Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6.
Article Details
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Chen X, Jiang J, Giri N, Hu P
Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6.
Xenobiotica. 2018 May;48(5):459-466. doi: 10.1080/00498254.2017.1342881. Epub 2017 Aug 18.
- PubMed ID
- 28648122 [ View in PubMed]
- Abstract
1. This study aimed to characterise the pharmacokinetics of dacomitinib, a pan-human epidermal growth factor receptor tyrosine kinase inhibitor, and its metabolite, PF-05199265, in healthy Chinese subjects. 2. In this open-label, single-centre, nonrandomised study (NCT02097433), 14 subjects received a single dacomitinib 45-mg oral dose. Pharmacokinetic samples for dacomitinib and PF-05199265 were collected pre- and postdose. Subjects were genotyped for cytochrome P450 (CYP)2D6 metaboliser status. Safety was assessed throughout the study. 3. The geometric mean (per cent coefficient of variability) area under the concentration-time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 1662 ngch/mL (26%) and 21.51 ng/mL (27%), respectively, for dacomitinib and 469 ngch/mL (65%) and 5.54 ng/mL (79%) for PF-05199265. Median times to Cmax were 8 and 4 h postdose for dacomitinib and PF-05199265, respectively; mean terminal half-life of dacomitinib was 62.7 h. Geometric mean apparent clearance and volume of distribution of dacomitinib were 27.06 L/h and 2415 L, respectively. The metabolite PF-05199265-to-dacomitinib ratios were 0.2907 for AUCinf and 0.2656 for Cmax. 4. Dacomitinib total (AUCinf) and peak exposures (Cmax) were similar among subjects with different CYP2D6 genotypes, whereas both parameters for PF-05199265 were higher in extensive metabolisers (n = 5) versus intermediate metabolisers (n = 8).
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Dacomitinib Cytochrome P450 2C9 Protein Humans NoSubstrateDetails Dacomitinib Cytochrome P450 2D6 Protein Humans UnknownSubstrateInhibitorDetails Dacomitinib Cytochrome P450 3A4 Protein Humans NoSubstrateDetails - Drug Reactions
Reaction Details - Food Interactions
Drug Interaction Dacomitinib Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of dacomitinib. Dacomitinib Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of dacomitinib.
