Modification of the pharmacokinetics of high-dose cyclophosphamide and cisplatin by antiemetics

Interpatient variability in exposure to certain chemotherapy agents can inf luence patient outcome, particularly with high-dose chemotherapy, We evalua ted the possibility of a pharmacokinetic (PK) drug-drug interaction between the antiemetic agents and high-dose cyclophosphamide, cisplatin and BCNU ( CPA/cDDP/BCNU). Twenty-three self-selected patients treated with high-dose CPA/cDDP/BCNU followed by autologous hematopoietic progenitor cell support (AHPCS) received ondansetron, lorazepam and diphenhydramine as antiemetics. PK parameters for each chemotherapeutic drug in the regimen were compared with those of 129 patients who received exactly the same chemotherapy but a n antiemetic regimen substituting prochlorperazine for ondansetron. In addi tion, we performed a review of the English literature for reported drug-dru g interactions between antiemetics and chemotherapy agents that led to modi fications in any PK parameters of the chemotherapy agent. Our retrospective study showed that the mean area under the curve (AUC) for both cyclophosph amide (76 600 vs 90 600 mu g/ml/min, P = 0.001) and cisplatin (525 vs 648 m u g/ml/min, P = 0.01) were significantly lower in the ondansetron group whe n compared with the prochlorperazine group. The AUC for BCNU was not signif icantly different in both groups (544 vs 677, P = 0.43). We found only one report of modifications of the PK parameters of high-dose chemotherapy agen ts due to drug-drug interactions with the most commonly used antiemetics in a review of the English literature between 1966 and 1995, We concluded tha t the AUC of high-dose cyclophosphamide and cisplatin are significantly low er when ondansetron, as opposed to prochlorperazine, is used as the antieme tic. The small sample size and heterogeneity of this group of patients prec ludes any outcome analysis of pharmacodynamic endpoints such as toxicity or antitumor effect. Nevertheless, the potential for interactions between ant iemetics and chemotherapy agents should be taken into account when using di fferent high-dose chemotherapy regimens.