Abstract C134: Survivin suppressant YM155: A pharmacokinetic comparison between U.S. and Japanese populations

Abstract

Abstract Survivin is a member of IAPs. YM155 is a compound that suppresses survivin, and has been shown to exhibit anti-tumor activity in preclinical and clinical studies. The current analysis is designed to compare the pharmacokinetics (PK) of YM155 between US and Japanese patient populations using data obtained from two phase 1 trials, one done in Japan and the other in the US. Patients with a confirmed solid tumor or NHL (US only) that were refractory to standard therapy or for which no standard therapy was available participated in these trials. YM155 was administered as a continuous IV infusion for 168 hours, every 21 days. During the first two treatment cycles, serial blood and urine samples were collected for up to 48 hours after the discontinuation of YM155 infusion on Day 7. Forty-one subjects in the US trial (including 5 subjects with NHL) and 33 subjects in the Japanese trial had adequate samples for PK evaluation. The maximum tolerated dose (MTD) was 4.8 mg/m2/day and 8.0 mg/m2/day in the US and Japanese populations, respectively. In both populations, median YM155 concentration appeared to reach steady-state 12–24 hours after the start of the YM155 infusion. After discontinuation of the YM155 infusion, plasma YM155 concentration declined rapidly in a biphasic pattern with mean terminal half-life between 6 and 29 hours. The geometric mean ratio [90 % confidence interval(CI)] of steady-state YM155 concentration (Css) and area under observed YM155 concentration-time curve extrapolated to infinity (AUCinf) between cycle 2 and cycle 1 was 1.09 (0.99 –1.29) and 1.02 (0.90–1.16) in the US, and 0.98 (0.80 – 1.21) and 1.00 (0.97–1.03) in the Japanese populations, respectively, suggesting that there was no time-dependence in YM155 exposure. The slope of regression of natural logarithm transformed Css and AUCinf on natural logarithm transformed dose (mean and 95% CI) was 0.66 (0.31–1.00) and 0.65 (0.29–1.00) in the US and 1.00 (0.86–1.14) and 0.99 (0.85–1.12) in the Japanese populations, respectively. At the US MTD dose of 4.8 mg/m2/day, Css (mean ± SD) during cycle 1 was 7.6 ± 2.6 ng/mL (n=24) in the US and 8.7 ± 1.4 ng/mL (n=6) in the Japanese populations. The geometric mean ratios (90 % CI) of AUCinf, Css, and clearance between Japanese and US populations were 1.06 (0.93 – 1.22), 1.14 (1.00 – 1.31) and 0.80 (0.70 – 0.92), respectively. In conclusion, data currently available suggests that PK of YM155 is time-independent in both the US and Japanese patient populations; there appear to be no differences between U.S. and Japanese patients in terms of blood plasma YM155 concentration and its time course, although high variability was observed. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C134.