Erschienen in:
01.04.2012 | Original Article
The effect of dacomitinib (PF-00299804) on CYP2D6 activity in healthy volunteers who are extensive or intermediate metabolizers
verfasst von:
Carlo L. Bello, Robert R. LaBadie, Grace Ni, Tanya Boutros, Carol McCormick, M. Noella Ndongo
Erschienen in:
Cancer Chemotherapy and Pharmacology
|
Ausgabe 4/2012
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Abstract
Purpose
This study evaluated the effect of a single 45-mg dose of dacomitinib (PF-00299804), an irreversible small-molecule inhibitor of human epidermal growth factor receptors-1, -2, and -4, on CYP2D6 activity in healthy volunteers (HV) using dextromethorphan (DM), a selective CYP2D6 probe.
Methods
Fourteen male HVs were enrolled in this open-label, randomized, cross-over, single-dose study of DM alone or with dacomitinib. Each HV received both treatments separated by a 14-day washout period. The pharmacokinetics of DM, dextrorphan (DX; the major DM metabolite), dacomitinib and PF-05199265 (an active metabolite of dacomitinib) were calculated.
Results
When combined with dacomitinib, the ratio of adjusted geometric means (90% CI) of DM area under the concentration–time curve (AUC)last was 955% (90% CI: 560%, 1,630%) and maximum plasma concentration (C
max) was 973% (90% CI: 590%, 1,606%), compared with DM alone. For dacomitinib plus DM, exposures were consistent with those in patients receiving single-dose dacomitinib. Terminal elimination half-life (t
1/2) was 51.4 h. Mild and moderate treatment-related adverse events were reported. No HV withdrew from the study.
Conclusions
Single-dose administration of dacomitinib plus DM was safe and well tolerated in HVs and resulted in a significant increase in systemic exposures of DM in extensive metabolizers. No effect was observed on the pharmacokinetics of dacomitinib. Drug–drug interaction may occur when dacomitinib is concomitantly administered with therapeutic agents metabolized by cytochrome P450 (CYP) 2D6. Administration of drugs which are highly dependent on CYP2D6 metabolism may require dose adjustment, or substitution with an alternative medication.