title: Association of high-dose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer.
abstract: This report investigates relationships between the pharmacokinetics and pharmacodynamics of high-dose alkylators used for the treatment of primary breast cancer. Eighty-five women with primary breast cancer involving >or=10 lymph nodes received four cycles of standard-dose chemotherapy followed by a high-dose regimen consisting of: cyclophosphamide (1875 mg/m(2) once daily x 3), cisplatin (165 mg/m(2) given over 72 h), carmustine (600 mg/m(2)), and stem cell transplantation. Dosages were attenuated in patients whose body weight exceeded their calculated ideal weight by >20%. Pharmacokinetics of the high-dose chemotherapeutic agents were evaluated in each patient by collection and analysis of serial blood samples. Area under the concentration time curve (AUC) for cyclophosphamide and carmustine was highly variable (>10-fold inter-patient range) with coefficients of variation > 50%, in contrast to cisplatin exposures (2-fold range; coefficient of variation 12%). The dosing method for overweight patients resulted in significantly lower systemic exposure to cisplatin (P = 0.035). The parent cyclophosphamide clearance on the 1st day of administration was significantly higher in patients who experienced acute cardiac toxicity (n = 5; P = 0.011), whereas carmustine disposition was not found to be different in those developing pulmonary toxicity (n = 25; P = 0.96). Kaplan-Meier analysis (median follow-up of 5.9 years) demonstrated that patients with lower cyclophosphamide AUC (faster parent drug clearance to potentially cytotoxic compounds) survived longer (P = 0.031). Inter-individual differences in the pharmacokinetic disposition of high-dose chemotherapy may explain variability in both response and toxicity. Prospective strategies, which attempt to individualize AUC, should be evaluated in this setting.
authors.affiliation: Bone Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina 27710, USA. wpetros@hsc.wvu.edu
authors.forename: William P
authors.initials: WP
authors.lastname: Petros
authors.forename: Gloria
authors.initials: G
authors.lastname: Broadwater
authors.forename: Donald
authors.initials: D
authors.lastname: Berry
authors.forename: Roy B
authors.initials: RB
authors.lastname: Jones
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Colleen J
authors.initials: CJ
authors.lastname: Gilbert
authors.forename: John P
authors.initials: JP
authors.lastname: Gibbs
authors.forename: O Michael
authors.initials: OM
authors.lastname: Colvin
authors.forename: William P
authors.initials: WP
authors.lastname: Peters
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D002330:Carmustine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D015996:Survival Rate; D013997:Time Factors
chemical_list: D003520:Cyclophosphamide; D002945:Cisplatin; D002330:Carmustine