An open-label, randomized, two-way crossover study to evaluate the potential inhibition of GW572016 metabolism by ketoconazole
Deborah Ann Smith, Chester L. Bowen, Jill M Herendeen, Andrew G. Stead, Kevin M. Koch, B. P. Andrew · Journal of Clinical Oncology · 2004
3071 Background: GW572016 is an oral, dual EGFR/ErbB2 tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer growth. In vitro studies indicate that GW572016 is metabolized predominantly by CYP3A4 and CYP3A5, and to lesser extent by CYP2C19. Therefore, the potential for a drug-drug interaction exists when GW572016 is co-administered with drugs that modulate CYP3A4 activity. The objective of this study was to assess the effect of ketoconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics (PK) of GW572016. Methods: This was an open-label, randomized, two-way crossover study in healthy adult subjects. Each treatment period was separated by a 7-day wash-out period. In Treatment A, randomized subjects received a single oral dose of 100 mg GW572016. Subjects randomized to Treatment B received ketoconazole 200 mg BID for 7 days. On Day 4 of Treatment B, a single oral dose of GW572016 was co-administered with ketoconazole. Plasma concentrations of GW572016 were obtained over a 72-hour period during each treatment period. Results: Twenty-two subjects (1 F: 21 M), median age 27.5 years (range 20–55 years) were enrolled in this study. Geometric least square means and 90% confidence interval estimates for AUCinf,Cmax and t1/2 ratios are listed in the table below. Ketoconazole treatment resulted in a 3.6-fold increase in the exposure of GW572016. Conclusion: In conclusion, exposure following a single oral dose of GW572016 was increased after administration of ketoconazole. A decrease in the dose of GW572016 may be necessary to avoid enhanced pharmacodynamic effects and/or adverse events when co-administered with CYP3A4 inhibitors such as ketoconazole. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline