Flavopiridol pharmacogenetics: clinical and functional evidence for the role of SLCO1B1/OATP1B1 in flavopiridol disposition.
BACKGROUND
Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.


RESULTS
Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.


CONCLUSIONS
Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy.
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America.
Wenjun
W
Ni
Jia
J
Ji
Zunyan
Z
Dai
Audrey
A
Papp
Amy J
AJ
Johnson
Sunjoo
S
Ahn
Katherine L
KL
Farley
Thomas S
TS
Lin
James T
JT
Dalton
Xiaobai
X
Li
David
D
Jarjoura
John C
JC
Byrd
Wolfgang
W
Sadee
Michael R
MR
Grever
Mitch A
MA
Phelps
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000818:Animals; D002460:Cell Line; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D005419:Flavonoids; D014453:Glucuronosyltransferase; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C503999:SLCO1B1 protein, human; C000715591:UGT1A9 protein, human; C077990:alvocidib