Clinical pharmacology and pharmacogenetics of flavopiridol 1-h i.v. infusion in patients with refractory neoplasms.
A phase I trial of flavopiridol administered as a 1-h i.v. infusion schedule was explored. Fifty-five patients were treated with flavopiridol at doses ranging from 12 to 78 mg/m2 daily for 5, 3 and 1 day every 3 weeks. Pharmacokinetic and pharmacodynamic analysis was performed together with analysis of a promoter polymorphism of the UGT1A1 gene. Peak concentrations and areas under the time-concentration curve of flavopiridol were linear within the doses studied. Estimated clearance was 13.8+/-4.9 l/h/m2 (mean+/-SD), volume of distribution at steady-state was 64.9+/-43.4 l/m2 and elimination half-life was 5.2+/-4.9 h. Forty-nine of the 55 patients were genotyped for the promoter polymorphism. We found five (10%) homozygous and 11 (22%) heterozygous patients for UGT1A1*28, which alters the reference sequence (TA)6TAA to the variant (TA)7TAA by an extra TA dinucleotide insertion within the TATA box. One patient was heterozygous for the sequence of five TA repeats, (TA)5TAA. The remaining 32 patients did not have the UGT1A1*28 allele (homozygous for the reference sequence). Associations of the UGT1A1 promoter genotype with either the pharmacokinetic parameters or diarrhea (occurrence and severity) were not observed in this study. The pharmacogenetic analyses did not support that the UGT1A1 promoter polymorphism could affect flavopiridol pharmacokinetics and alter the incidence and severity of diarrhea induced by the drug.
Zhai
Suoping
S
Clinical Pharmacology Research Core, Medical Oncology Clinical Research Unit Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Sausville
Edward A
EA
Senderowicz
Adrian M
AM
Ando
Yuichi
Y
Headlee
Donna
D
Messmann
Richard A
RA
Arbuck
Susan
S
Murgo
Anthony J
AJ
Melillo
Giovanni
G
Fuse
Eiichi
E
Figg
William D
WD
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010597:Pharmacogenetics; D010601:Pharmacology, Clinical; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
D000970:Antineoplastic Agents; D018844:Cyclin-Dependent Kinases; D005419:Flavonoids; D014453:Glucuronosyltransferase; D010880:Piperidines; D000099148:UGT1A1 Enzyme; C077990:alvocidib