Multiple-pool cell lifespan models for neutropenia to assess the population pharmacodynamics of unbound paclitaxel from two formulations in cancer patients.

PURPOSE: Our objective was to build a mechanism-based pharmacodynamic model for the time course of neutropenia in cancer patients following paclitaxel treatment with a tocopherol-based Cremophor-free formulation (Tocosol Paclitaxel) and Cremophor EL-formulated paclitaxel (Taxol). METHODS: A randomized two-way crossover trial was performed with 35 adult patients who received 175 mg/m(2) paclitaxel as either 15 min (Tocosol Paclitaxel) or 3 h (Taxol) intravenous infusions. Paclitaxel concentrations were measured by LC-MS/MS. NONMEM VI was used for population pharmacodynamics. RESULTS: The cytotoxic effect on neutrophils was described by four mechanism-based models predicated on known properties of paclitaxel that used unbound concentrations in the central, deep peripheral or an intracellular compartment as forcing functions. Tocosol Paclitaxel was estimated to release 9.8% of the dose directly into the deep peripheral compartment (DPC). All models provided reasonable fitting of neutropenic effects. The model with the best predictive performance assumed that this dose fraction was released into 22.5% of the DPC which included the site of toxicity. The second-order cytotoxic rate constant was 0.00211 mL/ng per hour (variability: 52% CV). The relative exposure at the site of toxicity was 2.21 +/- 0.41 times (average +/- SD) larger for Tocosol Paclitaxel compared to Taxol. Lifespan was 11.0 days for progenitor cells, 1.95 days for maturating cells, and 4.38 days for neutrophils. Total drug exposure in blood explained half of the variance in nadir to baseline neutrophil count ratio. CONCLUSIONS: The relative exposure of unbound paclitaxel at the site of toxicity was twice as large for Tocosol Paclitaxel compared to Taxol. The proposed mechanism-based models explained the extent and time course of neutropenia jointly for both formulations.

Mechanistic population pharmacokinetics of total and unbound paclitaxel for a new nanodroplet formulation versus Taxol in cancer patients.

PURPOSE: Our objectives were (1) to compare the disposition and in vivo release of paclitaxel between a tocopherol-based Cremophor-free formulation (Tocosol Paclitaxel) and Cremophor EL-formulated paclitaxel (Taxol) in human subjects, and (2) to develop a mechanistic model for unbound and total paclitaxel pharmacokinetics. METHODS: A total of 35 patients (average +/- SD age: 59 +/-13 years) with advanced non-hematological malignancies were studied in a randomized two-way crossover trial. Patients received 175 mg/m(2) paclitaxel as 15 min (Tocosol Paclitaxel) or 3 h (Taxol) intravenous infusion in each study period. Paclitaxel concentrations were determined by LC-MS/MS in plasma ultrafiltrate and whole blood. NONMEM VI was used for population pharmacokinetics. RESULTS: A linear disposition model with three compartments for unbound paclitaxel and a one-compartment model for Cremophor were applied. Total clearance of unbound paclitaxel was 845 L/h (variability: 25% CV). The prolonged release with Tocosol Paclitaxel was explained by the limited solubility of unbound paclitaxel of 405 ng/mL (estimated) in plasma. The 15 min Tocosol Paclitaxel infusion yielded a mean time to 90% cumulative input of 1.14 +/- 0.16 h. Tocosol Paclitaxel was estimated to release 9.8% of the dose directly into the deep peripheral compartment. The model accounted for the presence of drug-containing nanodroplets in blood. CONCLUSIONS: Population pharmacokinetic analysis indicated linear disposition and a potentially higher bioavailability of unbound paclitaxel following Tocosol Paclitaxel administration due to direct release at the target site. The prolonged release of Tocosol Paclitaxel supports 15 min paclitaxel infusions. This mechanistic model may be important for development of prolonged release formulations that distribute in and from the systemic circulation.

Tocol emulsions for drug solubilization and parenteral delivery.

Tocols represent a family of tocopherols, tocotrienols, and their derivatives, and are fundamentally derived from the simplest tocopherol, 6-hydroxy-2-methyl-2-phytylchroman, which is referred to as "tocol". The most common tocol is D-alpha-tocopherol, also known as vitamin E. Tocols can be excellent solvents for water insoluble drugs and are compatible with other cosolvents, oils and surfactants. This review highlights the major developments in the use of tocols in parenteral emulsions for drug delivery, with a focus on drug solubilization, physicochemical properties, and biopharmaceutical applications. Tocol emulsions offer an appealing alternative for the parenteral administration of poorly soluble drugs, including major chemotherapeutics such as paclitaxel. Data will be presented on solubilization of paclitaxel, a key chemotherapeutic agent, and its corresponding formulation development, toxicity, efficacy and pharmacokinetic studies in animal models and humans. The breadth of the utility of tocol-based emulsions will be discussed and examples of specific therapeutic drugs and applications will be provided. As these formulations progress further in the clinic, the therapeutic utility of tocol emulsions is anticipated to expand.