Phase I, Pharmacokinetic, and Pharmacogenetic Study of TAS-103
Reginald B. Ewesuedo, Lalitha Iyer, Annette Koenig, Soma Das, Shridar Mani, Nicholas J. Vogelzang, Bruce Brockstein, Richard L. Schilsky, Katie Kunkel, Wayne Brenckman, Mark J. Ratain. The University of Chicago, Chicago, IL.; Covance Labs, Madison, WI.; ClinTrials Res Inc, Morrisville, NC.
TAS-103 is a topoisomerase (topo) I &II inhibitor. Preclinical studies showed broad activity with weak or no cross-resistance to other topo I or II inhibitors. TAS-103 is extensively protein-bound (99%), and metabolized to TAS-103-glucuronide (TAS-103-G). Other metabolites include demethyl-TAS-103 (DM-TAS-103, active), DM-TAS-103-glucuronide, and TAS-103 N-oxide. In this study escalating doses (50 mg/m2-200 mg/m2, 1h i.v. infusion) of TAS-103 were administered weekly x3, with a 2-week rest period between cycles. This dosing schedule was selected based on schedule-dependent efficacy of TAS-103 in preclinical models. Since UGT1A1 is mainly responsible for glucuronidation of TAS-103, we hypothesized that polymorphism in the promoter region of UGT1A1 isoform gene should influence the pharmacokinetics and toxicity of TAS-103. Pharmacokinetic analysis was done at dose levels of 160 mg/m2 (n=11) and 200 mg/m2 (n=6). UGT1A1 genotypes were determined as homozygous for allele 7 (7/7), heterozygous (6/7) and homozygous for allele 6 (6/6--normal). The mean (±SD) estimated pharmacokinetic parameters were: AUC[TAS-103]- 4.43 (2.4) vs 6.85 (1.9), AUC[TAS-103-G]- 4.57 (3.9) vs 26.3 (12.8), CL[TAS-103]- 54.2 (21.4) vs 32.9 (10.7) for 160 mg/m2 and 200 mg/m2 doses respectively. We observed a high correlation between AUCs for TAS-103 and TAS-103G (r=0.83, p=0.8) and between TAS-103 AUC and ANC nadir (r=-0.59, p=0.002). Dose limiting toxicity (grade 4 neutropenia) was seen in 4 patients [160 mg/m2 (n=3), 200 mg/m2 (n=1)]. Of these, 2 patients each were of genotypes 7/7 & 6/7. Other toxicities included mild fatigue and anorexia. No significant correlation was found between UGT1A1 genotypes and PK parameters. Our results suggest a recommended phase II dose of 160 mg/m2 given by this dosing schedule. TAS-103-G may not be the major metabolite of TAS-103 in humans, given the high correlation between TAS-103 and TAS-103-G. Interpatient variability in oxidation and protein binding of TAS-103 are perhaps the primary determinants of TAS-103 pharmacokinetics and toxicity.
*** POSTED JUNE 28, 2000 ***