Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients

doi:10.1016/S0959-8049(03)00126-6

European Journal of Cancer

Volume 39, Issue 8, May 2003, Pages 1105-1114

https://doi.org/10.1016/S0959-8049(03)00126-6 Get rights and content

Abstract

The aim of this study was to validate and further develop a mechanism-based population pharmacokinetic model for paclitaxel (Taxol®; Bristol-Myers Squibb Co, Princeton, NJ, USA) based on the knowledge of Cremophor EL (CrEL) micelle entrapment and to evaluate the exposure/toxicity relationships. Paclitaxel (total and unbound) and CrEL concentrations were obtained according to a sparse sampling scheme with on average only 3.5 samples per course from 45 patients with solid tumours who received 3-hour infusions of paclitaxel (final dose range 112–233 mg/m²). The present data were predicted well by the mechanism-based model. In addition, bilirubin and body size were found to be significant as covariates. A change in body surface area (BSA) of 0.1 m² typically caused a change in clearance (CL) of 22.3 l/h and an increase in bilirubin of 10 μM typically caused a decrease in CL of 41 l/h. Toxicity was best described by a threshold model. In conclusion, even with a sparse sampling scheme, the same mechanism-based binding components as in the previously developed model could be identified. Once the CrEL and total paclitaxel plasma concentrations are known, the unbound concentrations, which are more closely related to the haematological toxicity, can be predicted.

Introduction

The non-linear pharmacokinetics of paclitaxel in plasma has been described in several studies. The non-linearity has mostly been described as both saturable elimination and distribution (saturable transport [1] or saturable binding [2]), but also as caused by the micelle-forming vehicle Cremophor EL (CrEL) 3, 4, 5. CrEL has been suggested to inhibit P-glycoprotein-mediated biliary secretion [6], cause lipoprotein dissociation that would alter protein binding [7] and, recently, it has been suggested to cause an alteration in the distribution in human blood by entrapment in micelles [5]. The free fraction of paclitaxel has been shown to decrease with increasing CrEL concentrations [5]. Paclitaxel has previously been shown to bind to both albumin and α₁-acid glycoprotein [8]. In our previous model [9], the non-linearity could be explained to a large extent by binding that was directly proportional to the CrEL concentration.

The pharmacokinetic/pharmacodynamic (PK/PD) relationship for paclitaxel toxicity has previously been described by a threshold model 6, 10 and also by more general models using a non-linear continuous function 11, 12. Since the free fraction of paclitaxel has been shown to vary over time and the drug effect is generally considered to be more closely related to the unbound drug, the PK/PD relationship based on the total concentration needs to be re-evaluated.

The aim of this study was to validate a previously developed mechanism-based population pharmacokinetic model that describes unbound and total plasma concentrations of paclitaxel, to extend the model with covariates and, based on new toxicity data, to characterise the PK/PD relationship based on unbound and total concentrations of paclitaxel.

Section snippets

Patients and methods

This study included 14 male and 31 female patients with different types of solid tumours (colorectal, gastric, gall bladder, breast, uterine, ovarian, pancreas) at advanced stages, not amenable to standard therapy. They received paclitaxel as a 3-hour intravenous (i.v.) infusion with an initial dose of 175 mg/m² every third week within a trial on the feasibility of chemotherapy selection based on drug sensitivity testing ex vivo. Dose adjustments, escalations and reductions, were based on any

Pharmacokinetics

Observed concentrations of CrEL, unbound (C_u) and total concentrations (C_p) of paclitaxel are shown in Fig. 1. The unbound concentrations were well described by the earlier model. As can be seen in Fig. 2, the predictions from model A and dose (i) (left panel) deviated to some extent from the line of identity. The bias in etas (interindividual variability+interoccasion variability), in the predictions from EB estimates based on Model A, dose and observed unbound concentrations (ii) (middle

Discussion

These data were well described by the previously developed model and also the unbound concentrations were well predicted from total plasma concentrations of paclitaxel, CrEL and the model. Both two and three compartment non-linear pharmacokinetic models have been used when describing paclitaxel pharmacokinetics 1, 2, 6. In this study, there was not enough data to support more than two compartments. No dose dependence could be seen in the free concentrations. The typical value of CL in the

Acknowledgements

We are grateful to the patients who kindly participated in this study. We would also like to thank Britt Jansson, Eric Brouwer and Karin Sjöberg for their technical assistance, Siv Jönsson for many helpful discussions regarding model building and, finally, we thank the Swedish Cancer Society and Bristol Myers Squibb Clinical Oncology Research Department for their financial support.

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¹: Current address: Clinical Pharmacology Research Core, Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD 20892, USA.

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Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients

Abstract

Introduction

Section snippets

Patients and methods

Pharmacokinetics

Discussion

Acknowledgements

Anal. Biochem.

Anal. Biochem.

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Drug Metab. Dispos.

Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles

Cancer Chemother. Pharmacol.

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

Br. J. Cancer

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Cancer Res.

Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans

J. Clin. Oncol.

Effects of Cremophor EL on distribution of Taxol to serum lipoproteins

Br. J. Cancer

Binding of taxol to human plasma, albumin and alpha 1-acid glycoprotein

Res. Commun. Chem. Pathol. Pharmacol.

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J. Clin. Oncol.

Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients

J. Clin. Oncol.