Taxol: Pharmacology, metabolism and clinical implications

Although several biliary metabolites have been identified, the pharmacological disposition of the bulk of an administered dose of taxol has not yet been determined. One possible explanation is that a substantial proportion of the drug is not metabolized and avidly binds to tubulin and/or other proteins for long periods. A study involving the JHOC, Research Triangle Institute, National Cancer Institute and Bristol-Myers Squibb is being planned to determine the complete metabolic fate of taxol using ¹⁴C labelled taxol. Metabolic studies are establishing optimum dosing regimens for patients with excretory organ dysfunction. The optimum use of taxol in combination with other anti-neoplastic agents, such as carboplatin, topotecan and cyclophosphamide, and potential interactions with other unrelated classes of agents are also currently being evaluated. Although the extent of hepatic metabolism may be low overall, it may still be enough to account for substantial interactions between taxol and other classes of anti-neoplastic agents, particularly those that modulate or are metabolized by cytochrome P450 enzymes. Although the mechanism for sequence dependent interactions between taxol and cisplatin is unknown, similar types of interactions may occur when taxol is combined with other anti-neoplastic agents that either differentially inhibit P450 enzyme functions or are metabolized in part by P450 enzymes such as the anthracyclines. The steps taken to develop the taxol-cisplatin doublet, which involved an extensive evaluation of toxicological and pharmacological differences between drug sequences during phase I testing and the effects of drug sequencing on cytotoxicity in vitro, could be used as a paradigm to develop other taxol based chemotherapy combinations. At JHOC, similar analyses of sequence dependence are currently being incorporated into developmental studies of taxol combined with cyclophosphamide, topotecan and doxorubicin. Another potential source of drug interactions and variable clinical results may be due to the differential effects of H₂ histamine antagonist premedications on the hepatic metabolism and biliary excretion of taxol. These agents have been successfully incorporated into the premedication regimen used for prophylaxis against hypersensitivity reactions (Rowinsky et al, 1990). Although cimetidine has been the most commonly administered H₂ antagonist in clinical trials of taxol to date, ranitidine and famotidine have also been used, and significant differences in the availability of these agents have been reported by different practitioners. However, the H₂ histamine antagonists may have variable modulatory effects on the activities of many hepatic P450 enzymes that may be involved in critical steps in taxol metabolism (Smogyi and Muirhead, 1987; Klotz and Kroemer, 1991). Hypothetically, the use of different H₂ histamine antagonists in clinical trials may portend variable effects on drug metabolism and may differentially affect pharmacological, toxicological and anti-tumour profiles. Both animal and human studies are under way to assess these potentially important concerns. A study of JHOC in which patients participating in the National Cancer Institute Treatment Referral Center ovarian cancer study were randomized to receive either intravenous famotidine 20 mg or intravenous cimetidine 300 mg before one course of taxol and then crossed over to the alternate H₂ histamine antagonist before the next course failed to demonstrate substantial pharmacological or toxicological differences (Slichenmyer et al, 1993; Slichenmyer W and Rowinsky E, unpublished). Cimetidine does not alter the metabolism and biliary excretion of taxol in rats or the metabolism of ³H labelled taxol in microsomal preparations in vitro (Eiseman et al, 1993; Klecker et al, 1993). In addition, the microsomal inhibitors ketoconazole and fluconazole, but not erythromycin, have been shown to inhibit the metabolism of ³H labelled taxol in vitro (Klecker et al, 1993). The initiation of broad phase II and III trials in multiple tumour types involving hundreds of patients also presents unique opportunities for studying population pharmacokinetics and pharmacodynamics of a new anti-cancer drug, particularly with respect to the influence of several critical pharmacological variables, including the effect of taxol C(ss) and AUC on response and toxicity. Several randomized phase II and III trials evaluating dose response and scheduling are incorporating limited pharmacological studies to address critical pharmacological issues.