen, Daryl
• Format: Journal Article
• Language: English
• Published: Bridgewater, NJ EM Inc USA 01.09.2012; Elsevier; Elsevier Limited
• Subjects: Administration, Oral; Adolescent; Adult; Aniline Compounds - administration & dosage; Aniline Compounds - adverse effects; Aniline Compounds - pharmacokinetics; Antifungal Agents - pharmacology; Area Under Curve; Biological and medical sciences; bosutinib; Butter; Chromosomes; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Drug Interactions; Drug therapy; Food; Gastrointestinal diseases; Humans; Internal Medicine; ketoconazole; Ketoconazole - pharmacology; Male; Medical Education; Medical sciences; Middle Aged; Nitriles - administration & dosage; Nitriles - adverse effects; Nitriles - pharmacokinetics; pharmacokinetics; Pharmacology. Drug treatments; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Quinolines - administration & dosage; Quinolines - adverse effects; Quinolines - pharmacokinetics; Studies; Substance abuse treatment; tyrosine kinase inhibitor; Young Adult; Philadelphia Pennsylvania; pharmacokinetics; ketoconazole; tyrosine kinase inhibitor; bosutinib; Antineoplastic agent; Human; Imidazole derivatives; Healthy subject; Ketoconazole; Enzyme; Tyrosine kinase inhibitor; Toxicity; Transferases; Single dose; Enzyme inhibitor; Bosutinib; Antifungal agent; Safety; Pharmacokinetics; Protein-tyrosine kinase
• ISSN: 0149-2918; 1879-114X; 1879-114X
• DOI: 10.1016/j.clinthera.2012.07.006

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. 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. 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. 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 Cmax and 2980 (802) to 23,000 (4020) ng·h/mL for AUC0–∞; mean AUC0–24 and AUC0–last ranged from 876 (234) to 7080 (1640) ng· h/mL and from 2740 (854) to 22,200 (3630) ng · h/mL, respectively. Cmax and AUC were linear and dose proportional. Mean Cmax at 600 mg was 2.1-fold higher than the steady-state Cmax previously observed for patients with chronic myelogenous leukemia who received bosutinib 500 mg once daily with food. 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.