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Effect of coadministration of ketoconazole, a strong CYP3A4 inhibitor, on pharmacokinetics and tolerability of motesanib diphosphate (AMG 706) in patients with advanced solid tumors

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Summary

Motesanib diphosphate is a novel angiogenesis inhibitor selectively targeting vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor and stem cell factor receptor. The purpose of this phase 1b, drug–drug interaction study was to investigate the effect of ketoconazole, a strong inhibitor of the cytochrome P450 3A4 isoenzyme, on the pharmacokinetics and tolerability of motesanib diphosphate. Fourteen patients with advanced solid tumors refractory to standard treatment were enrolled and received motesanib diphosphate 50 mg once daily from day 1 through 15. Patients were randomized to receive a single oral dose of ketoconazole 400 mg either on day 8 (Sequence 1; n = 7) or day 15 (Sequence 2; n = 7), while pharmacokinetic samples were collected. After completion of this part (day 16), 13 patients received an escalated once-daily dose of motesanib diphosphate 125 mg. Evaluable pharmacokinetic data (n = 12) suggest that ketoconazole modestly increased motesanib exposure. The motesanib area under the concentration–time curve (AUC) from 0 to 24 h increased by 86% (90% CI, 1.50–2.29; P < 0.001) and the maximum plasma concentration (C max) by 35% (90% CI, 1.12–1.64; P = 0.02), compared with motesanib diphosphate administration alone. The tolerability profile (with or without ketoconazole coadministration) was consistent with that from other motesanib diphosphate monotherapy studies. Treatment-related adverse events were mild to moderate and commonly included fatigue (50% of patients), hypertension (43%), diarrhea (21%), dizziness (14%), paresthesia (14%), and vomiting (14%). Hypertension was the most common related grade 3 event (21%). No grade 4 or 5 treatment-related adverse events occurred.

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Acknowledgment

The authors would like to thank Tina Guthrie for excellent data management; Bernd Bruenner, Ph.D., Shekman Wang, Ph.D., Sekhar Surapaneni, Ph.D., and Gil Leong, B.S., for bioanalytical and pharmacokinetic support; Bart Mitchell and Mandy Parson for clinical management support; and Linda Merkel, Ph.D. and Rick Davis, M.S., R.Ph., whose work was funded by Amgen Inc., for assistance in drafting this manuscript.

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Authors and Affiliations

  1. Karmanos Cancer Institute, 4100 John R, 4 HWCRC, Detroit, MI, 48201, USA

    Patricia LoRusso, Elisabeth I. Heath, Lisa Malburg & Mary Jo Pilat

  2. Amgen Inc., Thousand Oaks, CA, USA

    Jesse McGreivy, Yu-Nien Sun, Rebeca Melara, Lucy Yan, Megan Ingram, Jeffrey Wiezorek & Li Chen

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  1. Patricia LoRusso
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Correspondence to Patricia LoRusso.

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LoRusso, P., Heath, E.I., McGreivy, J. et al. Effect of coadministration of ketoconazole, a strong CYP3A4 inhibitor, on pharmacokinetics and tolerability of motesanib diphosphate (AMG 706) in patients with advanced solid tumors. Invest New Drugs 26, 455–462 (2008). https://doi.org/10.1007/s10637-008-9144-1

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  • DOI: https://doi.org/10.1007/s10637-008-9144-1

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