title: Modification of the pharmacokinetics of high-dose cyclophosphamide and cisplatin by antiemetics.
abstract: Interpatient variability in exposure to certain chemotherapy agents can influence patient outcome, particularly with high-dose chemotherapy. We evaluated 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 an antiemetic regimen substituting prochlorperazine for ondansetron. In addition, we performed a review of the English literature for reported drug-drug interactions between antiemetics and chemotherapy agents that led to modifications in any PK parameters of the chemotherapy agent. Our retrospective study showed that the mean area under the curve (AUC) for both cyclophosphamide (76,600 vs 90,600 microg/ml/min, P=0.001) and cisplatin (525 vs 648 microg/ml/min, P = 0.01) were significantly lower in the ondansetron group when compared with the prochlorperazine group. The AUC for BCNU was not significantly 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 agents due to drug-drug interactions with the most commonly used antiemetics in a review of the English literature between 1966 and 1995. We concluded that the AUC of high-dose cyclophosphamide and cisplatin are significantly lower when ondansetron, as opposed to prochlorperazine, is used as the antiemetic. The small sample size and heterogeneity of this group of patients precludes any outcome analysis of pharmacodynamic endpoints such as toxicity or antitumor effect. Nevertheless, the potential for interactions between antiemetics and chemotherapy agents should be taken into account when using different high-dose chemotherapy regimens.
authors.affiliation: University of Colorado Bone Marrow Transplant Program, University of Colorado Cancer Center, Denver, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Cagnoni
authors.forename: S
authors.initials: S
authors.lastname: Matthes
authors.forename: T C
authors.initials: TC
authors.lastname: Day
authors.forename: S I
authors.initials: SI
authors.lastname: Bearman
authors.forename: E J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: R B
authors.initials: RB
authors.lastname: Jones
mesh_terms: D000328:Adult; D000932:Antiemetics / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000627:therapeutic use; D002330:Carmustine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003432:Cross-Linking Reagents / Q000493:pharmacokinetics / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods / Q000639:trends; D006801:Humans; D008140:Lorazepam / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D017294:Ondansetron / Q000009:adverse effects / Q000627:therapeutic use; D011346:Prochlorperazine / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D012189:Retrospective Studies; D014182:Transplantation, Autologous / Q000379:methods
chemical_list: D000932:Antiemetics; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D011838:Radiation-Sensitizing Agents; D017294:Ondansetron; D003520:Cyclophosphamide; D008140:Lorazepam; D002945:Cisplatin; D002330:Carmustine; D011346:Prochlorperazine