Pharmacokinetic profiles of significant adverse events with crizotinib in Japanese patients with ABCB1 polymorphism.
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 2.84× and 2.61× 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.
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.|Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
Yutaka
Y
Fujiwara
Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.
Akinobu
A
Hamada
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.|First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Hidenori
H
Mizugaki
Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.
Hiroaki
H
Aikawa
Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.
Toshiyuki
T
Hata
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Hidehito
H
Horinouchi
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Shintaro
S
Kanda
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Yasushi
Y
Goto
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Kota
K
Itahashi
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Hiroshi
H
Nokihara
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.|Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
Noboru
N
Yamamoto
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Yuichiro
Y
Ohe
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D044466:Asian People / Q000235:genetics; D001835:Body Weight; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000077547:Crizotinib; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011720:Pyrazoles / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011725:Pyridines / Q000009:adverse effects* / Q000493:pharmacokinetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
Crizotinib; EML4-ALK fusion protein; non-small-cell lung cancer; pharmacogenomics; pharmacokinetics