Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours

Lassen, U. et al. (2013) Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours. Cancer Chemotherapy and Pharmacology, 71(2), pp. 543-549. (doi: 10.1007/s00280-012-2038-0)

Abstract

<p>Purpose: To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours.</p> <p>Methods: In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib.</p> <p>Results: In the ketoconazole study, 46 patients were dosed; 38 were evaluable for C ss,max, 36 for AUCss. gMean AUCss and C ss,max for cediranib 20 mg increased by 21 % (94 % CI 9–35 %) and 26 % (94 % CI 10–43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C ss,max and 41 for AUCss. gMean AUCss and C ss,max for cediranib 45 mg decreased by 39 % (90 % CI 34–43 %) and 23 % (90 % CI 16–30 %), respectively, in the presence of rifampicin. gMean ratios for AUCss and C ss,max were >1 for ketoconazole and >1 for rifampicin and CIs were outside the pre-specified equivalence boundaries, indicating a statistically significant effect. Significant inter-patient variability in cediranib AUCss and C ss,max was observed. The safety profile of cediranib was similar to that reported previously.</p> <p>Conclusions: Co-administration of ketoconazole or rifampicin had statistically significant effects on steady-state pharmacokinetics of cediranib in patients with advanced solid tumours. Therefore, caution is advised when administering cediranib with potent enzyme inhibitors or inducers.</p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Evans, Professor Jeff
• Authors: Lassen, U., Miller, W.H., Hotte, S., Evans, T.R.J., Kollmansberger, C., Adamson, D., Nielsen, D.L., Spicer, J., Chen, E., Meyer, T., Brown, K., Rafi, R., and Sawyer, M.B.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Chemotherapy and Pharmacology
• ISSN: 0344-5704
• Published Online: 30 November 2012