Taxol

Clinical Pharmacology

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CLINICAL PHARMACOLOGY

Taxol

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Following intravenous administration of TAXOL, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.

Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of TAXOL at dose levels of 135 and 175 mg/m² were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table.

TABLE 1: SUMMARY OF PHARMACOKINETIC PARAMETERS—MEAN VALUES

Dose (mg/m²)	Infusion Duration (h)	N (patients)	Cmax(ng/mL)	AUC_(0–∞) (ng•h/mL)	T-HALF (h)	CL_T(L/h/m²)
135	24	2	195	6300	52.7	21.7
175	24	4	365	7993	15.7	23.8
135	3	7	2170	7952	13.1	17.7
175	3	5	3650	15007	20.2	12.2
Cmax=Maximum plasma concentration AUC_(0–∞)=Area under the plasma concentration-time curve from time 0 to infinity CL_T=Total body clearance

It appeared that with the 24-hour infusion of TAXOL, a 30% increase in dose (135 mg/m² vs 175 mg/m²) increased the Cmax by 87%, whereas the AUC_(0-∞) remained proportional. However, with a 3-hour infusion, for a 30% increase in dose, the Cmax and AUC_(0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour infusion of TAXOL, ranged from 227 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding of paclitaxel.

The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15 to 135 mg/m² given by 1-hour infusions (n=15), 30 to 275 mg/m² given by 6-hour infusions (n=36), and 200 to 275 mg/m² given by 24-hour infusions (n=54) in Phase 1 and 2 studies. Values for CLT and volume of distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of TAXOL in patients with AIDS-related Kaposi's sarcoma have not been studied.

Brand Name: Taxol
Generic Name: Paclitaxel