Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6. (4th May 2018)

• Record Type: Journal Article
• Authors: Chen, Xia; Jiang, Ji; Giri, Nagdeep; Hu, Pei
• Is Part Of: Xenobiotica. Volume 48:Number 5(2018:May)
• Page Start: 459
• Page End: 466
• Publication Date: 2018-05-04
• Subjects: China -- CYP2D6 -- dacomitinib -- PF-00299804 -- PF-05199265 -- pharmacokinetics -- tyrosine kinase inhibitor; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2017.1342881
• Languages: English
• ISSNs: 0049-8254

Abstract

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 ( C max ) were 1662 ngċh/mL (26%) and 21.51 ng/mL (27%), respectively, for dacomitinib and 469 ngċh/mL (65%) and 5.54 ng/mL (79%) for PF-05199265. Median times to C max 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 C max . 4. Dacomitinib total (AUCinf ) and peak exposures ( C max ) 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).