Purpose: To investigate the pharmacokinetics and pharmacodynamics of 9- aminocamptothecin (9-AC) infused over 72 hours at doses of 5 to 74 μg/m2/h. Patients and Methods: 9-AC lactone and total (lactone plus carboxylate) plasma concentrations were measured in 44 patients with solid tumors using a high-performance liquid chromatography (HPLC) assay. Fifteen patients underwent extended pharmacokinetic sampling to determine the distribution and elimination kinetics of 9-AC. Results: At steady-state, 8.7% ± 4.7% (mean ± SD) of the total drug circulated in plasma as the active 9-AC lactone. Clearance of 9-AC lactone was uniform (24.5 ± 7.3 L/h/m2) over the entire dose range examined; however, total 9-AC clearance was nonlinear and increased at higher dose levels. In 15 patients treated at dose levels ≤ 47 μg/m2/h, the volume of distribution at steady-state for 9-AC lactone was 195 ± 114 L/m2 and for total 9-AC it was 23.6 ± 10.6 L/m2. The elimination half-life was 4.47 ± 0.53 hours for 9-AC lactone and 8.38 ± 2.10 hours for total 9-AC. In pharmacodynamic studies, dose-limiting neutropenia correlated with steady-state lactone concentrations (Css) (R2 = .77) and drug dose (R2 = .71). Conclusion: Plasma 9-AC concentrations rapidly declined to low levels following the end of a 72-hour infusion and the mean fraction of total 9-AC circulating in plasma as the active lactone was less than 10%. The pharmacokinetics of 9-AC may have o great impact on its clinical activity and should be considered in the design of future clinical trials of this topoisomerase I inhibitor.
ASJC Scopus subject areas
- Cancer Research