EVALUATION OF CARBOPLATIN PHARMACOKINETICS IN THE ABSENCE AND PRESENCE OF PACLITAXEL

In a clinical trial of paclitaxel (Taxol) and carboplatin in combinati on, the severity of thrombocytopenia was less than would be expected w ith an equivalent dose of carboplatin alone. To determine whether a ph armacokinetic interaction was responsible for this observation, the ef fect of pretreatment with Taxol on the pharmacokinetics of carboplatin was examined in 11 patients. Each patient was randomized to one of tw o treatment groups that determined the order of drug treatments. The t reatments were carboplatin as a 30-min infusion alone or immediately f ollowing 175 mg/m(2) Taxol administered as a 3-h i.v. infusion. The tr eatments were separated by 1 week. The carboplatin dose was chosen to produce a target area under the concentration-time curve (AUC) of 3.75 mg-min/ml according to a previously published formula (A. H. Calvert et al., J. Clin Oncol., 7: 1748-1756, 1989). The mean administered dos e of carboplatin was 338 mg. Serial blood samples were collected over 24 h and analyzed for total and free platinum, and, in some patients, Taxol. The pharmacokinetics of carboplatin (i.e., total clearance and volume of distribution at steady state), was not significantly affecte d by pretreatment with Taxol. Total clearances of carboplatin were 67. 2 +/- 28.8 ml/min and 64.6 +/- 27.9 ml/min in the absence and presence of Taxol, respectively (P = 0.56). The AUC of free carboplatin (3.45 mg-min/ml) obtained in the absence of Taxol was not significantly diff erent from that measured in the presence of Taxol (3.27 mg-min/ml). Th e AUC of carboplatin in both the absence and presence of Taxol agreed with the projected target AUC of 3.75 mg-min/ml. In conclusion, the ap plication of an individualized dosing strategy is valid for the calcul ation of the carboplatin dose in this combination. The pharmacokinetic s of carboplatin is not altered by pretreatment with Taxol at a standa rd dose, and a pharmacokinetic interaction is not responsible for the altered toxicity of the combination.