Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition

Abstract

BackgroundFlavopiridol 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.Methodology/Principal FindingsThirty-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/SignificancePolymorphisms 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.

Genome-wide study of methotrexate clearance replicates SLCO1B1

“…The nonsynonymous rs4149056 (T521C) SNP has been the subject of multiple clinical studies of statins and other agents. 26,[30][31][32][33][34] However, even after adjustment for the …”

The Expression and Function of Organic Anion Transporting Polypeptides in Normal Tissues and in Cancer

“…OATP1B1 and OATP1B3 are thought to be important for uptake of a wide variety of xenobiotics into hepatocytes and can transport many of the aforementioned substrates, including estrone-3-sulfate and, in the case of OATP1B3, also testosterone (61). OATP1B1 has been implicated in the transport of the camptothecin analogs gimatecan and BNP1350 (73), the irinotecan metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) (74), the cyclin-dependent kinase inhibitor flavopiridol (75), the Her2 tyrosine kinase inhibitor CP-724,714 (76), methotrexate (18, 77), and the bile-acid cisplatin derivative cis -diammine-chloro-cholylglysinate-platinum II (78). OATP1B3 transports methotrexate (18); the taxanes paclitaxel (79, 80) and docetaxel (79); and, to a lesser extent, imatinib (71).…”

Exposure–Response Analysis of Alvocidib (Flavopiridol) Treatment by Bolus or Hybrid Administration in Newly Diagnosed or Relapsed/Refractory Acute Leukemia Patients

“…Of note, previous flavopiridol models reported in the literature have all used 2 compartment models even when richer sampling schemes were used (8,24–26). A 2 compartment structure was therefore adopted to describe flavopiridol pharmacokinetics.…”

“…Karp et al documented a two-compartment population pharmacokinetic model that used total flavopiridol concentrations from patients with acute leukemias (8). Efforts from Ji et al, Ni et al, and Phelps et al modeled flavopiridol and the glucuronide metabolite of flavopiridol in patients with chronic lymphocytic leukemia (24–26). These models identified relationships between the glucuronide metabolite and tumor lysis syndrome, the role of transporter polymorphisms on disposition and response, and relationships between flavopiridol and response or cytokine-release syndrome.…”