PMID- 33771716 OWN - NLM STAT- MEDLINE DCOM- 20210621 LR - 20220219 IS - 1879-0720 (Electronic) IS - 0928-0987 (Linking) VI - 162 DP - 2021 Jul 1 TI - Evaluation of the pharmacokinetic effects of itraconazole on alflutinib (AST2818): an open-label, single-center, single-sequence, two-period randomized study in healthy volunteers. PG - 105815 LID - S0928-0987(21)00117-2 [pii] LID - 10.1016/j.ejps.2021.105815 [doi] AB - Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor for the treatment of lung cancer patients with T790M-resistant mutations. It is metabolized mainly by the CYP3A4 enzyme. At the same time, it has the potential to induce CYP3A4. In this study, we aimed to estimate the effect of itraconazole (a strong inhibitor of CYP3A4) on the pharmacokinetics of alflutinib. For this aim, a single-center, open-label, single-sequence, two-period trial was designed. The pharmacokinetic parameters of AST2818 and its active metabolite AST5902 were established from blood concentration measurements, and adverse events (AEs) of two periods of treatment were documented. For AST2818, the C(max), AUC(0-t), and AUC(0-infinity) in period II (coadministration of itraconazole) increased by 6.5 ng/mL, 1263.0 h*ng/mL, and 1067.0 h*ng/mL, respectively. And the corresponding 90% CIs were 1.23 (1.14-1.32), 2.41 (2.29-2.54), and 2.22 (2.11-2.34), respectively. The C(max), AUC(0-t), and AUC(0-infinity) of AST5902 in period II decreased by 4.849 ng/mL, 415.60 h*ng/mL, and 391.4 h*ng/mL, respectively. Moreover, the corresponding 90% CIs were 0.09 (0.08-0.10), 0.18 (0.17-0.19), and 0.14 (0.13-0.15), respectively. Nonetheless, in period II, plasma concentrations of total active components (AST2818 and AST5902) changed marginally. The AUC(0-infinity) of total active components increased 60%, and the corresponding C(max) increased 8%. Possible treatment-related AEs assessed by investigators were fewer in period II (23.3% vs 36.7%). In conclusion, the total exposure of AST2818 and active metabolite AST5902 increased following the coadministration of itraconazole, but it was still safe and well-tolerated. CI - Copyright (c) 2021. Published by Elsevier B.V. FAU - Heng, Jianfu AU - Heng J AD - Department of Clinical Pharmaceutical Research Institution, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. FAU - Tang, Qi AU - Tang Q AD - Department of Clinical Pharmaceutical Research Institution, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. FAU - Chen, Xue AU - Chen X AD - Department of Early Clinical Trail Center, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. FAU - Bao, Jingjing AU - Bao J AD - Shanghai Allist Pharmaceuticals Co., Ltd, Shanghai, 201203, China. FAU - Deng, Jun AU - Deng J AD - Department of Early Clinical Trail Center, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. FAU - Chen, Yong AU - Chen Y AD - Department of Early Clinical Trail Center, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. FAU - Zhao, Jiao AU - Zhao J AD - Department of Early Clinical Trail Center, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. FAU - Zhu, Songlin AU - Zhu S AD - Department of Clinical Pharmaceutical Research Institution, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. FAU - Liu, Xiaobao AU - Liu X AD - Department of Clinical Pharmaceutical Research Institution, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. FAU - Yang, Feng AU - Yang F AD - Department of Clinical Pharmaceutical Research Institution, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. FAU - Jiang, Yun AU - Jiang Y AD - Department of Clinical Pharmaceutical Research Institution, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. FAU - Yang, Nong AU - Yang N AD - Department of Lung Cancer and Gastroenterology, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. FAU - Li, Kunyan AU - Li K AD - Department of Clinical Pharmaceutical Research Institution, Hunan Cancer Hospital, Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan, 410013, China. Electronic address: likunyan@hnca.org.cn. LA - eng PT - Journal Article PT - Randomized Controlled Trial DEP - 20210323 PL - Netherlands TA - Eur J Pharm Sci JT - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JID - 9317982 RN - 0 (Indoles) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridines) RN - 0 (Pyrimidines) RN - 304NUG5GF4 (Itraconazole) RN - A49A7A5YN4 (aflutinib) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM EIN - Eur J Pharm Sci. 2022 Apr 1;171:106143. PMID: 35181200 MH - Area Under Curve MH - Cross-Over Studies MH - ErbB Receptors MH - Healthy Volunteers MH - Humans MH - Indoles MH - *Itraconazole MH - *Lung Neoplasms MH - Mutation MH - Protein Kinase Inhibitors MH - Pyridines MH - Pyrimidines OTO - NOTNLM OT - Alflutinib OT - CYP3A4 inhibitor OT - drug-drug-interactions OT - itraconazole OT - pharmacokinetic EDAT- 2021/03/28 06:00 MHDA- 2021/06/22 06:00 CRDT- 2021/03/27 05:50 PHST- 2020/08/26 00:00 [received] PHST- 2020/12/31 00:00 [revised] PHST- 2021/03/16 00:00 [accepted] PHST- 2021/03/28 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2021/03/27 05:50 [entrez] AID - S0928-0987(21)00117-2 [pii] AID - 10.1016/j.ejps.2021.105815 [doi] PST - ppublish SO - Eur J Pharm Sci. 2021 Jul 1;162:105815. doi: 10.1016/j.ejps.2021.105815. Epub 2021 Mar 23.