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The ATP-binding cassette transporter ABCB1 (P-glycoprotein) functions as an efflux transporter for many anticancer drugs, and is highly expressed at the biliary surface of hepatocytes. There is increasing evidence that genetic variants in the ABCB1gene contribute to interindividual pharmacokinetic variability of substrate drugs. The aim of this study was to evaluate relationships between the pharmacokinetics of the cyclic depsipeptide FK228 (formerly FR901228), an investigational histone deacetylase inhibitor and a known substrate for ABCB1 (Piekarz et al., Blood 103:4636-43, 2004), and allelic variants in ABCB1 as a putative marker of relevance for drug elimination. FK228 was administered to 42 patients with cancer (17 female, 25 male) as a 4-hour continuous infusion at a dose of 14 mg/m2 (n=37) or 18 mg/m2 (n=5). Serial blood samples were obtained following the first administration, and concentrations of FK228 in plasma were determined by a validated assay based on liquid chromatography-mass spectrometry. Pharmacokinetic parameters, including dose-normalized area under the curve (AUC) and clearance (CL), were calculated by noncompartmental analysis. All patients were genotyped by direct nucleotide sequencing for 3 common exonic single-nucleotide polymorphisms (SNPs) in ABCB1 at sites in exon 12 (1236C>T; G411G), exon 21 (2677G>A/T; A893S or T), and exon 26 (3435C>T; I1143I). The systemic clearance of FK228 was dose-independent (P=0.86), and hence data from both dose groups were combined following standard dose-correction. Substantial interindividual pharmacokinetic variability (>18-fold) was observed for FK228 at a mean (± SD) clearance of 17.0 ± 11.9 L/h. The frequencies of the rarest alleles in this predominantly white population were 0.410 (1236C>T), 0.357 (2677G>T), 0.024 (2677G>A), and 0.476 (3435C>T), which is consistent with previously reported estimates. Overall, ∼40% linkage was observed among the three ABCB1 SNPs (assigned haplotype ABCB1*13). None of the tested ABCB1 variants was associated with a significant difference in FK228 pharmacokinetics (1236C>T, P>0.801; 2677G>A/T, P>0.364; 3435C>T, P>768). FK228 mediated thrombocytopenia, assessed by the percentage decrease in platelet count at nadir, was also not statistically significantly associated with any of the variant genotypes (P>0.238). A trend was noted for an increase in the AUC of FK228 in 9 patients homozygous wild-type (mean, 2285 ng.h/ml) versus 11 patients heterzygous mutant (mean, 2031 ng.h/ml) versus 5 patients homozygous variant for haplotype ABCB1*13 (mean, 1555 ng.h/ml), although differences were not statistically significant (P=0.815, Kruskal-Wallis test). Overall, this study indicates that ABCB1 genotype status is not correlated with FK228 pharmacokinetics, and it remains therefore currently unclear which patients are at increased risk of severe toxicity following FK228 treatment.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]