Pharmacokinetics and pharmacodynamics of topotecan in the laboratory and the clinic

Abstract

Topotecan, a water-soluble analogue of camptothecin, entered clinical study in the late 1980s. Extensive clinical trials have culminated in the approval of a single agent regimen of 30 minute infusions daily for 5 days each 3 weeks, for use in small cell lung and ovarian cancer. Phase I studies described the dose limiting toxicity of myelosuppression, predominantly neutropenia. Combination regimens are now under development to increase clinical benefit. The approved regimen was one of many undergoing clinical development and the optimal schedule for maximal clinical efficacy has not been defined. Schedule selection for development has been determined by toxicity and tumour response within early clinical studies. However, evidence of clinical benefit is often limited within phase I studies due to small patient numbers and the wide range of chemo-resistant or chemo-refractory cancers. Although further information is gained from pharmacokinetic and pharmacodynamic studies, identification and validation of a surrogate endpoint of clinical effect would aid treatment development and schedule design. Topotecan, an inhibitor of the topoisomerase I enzyme, stabilises the cleavable complex formed by topoisomerase I and DNA during generation of DNA single strand breaks. Persistence of these breaks interferes with DNA replication and leads to abnormal DNA products. The cleavable complex is a logical candidate for study as a potential surrogate of downstream clinical effect. The cleavable complex is correlated with cytotoxicity in vitro but the assay was not sufficiently sensitive to assay cleavable complex formation in peripheral lymphocytes of patients receiving treatment as part of a phase I clinical study of carboplatin and topotecan. The clinical study of carboplatin and topotecan resulted in greater than expected myelotoxicity. Pharmacokinetic study of both drugs in two treatment schedules did not reveal evidence of an interaction between platinum and topotecan to explain this toxicity. In vitro study of sequential treatment with cisplatin and topotecan also did not show any evidence of a synergistic effect. The combination of platinum and topotecan is an active treatment combination but delivery is difficult due to myelosuppression. The mechanism underlying this interaction has not been elucidated.