Mechanism-Based Pharmacokinetic Model for Paclitaxel

Henningsson, Anja; Karlsson, Mats O.; Viganò, Lucia; Gianni, Luca; Verweij, Jaap; Sparreboom, Alex

doi:10.1200/jco.2001.19.20.4065

Cited by 131 publications

(102 citation statements)

References 15 publications

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“…The pharmacokinetics of BMS-184476 in combination with carboplatin in this study appeared linear as was observed for BMS-18476 as a single agent (Plummer et al, 2002). This is in contrast to the nonlinear pharmacokinetic behaviour of paclitaxel (Gibaldi and Perrier, 1982;Henningsson et al, 2001).…”

Section: Discussionmentioning

confidence: 91%

Phase I trial of the novel taxane BMS-184476 administered in combination with carboplatin every 21 days

et al. 2004

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The aim of the study was to determine the maximum-tolerated dose and dose-limiting toxicities for BMS-184476, in combination with carboplatin, in patients with advanced solid tumours and to describe any preliminary antitumour activity associated with this regimen. Patients received combination therapy with BMS-184476 given intravenously over 1 h followed by carboplatin administered over 30 min on day 1 of a 21-day cycle. In all, 28 patients received 146 cycles of BMS-184476 and carboplatin. Patients were enrolled at four dose levels: BMS-184476 (mg m À2 )/carboplatin (mg min ml À1 ): 40/5, 50/5, 50/6 and 60/6. Dose-limiting toxicity at 60/6 was neutropenia. Among 27 evaluable patients, 11 demonstrated stable disease for a median of 8.5 cycles. In 22 patients, the pharmacokinetics of BMS-184476 appeared independent of dose of BMS-184476. The mean7s.e.m. values for clearance (Cl), volume of distribution at steady state and apparent terminal half-life of BMS-184476 in the four dose groups during cycle 1 were 192725 ml min m À2 , 377769 l m À2 and 33.775.9 h, respectively. An increase in the dose of carboplatin from 5 to 6 mg min ml À1 may have decreased Cl of BMS-184476. BMS-184476 in combination with carboplatin was well tolerated at a dose of 50/6 and shows evidence of antitumour activity in a pretreated population.

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Section: Discussionmentioning

confidence: 91%

Phase I trial of the novel taxane BMS-184476 administered in combination with carboplatin every 21 days

et al. 2004

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“…In addition, CrEL significantly alters the pharmacokinetics of paclitaxel (2)(3)(4)(5). The pharmacokinetic behavior of paclitaxel has been proposed to be distinctly nonlinear because the drug is trapped in micelles, making it less available for tissue distribution, metabolism, and biliary excretion, whereas CrEL-free paclitaxel appears to be linear (6,7). Moreover, paclitaxel must be prepared in either a glass bottle or in non-polyvinyl chloride infusion systems with in-line filtration to prevent precipitation from CrEL and solvent (8).…”

Section: Introductionmentioning

confidence: 99%

Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies

Kim

Kim²,

Chung³

et al. 2004

Clinical Cancer Research

716

467

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Purpose:The rationale for developing an alternative paclitaxel formulation concerns Cremophor EL-related side effects, and a novel paclitaxel delivery system might augment its therapeutic efficacy. Genexol-PM is a polymeric micelle formulated paclitaxel free of Cremophor EL. A phase I study was performed to determine the maximum tolerated dosage, dose-limiting toxicities, and the pharmacokinetic profile of Genexol-PM in patients with advanced, refractory malignancies.Experimental Design: Twenty-one patients were entered into the study. Genexol-PM was i.v. administered over 3 h every 3 weeks without premedication. The Genexol-PM dose was escalated from 135 mg/m 2 to 390 mg/m 2 . Results: All of the patients were evaluable for toxicity and response. Acute hypersensitivity reactions were not observed. Neuropathy and myalgia were the most common toxicities. During cycle 1, grade 3 myalgia occurred in 1 patient at 230 and 300 mg/m 2 , respectively. At 390 mg/m 2 , 2 of 3 patients developed grade 4 neutropenia or grade 3 polyneuropathy. Therefore, the maximum tolerated dosage was determined to be 390 mg/m 2 . There were 3 partial responses (14%) among the 21 patients. Of the 3 responders, 2 were refractory to prior taxane therapy. The paclitaxel area under the curve from time 0 to infinity and peak or maximum paclitaxel concentration seemed to increase with escalating dose, except at 230 mg/m 2 , which suggests that Genexol-PM has linear pharmacokinetics. Conclusion:The main dose-limiting toxicities were neuropathy, myalgia, and neutropenia, and the recommended dosage for a phase II study is 300 mg/m 2 . Genexol-PM is believed to be superior to conventional paclitaxel in terms of the obviation of premedication and the delivery of higher paclitaxel doses without additional toxicity.

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“…Later, the formulation vehicle of paclitaxel, Cremophor EL, was reported to be the cause of the (apparent) nonlinear plasma behavior of paclitaxel, probably by entrapment of paclitaxel into micelles (3 -7). Generally, substantial interpatient variability of paclitaxel pharmacokinetic variables has been noted (8).…”

mentioning

confidence: 99%

Quantitative Effect of Gender, Age, Liver Function, and Body Size on the Population Pharmacokinetics of Paclitaxel in Patients with Solid Tumors

Joerger

Huitema

Bongard

et al. 2006

Clinical Cancer Research

102

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Background:The aim of this study was to quantitatively assess the effect of anthropometric and biochemical variables and third-space effusions on paclitaxel pharmacokinetics in solid tumor patients. Materials and Methods: Plasma concentration-time data of paclitaxel were collected in patients with non^small cell lung cancer (n = 84), ovarian cancer (n = 40), and various solid tumors (n = 44), totaling 168 patients. Paclitaxel was given as a 3-hour infusion (n = 163) at doses ranging from 100 to 250 mg/m 2 , or as a 24-hour infusion (n = 5) at a dose of 135 or 175 mg/m 2 . Data were analyzed using nonlinear mixed-effect modeling. Results: A three-compartment model with saturable elimination and distribution was used to describe concentration-time data. Male gender and body surface area were positively correlated with maximal elimination capacity of paclitaxel (VM EL ); patient age and total bilirubin were negatively correlated withVM EL (P < 0.005 for all correlations).Typically, male patients had a 20% higher VM EL ; a 0.2 m 2 increase of body surface area led to a 9% increase of VM EL ; a 10-year increase of patient age led to a 5% decrease of VM EL ; and a 10-Amol increase of total bilirubin led to a 14% decrease of VM EL . Third-space effusions were not correlated with paclitaxel pharmacokinetics. Conclusions: This extended retrospective population analysis showed patient gender to significantly and independently affect paclitaxel distribution and elimination. Body surface area, total bilirubin, and patient age were confirmed to affect paclitaxel elimination. This pharmacokinetic model allowed quantification of the covariate effects on the elimination of paclitaxel and may be used for covariate-adapted paclitaxel dosing.Paclitaxel formulated in Cremophor EL is regularly administered to patients with non -small cell lung cancer (NSCLC), ovarian cancer, and breast cancer. The pharmacokinetics of paclitaxel were initially believed to be linear, but Sonnichsen and Gianni reported that paclitaxel pharmacokinetics were best described with a two-and three-compartment model, respectively, with saturable elimination and saturable distribution to the tissues (1, 2). Later, the formulation vehicle of paclitaxel, Cremophor EL, was reported to be the cause of the (apparent) nonlinear plasma behavior of paclitaxel, probably by entrapment of paclitaxel into micelles (3 -7). Generally, substantial interpatient variability of paclitaxel pharmacokinetic variables has been noted (8).Hepatic metabolism and biliary excretion are the most important elimination routes of paclitaxel and its metabolites (9). Paclitaxel has been shown to bind extensively to plasma proteins (from 95% to < 97%), with high central (mean = 13.8 L/m 2 ) and steady-state (mean = 182 L/m 2 ) volumes of distribution (10-13). However, data on specific tissue and compartment distribution of paclitaxel in humans following i.v. administration are limited. Paclitaxel concentrations in ascites have been analyzed in single patients, where the concentration ...

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Mechanism-Based Pharmacokinetic Model for Paclitaxel

Abstract: Earlier PK models for paclitaxel have been empirical. This study shows that a mechanistic model can be used to describe the nonlinear PK of paclitaxel. There is an indication that the PK/PD relationship is not the same for unbound and total plasma concentrations.

Cited by 131 publications

References 15 publications

Phase I trial of the novel taxane BMS-184476 administered in combination with carboplatin every 21 days

Phase I trial of the novel taxane BMS-184476 administered in combination with carboplatin every 21 days

Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies

Quantitative Effect of Gender, Age, Liver Function, and Body Size on the Population Pharmacokinetics of Paclitaxel in Patients with Solid Tumors

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