Pharmacokinetics of Low-dose Carboplatin and Applicability of a Method of Calculation for Estimating Individual Drug Clearance

Background: Carboplatin is the only cancer drug for which conventional doses are individually adjusted according to estimated clearance and target area under the curve (AUC). The aim of this prospective study was (i) to evaluate intra- and interpatient variability of ultrafilterable (UF) carboplatin AUC(0-)(infinity) and (ii) to test whether the prediction of carboplatin clearance according to the Chatelut formula established for conventional carboplatin doses was accurate for low carboplatin doses.

Materials And Methods: Thirty-one head and neck cancer patients (29 men, two women, mean age 55.9 years) received concomitant radiotherapy (Rgamma 2 Gy/day) and chemotherapy (carboplatin 50 mg/m(2)/day i.v.) for 7 weeks: Rgamma was administered 5 days/week (days 1-5) and carboplatin 2 days/week (days 1 and 4). Pharmacokinetics was performed once per week. A limited sample strategy based on Bayesian analysis was first validated and blood was subsequently taken 1 and 4 h after the end of carboplatin administration.

Results: A total of 143 cycles was analyzed. Ultrafilterable carboplatin AUC(0-)(infinity) ranged from 0.360 to 4.200 mg.min/ml (mean 0.830, median 0.670). As a corollary, UF carboplatin clearance ranged from 19.1 to 244.7 ml/min. Ultrafilterable carboplatin concentrations were very stable over time: AUC(0-)(infinity) variability due to treatment duration contributed to <1% of the total variance, while interpatient variability contributed to 68.6%. Accordingly, intrasubject effect was not significant (P = 0.38) whereas intersubject effect was highly significant (P <0.001). These results suggest that optimal dosage for targeting a given AUC may vary within a 13-fold range between patients. The Chatelut formula, based on creatininemia, body weight, age and sex, over estimates carboplatin clearance by 40% on average (bias 95% CI 29.6% to 51.1%). No significant relationship was observed between either bone marrow toxicity or creatinine clearance decrease and carboplatin pharmacokinetics.

Conclusions: The Chatelut carboplatin clearance model established for conventional carboplatin dosages (>100 mg/m(2)) is not applicable for targeting low AUC (<1 mg x min/ml).