First-in-human, phase I single-ascending-dose study of the safety, pharmacokinetics, and relative bioavailability of sel
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PHASE I STUDIES
First-in-human, phase I single-ascending-dose study of the safety, pharmacokinetics, and relative bioavailability of selatinib, a dual EGFR-ErbB2 inhibitor in healthy subjects Meng-na Wang 1 & Yun Kuang 1 & Li-ying Gong 1,2,3 & Ye Hua 1 & Qi Pei 4 & Cheng-xian Guo 1,2 & Yu Cao 3 & Jie Huang 1,2 & Guo-ping Yang 1,2,4 Received: 6 May 2020 / Accepted: 28 May 2020 # The Author(s) 2020
Summary We assessed the pharmacokinetics and safety of a single oral administration of selatinib to healthy Chinese subjects and evaluated the potential bioavailability advantage of selatinib relative to lapatinib. Healthy subjects aged 18–40 years were enrolled in this two-part study: Part 1, a single ascending dose (50–500 mg), randomized, double-blind, placebo-control study with 64 subjects; and Part 2, an open-label, positive control, randomized, three-treatment, three-period, three-sequence crossover design study, with 6 subjects administered a single 500-mg dose of selatinib tablets (A), selatinib suspension (B), or lapatinib tablets C) per cycle. In part 1, selatinib was well-tolerated up to the planned maximum dose of 500 mg; thus the maximum tolerated dose was not attained. Twenty-two adverse events were observed in 19 (36.5%) of the 52 subjects administered the test drug. The most common drug-related adverse event was diarrhea. The mean selatinib peak plasma concentration was 69.4–494 ng/mL, which was achieved in a median peak time of 3.5–4.5 h, with a mean elimination half-life between 13.8 and 15.8 h. In Part 2, A and B showed similar bioavailability. Plasma exposure to the active drug (selatinib plus the metabolite, lapatinib) after A intake was more than two-fold higher than that of the same dose of C. In the dose range of 50–500 mg, selatinib was safe and well-tolerated by healthy Chinese subjects, and it conformed with linear pharmacokinetics. Active exposure to selatinib was much greater than that to lapatinib, supporting its development as an adjuvant for anticancer treatment. Keywords Tyrosine kinase inhibitor . Selatinib . First-in-human . Safety . Pharmacokinetics Meng-na Wang and Yun Kuang contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00959-6) contains supplementary material, which is available to authorized users. * Jie Huang [email protected] * Guo-ping Yang [email protected] 1
Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China
2
Research Center of Drug Clinical Evaluation of Central South University, Changsha, Hunan 410013, People’s Republic of China
3
Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China
4
Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China
Introduction Selatinib ditosilate, an oral, reversible, dual inhibitor of epidermal growth factor re
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