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Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates
S M Blaney1, D E Cole, F M Balis
1Walter Reed Army Medical Center, Washington, DC 20307.
Abstract:
Topotecan, a water soluble semisynthetic analogue of camptothecin, is a topoisomerase I inhibitor that has recently entered phase II clinical trials. Topotecan has shown significant preclinical activity in refractory murine tumors and in human tumor xenograft models. In addition, objective antineoplastic activity has been observed in recent adult phase I clinical trials. Topotecan is unstable in solution and is rapidly and spontaneously converted to a less active open ring form which predominates at physiological pH. This study was undertaken to better define the pharmacokinetic behavior of this highly unstable compound in both plasma and cerebrospinal fluid (CSF) and to measure the degree of CSF penetration of this novel antineoplastic agent. Three nonhuman primates with indwelling Ommaya reservoirs received 10 mg/m2 i.v. topotecan administered as a 10-min infusion. Frequent plasma and CSF samples were obtained and immediately extracted and assayed with a reverse phase high performance liquid chromatography assay to quantitate the concentration of topotecan (lactone). Samples were then acidified and reinjected to quantitate total drug (lactone ring plus open ring). Peak plasma concentrations of topotecan ranged from 0.27 to 0.45 microM. Plasma disappearance of the lactone ring was biexponential with a distribution half-life (t1/2 alpha) of 22 +/- 5 min and an elimination half-life (t1/2 beta) of 1.3 +/- 0.1 h. Total body clearance of topotecan was 72.1 +/- 15.8 liters/h/m2. The volume of distribution at steady state was 88.6 +/- 33.2 liters/m2. Peak CSF concentrations of topotecan occurred at 30 min following drug administration and ranged from 0.044 to 0.074 microM. CSF disappearance paralleled that in plasma. The mean ratio of the area under the CSF concentration-time curve to that in plasma was 0.32 (range, 0.29 to 0.37). The mean CSF penetration of topotecan exceeds 30%, which is significantly greater than the penetration of most structurally similar chemotherapeutic agents. The impact of chemotherapy on the survival of patients with primary or metastatic central nervous system malignancies is very limited. Therefore, this novel antineoplastic agent is an excellent candidate for further study in patients with high risk or refractory central nervous system tumors.
Insights
Topotecan, a topoisomerase I inhibitor, shows significant preclinical and clinical antineoplastic activity. This study defines its pharmacokinetic behavior and cerebrospinal fluid (CSF) penetration, exceeding 30% in nonhuman primates.
Area of Science:
- Pharmacology
- Oncology
- Drug Development
Background:
- Topotecan is a topoisomerase I inhibitor with demonstrated preclinical and clinical antineoplastic activity.
- The drug exhibits instability in solution, converting to a less active open-ring form at physiological pH.
- Limited chemotherapy efficacy in central nervous system (CNS) malignancies necessitates novel therapeutic strategies.
Purpose of the Study:
- To elucidate the pharmacokinetic profile of topotecan in plasma and cerebrospinal fluid (CSF).
- To quantify the extent of topotecan penetration into the CSF.
- To assess the potential of topotecan for treating CNS tumors.
Main Methods:
- Pharmacokinetic analysis of topotecan in plasma and CSF of three nonhuman primates.
- Administration of 10 mg/m2 i.v. topotecan via a 10-min infusion.
- Quantification using reverse-phase high-performance liquid chromatography (HPLC) to measure lactone and total drug concentrations.
Main Results:
- Peak plasma concentrations of topotecan ranged from 0.27 to 0.45 microM.
- Plasma elimination half-life (t1/2 beta) was 1.3 +/- 0.1 hours, with a volume of distribution of 88.6 +/- 33.2 liters/m2.
- Peak CSF concentrations ranged from 0.044 to 0.074 microM, with a mean CSF to plasma AUC ratio of 0.32, indicating >30% CSF penetration.
Conclusions:
- Topotecan exhibits favorable pharmacokinetic properties and significant penetration into the CSF (>30%).
- The drug's ability to cross the blood-brain barrier makes it a promising candidate for CNS malignancies.
- Further investigation of topotecan in patients with high-risk or refractory CNS tumors is warranted.