Pharmacokinetics of paclitaxel and carboplatin in combination.
Kearns CmChandra P. BelaniKadir ErkmenMichael ZuhowskiD. HiponiaD ZacharskiChristine EngstromRajeev RamanathanTrenn MrJoseph Aisner
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In a clinical trial of paclitaxel (Taxol) and carboplatin in combination, the severity of thrombocytopenia was less than would be expected with an equivalent dose of carboplatin alone. To determine whether a pharmacokinetic interaction was responsible for this observation, the effect of pretreatment with Taxol on the pharmacokinetics of carboplatin was examined in 11 patients. Each patient was randomized to one of two treatment groups that determined the order of drug treatments. The treatments were carboplatin as a 30-min infusion alone or immediately following 175 mg/m2 Taxol administered as a 3-h i.v. infusion. The treatments 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 dose 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 affected 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 different from that measured in the presence of Taxol (3.27 mg-min/ml). The 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 application of an individualized dosing strategy is valid for the calculation of the carboplatin dose in this combination. The pharmacokinetics of carboplatin is not altered by pretreatment with Taxol at a standard dose, and a pharmacokinetic interaction is not responsible for the altered toxicity of the combination.
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PURPOSE: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine analog valspodar (PSC 833), an inhibitor of P-glycoprotein function. PATIENTS AND METHODS: Fifty-eight patients were treated with escalating doses of paclitaxel ranging from 54 to 94.5 mg/m 2 and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg·min/mL, every 21 days. The dose of valspodar was fixed at 5 mg/kg every 6 hours for a total of 12 doses from day 0 to day 3. The MTD was determined for the following two groups: (1) previously treated patients, where paclitaxel and carboplatin doses were escalated; and (2) chemotherapy-naïve patients, where paclitaxel dose was escalated and carboplatin AUC was fixed at 6 mg·min/mL. PK studies of paclitaxel and carboplatin were performed on day 1 of course 1. RESULTS: Fifty-eight patients were treated with 186 courses of paclitaxel, carboplatin, and valspodar. Neutropenia, thrombocytopenia, and hepatic transaminase elevations were DLTs. In previously treated patients, no DLTs occurred at the first dose level (paclitaxel 54 mg/m 2 and carboplatin AUC 6 mg·min/mL). However, one of 12, two of six, two of four, four of 11, and two of five patients experienced DLTs at doses of paclitaxel (mg/m 2 )/carboplatin AUC (mg·min/mL) of 67.5/6, 81/6, 94.5/6, 67.5/7.5, and 67.5/9, respectively. In chemotherapy-naïve patients, one of 17 developed DLT at paclitaxel 81 mg/m 2 and carboplatin AUC 6 mg/mL·min. There was prolongation of the terminal phase of paclitaxel elimination as evidenced by an increased time that plasma paclitaxel concentration was ≥ 0.05 μmol/L, ranging from 16.6 ± 6.7 hours to 41.5 ± 9.8 hours for paclitaxel doses of 54.5 mg/m 2 to 94.5 mg/m 2 , respectively. CONCLUSION: The recommended phase II dose in chemotherapy-naïve patients is paclitaxel 81 mg/m 2 , carboplatin AUC 6 mg·min/mL, and valspodar 5 mg/kg every 6 hours. In previously treated patients, the recommended phase II dose is paclitaxel 67.5 mg/m 2 , carboplatin AUC 6 mg·min/mL, and valspodar 5 mg/kg every 6 hours. The acceptable toxicity profile supports the rationale for performing disease-directed evaluations of paclitaxel, carboplatin and valspodar on the schedule evaluated in this study.
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Urothelial carcinoma of the bladder (UCB) with glandular differentiation is a histological variant (HV) that is more likely to have positive extravesical tumors or nodes than those in pure UCB. Cisplatin-based neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) is more effective for pure UCB; however, few reports are available on second-line chemotherapy for recurrence of UCB with HV. Here we report a 65-year-old Japanese male diagnosed with local recurrence UCB with HV after NAC + RC who safely achieved complete response with paclitaxel, carboplatin, and gemcitabine combination chemotherapy.
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