Oral topotecan: Bioavailability, pharmacokinetics and impact of ABCG2 genotyping in Chinese patients with advanced cancers.
Oral topotecan (Hycamtin(®)) has been recently approved for the treatment of relapsed small cell lung cancer (SCLC) in 2007, however, the bioavailability and pharmacokinetic data of topotecan for Chinese patients is still limited. Xinze(®) is a new and the only capsule formulation of topotecan used in China that is similar to Hycamtin(®). The current study aimed to investigate the absolute bioavailability and pharmacokinetics of Xinze(®) in Chinese patients with advanced cancers. On day 1, an IV dose of 1.5 mg/m(2)/d as a 30 min continuous infusion was administered. Patients took the oral topotecan at one of two dose levels: 1.5 mg/m(2)/d (six patients) or 1.9 mg/m(2)/d (seven patients) on day 2. Plasma pharmacokinetics of total topotecan and topotecan in the lactone form were performed on both days using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Single-nucleotide polymorphisms (SNPs) identified in exon 5 (421C>A) and in exon 2 (34G>A) in ATP-binding cassette sub-family G member 2 (ABCG2) were analyzed by direct sequencing. Safety assessments were performed throughout the study. The maximum plasma concentration (Cmax) reached at 1-2 h and the elimination half-life time (T1/2) was approximately 4.2 h after oral administration. The absolute bioavailability of total topotecan in the 1.5 mg/m(2)/d and 1.9 mg/m(2)/d groups averaged 41.23 ± 11.8% and 36.00 ± 14.8%, respectively. The patients with heterozygous SNPs had essentially the same bioavailability and pharmacokinetics. The bioavailability of topotecan after oral administration illustrates good systemic exposure at dosages of 1.5 mg/m(2)/d and 1.9 mg/m(2)/d over a five-day schedule in Chinese patients. On a dose-normalized basis, the values of Cmax and AUC0-t for total topotecan in Chinese patients were higher than in Caucasians following oral and intravenous administration, while the T1/2 was consistent.
Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, 17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, PR China.
Ning
N
Li
Yuanyuan
Y
Song
Ping
P
Du
Yinchen
Y
Shen
Jianliang
J
Yang
Lin
L
Gui
Shuai
S
Wang
Jianfei
J
Wang
Yan
Y
Sun
Xiaohong
X
Han
Yuankai
Y
Shi
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D001682:Biological Availability; D002681:China; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019772:Topotecan / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D019772:Topotecan
ABCG2; ATP-binding cassette sub-family G member 2; AUC(0–t); AUC(0–∞); Bioavailability; C(max); Chinese; MTD; Oral topotecan; Pharmacokinetics; SCLC; SNPs; T(1/2); UHPLC-MS/MS; area under the curve extrapolated to infinity; area under the curve up to the latest measured time point; elimination half-life time; maximum plasma concentration; maximum tolerated dose; single-nucleotide polymorphisms; small cell lung cancer; ultra-high-performance liquid chromatography-tandem mass spectrometry