Pharmacologic modulation of taxanes

In the 90's the taxanes paclitaxel and docetaxel, both belonging to the so-called naturally occurring drugs, because of their origin from the yew trees Taxus brevifolia and Taxus baccata, respectively, were registered for clinical use in the treatment of cancer patients. Although their mechanism of action is the same, inducing cell death by promoting polymerization of tubulin into microtubules and particularly by inhibiting depolymerization of these microtubules, they are not simply two of a kind. Differences in activity, toxicity and pharmacokinetic behavior have been described over the last decade. In order to increase activity they have been combined with various other (anticancer) agents. To judge combination treatment on its merits, changes in the pharmaco-dynamics as well as modulations in the pharmacokinetics of the combined drugs have to be evaluated. This thesis explores the influence of other chemical entities on the pharmacokinetics of docetaxel and paclitaxel. Intended modulation of docetaxel by co-administration of a multidrug-resistance convertor is the topic of the first part of the thesis, the unintended and underestimated pharmacokinetic implications of the choice of Cremophor EL as the formulation vehicle of paclitaxel is the subject of the second part. Multidrug resistance is the phenomenon thought to be partly responsible for failure of cancer treatment with naturally occurring anticancer drugs such as taxanes. It is associated with overexpression of the transmembrane transport protein P-glycoprotein, which acts as an ATP-dependent drug efflux pump, yielding to a decrease in the intracellular concentrations of the substrate drugs. Abundant effort has been put into the development of agents that are able to inhibit P-glycoprotein, and when used in combination with anticancer drugs increase the intracellular exposure to these drugs. However, many clinical studies involving a wide range of P-glycoprotein inhibitors and coadministered anticancer drugs have shown that these combination treatments almost always resulted in increased toxicity of the anticancer drugs particularly because of pharmacokinetic interaction between the two agents due to competition at the level of cytochrome-P450 3A isozymes, the major metabolic pathway of many drugs including docetaxel. Recently, a new 'second generation' P-glycoprotein inhibitor, R101933, has been developed which known major metabolic route is cytochrome-P450 unrelated. Since docetaxel is known to be a more pure substrate of P-glycoprotein than paclitaxel, it was obvious that co-treatment of docetaxel with R1 01933 could have great clinical importance. Therefore, we performed several pharmacokinetic and phase I studies with docetaxel combined with R101933, orally as well as intravenously. In order to determine the physiological and pharmacological consequences of inhibition of P-glycoprotein activity with respect to the disposition of docetaxel we monitored both plasma and fecal drug levels of docetaxel. Modulation of P-glycoprotein, particularly in the hepatobiliary tract, by Cremophor EL, the formulation vehicle of paclitaxel, was postulated as one of the explanations of the distinctly nonlinear pharmacokinetic behavior of this taxane. The operation of Michaelis-Menten kinetics, saturable distribution in combination with saturable elimination, was hypothesized as another cause of the nonlinear disposition of paclitaxel. However, studies in mice demonstrated that in the absence of Cremophor EL the pharmacokinetic behavior of paclitaxel was linear. An explanation could be that, by its nature, Cremophor EL in blood is capable of forming micelles with a highly hydrophobic interior that can entrap the solubilised compound, consequently influencing the pharmacokinetic behavior of this drug. So we postulated that the nonlinear disposition of paclitaxel is caused by dose and time-related variations in Cremophor EL concentrations in the central compartment. To prove this hypothesis we performed a comprehensive pharmacokinetic analysis of paclitaxel and Cremophor EL in vitro and in patients, measuring paired whole blood and plasma levels of paclitaxel. Based on the results of these studies, we were able to develop and describe explicit modeling of the disposition of paclitaxel and free paclitaxel to permit a formal explanation of the observed phenomenon.

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