PHARMACOKINETICS OF PACLITAXEL AND METABOLITES IN A RANDOMIZED COMPARATIVE-STUDY IN PLATINUM-PRETREATED OVARIAN-CANCER PATIENTS

Purpose: To investigate the pharmacokinetics and pharmacodynamics of paclitaxel in a randomized comparative study with four different treatment arms in patients with platinum-pretreated ovarian carcinoma. Patients and Methods: Eighteen patients were entered onto this study in which paclitoxel was administered at a high dose of 175 mg/m2 versus a low dose of 135 mg/m2 on a 3- or 24-hour infusion schedule. A solid-phase extraction technique for sample pretreatment followed by a reverse-phase high-performance liquid chromatographic (HPLC) assay was used for analysis of plasma. Results: Grade 3 neutropenia occurred in all four treatment arms. However, it was more severe on the 24-hour infusion schedule. Paclitaxel concentrations as low as 0.012 μmol/L were measured with the HPLC assay. With this low quantitation threshold, we found the plasma disappearance of paclitaxel to be triphasic, with half-lives t( 1/2 )(α), t( 1/2 )(β), and t( 1/2 )(γ) mean values for the different treatment arms of 0.19 hours (range, 0.01 to 0.4), 1.9 hours (range, 0.5 to 2.8), and 20.7 hours (range, 4 to 65), respectively. Eleven possible metabolites were found, of which three were identified as taxanes by on-line HPLC-photodiode array (PDA) detection. Investigation of pharmacodynamics shows no clear relationship between the pharmacokinetic parameters area under the plasma concentration time curve (AUC), area under the plasma concentration moment curve (AUMC), maximal plasma concentration (C(max)), clearance, and toxicity. However, a relationship was found between the duration of plasma concentrations above a threshold of 0.1 μmol/L with absolute neutrophil count (ANC) and white blood cell count (WBC). Conclusion: Paclitaxel is metabolized, and putative metabolic products can be found in plasma of patients treated with the drug. Our results indicate that myelosuppression can be predicted by the measurement of the duration of plasma concentrations above the threshold of 0.1 μmol/L.