Combination Metronomic Oral Topotecan and Pazopanib: A Pharmacokinetic Study in Patients with Gynecological Cancer

Abstract

Background: Combination metronomic topotecan plus pazopanib is active against preclinical models of gynecological cancer. Both agents are substrates for ATP-binding cassette family transporters so there is an increased likelihood for pharmacokinetic (PK) drug-drug interactions. Patients and Methods: PK analyses of topotecan were performed during three cycles of a phase I dose-escalation study of metronomic topotecan and pazopanib in consenting adult patients with gynecological cancer. Concentration time data were analyzed using a population PK approach. Results: Twenty-one patients were evaluable for serial PK studies. Considerable inter- and intra-patient variability was observed in the PK parameters, attributable primarily to highly variable oral bioavailability. No difference in topotecan disposition was detected between administration cycles, nor between the off- versus on-pazopanib studies. 

Conclusion: The lack of a statistically significant drug-drug interaction agrees with preclinical findings suggesting that pazopanib does not influence the PK of metronomic topotecan. No adjustment of low dose metronomic topotecan dosing is merited when used in conjunction with pazopanib.