Pharmacodynamics and pharmacokinetics of a 72-hour infusion of 9- aminocamptothecin in adult cancer patients

C. H. Takimoto, W. Dahut, M. T. Marino, H. Nakashima, M. D. Liang, N. Harold, R. Lieberman, S. G. Arbuck, R. A. Band, A. P. Chen, J. M. Hamilton, L. R. Cantilena, C. J. Allegra, J. L. Grem

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43 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1492-1501
Number of pages10
JournalJournal of Clinical Oncology
Issue number4
StatePublished - Apr 1997
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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