Pharmacokinetics of gimatecan, and orally administered camptothecin analogue, in patients with malignant gliomas

Abstract

2039 Background: Gimatecan (GTN) is a lipophilic camptothecin analogue with excellent activity against in vivo tumor models when given orally (p.o.). This report describes the pharmacokinetics (PK) of GTN in a phase I trial in adults with recurrent malignant gliomas. Methods: GTN was given p.o. once a day for 5 days every 4 weeks. The dose was independently escalated in patients based upon whether or not enzyme inducing antiseizure drugs (EIASDs) were used concurrently. At least 3 patients were evaluated at each dose level. Sampling to define GTN plasma profiles for first and fifth daily doses was performed during cycle 1. Total GTN (intact lactone + carboxylate forms) was measured in plasma by HPLC with fluorescence detection (limit of detection, 1.0 ng/ml). PK parameters were estimated by noncompartmental methods and are reported as mean ± SD values. Results: PK data are available at 4 doses ranging from 0.33–1.23 mg/m2/day in 14 non-EIASD patients and from 0.33–1.60 mg/m2/day in 12 patients receiving EIASDs. There has been no dose limiting toxicity. GTN reached a peak concentration in plasma (Cmax) within 2 h for 90% of all doses (N = 51). In the non-EIASD group, GTN had a long terminal half-life of 57 ± 22 h and an apparent clearance (CL/f) of 1.2 ± 0.9 L/h. CL/f was not significantly associated with body surface area suggesting that flat dosing may be appropriate. In patients receiving 1.23 mg/m2/day (N= 5), there was only a 5-fold difference between the trough concentration 24 h after dose 1 (16 ± 5 ng/ml) and the Cmax for dose 5 (76 ± 21 ng/ml). The mean drug accumulation factor was 2.7 ± 0.6 based upon the 24 h area under the curve for doses 1 and 5. EIASDs had a marked effect on GTN PK, increasing CL/f by a factor of 2–10 and decreasing the apparent half-life to a similar extent. Conclusions: Treatment with well tolerated doses of GTN p.o. on a daily x 5 schedule provides prolonged systemic exposure to potentially effective drug levels. As with other anticancer agents, EIASDs significantly increased the clearance of GTN; greater doses will be required to achieve plasma levels that are comparable to patients not taking EIASDs. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sigma-Tau Research Sigma-Tau Research