PMID- 27270784 OWN - NLM STAT- MEDLINE DCOM- 20170201 LR - 20221207 IS - 1349-7006 (Electronic) IS - 1347-9032 (Print) IS - 1347-9032 (Linking) VI - 107 IP - 8 DP - 2016 Aug TI - Pharmacokinetic profiles of significant adverse events with crizotinib in Japanese patients with ABCB1 polymorphism. PG - 1117-23 LID - 10.1111/cas.12983 [doi] AB - Crizotinib is a standard treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC). We undertook this study to investigate the pharmacokinetics of crizotinib and clinical and pharmacogenomic factors that may increase the risk of adverse events (AEs). We defined clinically significant AEs as grade 4 hematological toxicity, grade >/=3 non-hematological toxicity, and any grade of interstitial lung disease. Eight subjects with ALK-positive NSCLC scheduled to receive crizotinib 250 mg twice daily were studied. Six patients were female and two were male, and most of the patients had low body weight with a median body weight of 46.8 kg (range, 42.4-61.0 kg). All patients developed AEs, five developing six clinically significant AEs. Six patients required dose reduction. In pharmacokinetic analysis, blood samples were obtained on days 1 and 15. The mean area under the plasma concentration-time curve from 0-12 h (AUC0-12 ) on day 15 was significantly increased in patients with clinically significant AEs (n = 5) compared with those without (n = 3) (P = 0.04). Genetic polymorphisms of ABCB1 were analyzed. One patient with the ABCB1 1236TT-2677TT-3435TT genotype was an outlier, with an AUC0-12 and peak concentrations on day 15 of 2.84x and 2.61x the mean, respectively, compared with those with other genotypes. Our results suggest that some Japanese NSCLC patients treated with crizotinib developed clinically significant toxicities that were related to altered pharmacokinetics parameters due to genotype and body weight factors. CI - (c) 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. FAU - Fujiwara, Yutaka AU - Fujiwara Y AD - Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. AD - Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan. FAU - Hamada, Akinobu AU - Hamada A AD - Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan. FAU - Mizugaki, Hidenori AU - Mizugaki H AD - Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. AD - First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan. FAU - Aikawa, Hiroaki AU - Aikawa H AD - Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan. FAU - Hata, Toshiyuki AU - Hata T AD - Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan. FAU - Horinouchi, Hidehito AU - Horinouchi H AD - Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Kanda, Shintaro AU - Kanda S AD - Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Goto, Yasushi AU - Goto Y AD - Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Itahashi, Kota AU - Itahashi K AD - Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Nokihara, Hiroshi AU - Nokihara H AD - Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Yamamoto, Noboru AU - Yamamoto N AD - Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. AD - Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan. FAU - Ohe, Yuichiro AU - Ohe Y AD - Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. LA - eng PT - Journal Article DEP - 20160721 PL - England TA - Cancer Sci JT - Cancer science JID - 101168776 RN - 0 (ABCB1 protein, human) RN - 0 (ATP Binding Cassette Transporter, Subfamily B) RN - 0 (Pyrazoles) RN - 0 (Pyridines) RN - 53AH36668S (Crizotinib) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM MH - ATP Binding Cassette Transporter, Subfamily B/genetics MH - Aged MH - Anaplastic Lymphoma Kinase MH - Asian People/genetics MH - Body Weight MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/*metabolism MH - Crizotinib MH - Female MH - Genotype MH - Humans MH - Japan MH - Lung Neoplasms/*drug therapy/genetics/*metabolism MH - Male MH - Middle Aged MH - Polymorphism, Genetic/*genetics MH - Polymorphism, Single Nucleotide/genetics MH - Pyrazoles/*adverse effects/*pharmacokinetics MH - Pyridines/*adverse effects/*pharmacokinetics MH - Receptor Protein-Tyrosine Kinases/metabolism PMC - PMC4982581 OTO - NOTNLM OT - Crizotinib OT - EML4-ALK fusion protein OT - non-small-cell lung cancer OT - pharmacogenomics OT - pharmacokinetics EDAT- 2016/06/09 06:00 MHDA- 2017/02/02 06:00 PMCR- 2016/08/01 CRDT- 2016/06/09 06:00 PHST- 2016/03/14 00:00 [received] PHST- 2016/05/24 00:00 [revised] PHST- 2016/06/06 00:00 [accepted] PHST- 2016/06/09 06:00 [entrez] PHST- 2016/06/09 06:00 [pubmed] PHST- 2017/02/02 06:00 [medline] PHST- 2016/08/01 00:00 [pmc-release] AID - CAS12983 [pii] AID - 10.1111/cas.12983 [doi] PST - ppublish SO - Cancer Sci. 2016 Aug;107(8):1117-23. doi: 10.1111/cas.12983. Epub 2016 Jul 21.