Effect of Ketoconazole on the Pharmacokinetics of Oral Bosutinib in Healthy Subjects

Abstract

Bosutinib (SKI-606), a dual inhibitor of Src and Abl tyrosine kinases, is being developed for the treatment of chronic myelogenous leukemia. The effect of coadministration of ketoconazole on the pharmacokinetic (PK) profile of bosutinib was evaluated in an open-label, randomized, 2-period, crossover study. Healthy subjects (fasting) received a single dose of oral bosutinib 100 mg alone and with multiple once-daily doses of oral ketoconazole 400 mg. PK sampling occurred through 96 hours. The least square geometric mean treatment ratios (90% confidence interval [CI]) of C(max(bosutinib+ketoconazole))/C(max(bosutinib alone)), AUC(T(bosutinib+ketoconazole))/AUC(T(bosutinib alone)), and AUC((bosutinib+ketoconazole))/AUC((bosutinib alone)) were assessed. Compared with bosutinib administered alone, coadministration with ketoconazole increased bosutinib C(max) 5.2-fold, AUC(T) 7.6-fold, and AUC 8.6-fold. Ketoconazole coadministration decreased the mean apparent clearance of bosutinib approximately 9-fold and increased the mean (SD) terminal half-life from 46.2 (16.4) hours to 69.0 (29.1) hours. The incidence of adverse events (AEs) was comparable between the 2 treatments. The most common AEs were headache, nausea, and increased blood creatinine. No safety-related discontinuations or serious AEs occurred. These PK results indicate that bosutinib is susceptible to interaction with potent CYP3A4 inhibitors.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…Caution and periodic ECG monitoring are advised when using nilotinib 71, 73, 74, 76, 77, 79, 80. QTc prolongation was common (37%) in patients with hepatic impairment treated with bosutinib,10 but this was not seen in other smaller studies 11, 12. QTc prolongation was infrequent or absent with afatinib, crizotinib, ceritinib, dovitinib, imatinib, lapatinib, lenvatinib, nintedanib, pazopanib, and ponatinib 9, 14, 16, 17, 19, 24, 26, 27, 29, 30, 31, 32, 33, 35, 36, 38, 39, 72, 78, 81, 161, 162, 163, 164…”

Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects

“…Methods for extraction of bosutinib and its two most predominant metabolites (M2 and M5) were as described previously [22]. Plasma samples (100 μL), internal standard (d 8 -bosutinib, 250 ng/mL), carbonate buffer pH 10 (100 μL), and 1-chlorobutane (1000 μL) were added sequentially to a 96-well plate and mixed.…”

“…Preclinical data suggest that bosutinib is primarily metabolized in the liver by the cytochrome P450 (CYP) 3A4 enzyme of the CYP metabolic pathway [22], with no metabolism observed by other CYP enzymes, including CYP 3A5. The two predominant metabolites of bosutinib, oxydechlorinated bosutinib (M2) and N-desmethyl bosutinib (M5; Figure 1) [23], are relatively inactive, associated with little ( ≤ 5%) of the bosutinib activity observed in vitro (data on file).…”

“…Clinically, the pharmacokinetics of bosutinib is affected by coadministration with ketoconazole, an antifungal agent and potent CYP3A4 inhibitor [24], resulting in increased bosutinib exposures, peak plasma concentration (C max ), and area under the concentration-time curve (AUC) in healthy subjects [22]. Supratherapeutic exposures for bosutinib 500 mg when coadministered with ketoconazole were reported in a second study [25].…”

“…The results from coadministration of bosutinib with a CYP3A4 inhibitor [22] suggest that bosutinib may be susceptible to drug interactions with CYP3A4 inducers but with potentially opposite effects, including decreased bosutinib plasma concentrations, subtherapeutic exposures, and/or reduced clinical activity. Rifampin is an oral semisynthetic antibiotic that potently induces CYP3A4 and several other CYP enzymes [26][27][28] and is used for evaluating potential drug-drug interactions [24].…”