Safety and pharmacology of paclitaxel in patients with impaired liver function:

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British Journal of Clinical Pharmacology

OnlineEarly Articles

To cite this article: M. Joerger, A. D. R. Huitema, M. T. Huizing, P. H. B.

Willemse, A. de Graeff, H. Rosing, J. H. M. Schellens, J. H. Beijnen, J. B.

Vermorken

Safety and pharmacology of paclitaxel in patients with impaired liver

function: a population pharmacokinetic-pharmacodynamic study

British Journal of Clinical Pharmacology (OnlineEarly Articles).

doi:10.1111/j.1365-2125.2007.02956.x

Abstract

Safety and pharmacology of paclitaxel in patients with impaired liver

function: a population pharmacokinetic–pharmacodynamic study

M. Joerger,1,21Department of Pharmacy & Pharmacology, the Netherlands Cancer

Institute/Slotervaart Hospital and 2Department of Medical Oncology, Antoni

van Leeuwenhoek Hospital/the Netherlands Cancer Institute, Amsterdam, the

Netherlands, Markus Joerger, MD, Cantonal Hospital, Department of Oncology

and Haematology, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland.

Tel: +41 7 1494 1111

E-mail: markus.joerger@... A. D. R. Huitema,11Department of Pharmacy &

Pharmacology, the Netherlands Cancer Institute/Slotervaart Hospital and M.

T. Huizing,33Department of Medical Oncology, University Hospital Antwerpen,

Edegem, Belgium, P. H. B. Willemse,44Department of Medical Oncology,

University Medical Centre, Groningen, A. de Graeff,55Department of Internal

Medicine, University Medical Centre and H. Rosing,11Department of Pharmacy &

Pharmacology, the Netherlands Cancer Institute/Slotervaart Hospital and J.

H. M. Schellens,2,62Department of Medical Oncology, Antoni van Leeuwenhoek

Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands,

6Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of

Pharmaceutical, Sciences, Utrecht University, Utrecht, the Netherlands J. H.

Beijnen1,2,61Department of Pharmacy & Pharmacology, the Netherlands Cancer

Institute/Slotervaart Hospital and 2Department of Medical Oncology, Antoni

van Leeuwenhoek Hospital/the Netherlands Cancer Institute, Amsterdam, the

Netherlands, 6Division of Drug Toxicology, Department of Biomedical

Analysis, Faculty of Pharmaceutical, Sciences, Utrecht University, Utrecht,

the Netherlands & J. B. Vermorken33Department of Medical Oncology,

University Hospital Antwerpen, Edegem, Belgium, 1Department of Pharmacy &

Pharmacology, the Netherlands Cancer Institute/Slotervaart Hospital and

2Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/the

Netherlands Cancer Institute, Amsterdam, the Netherlands, 3Department of

Medical Oncology, University Hospital Antwerpen, Edegem, Belgium,

4Department of Medical Oncology, University Medical Centre, Groningen,

5Department of Internal Medicine, University Medical Centre and 6Division of

Drug Toxicology, Department of Biomedical Analysis, Faculty of

Pharmaceutical, Sciences, Utrecht University, Utrecht, the Netherlands

Markus Joerger, MD, Cantonal Hospital, Department of Oncology and

Haematology, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland.

Tel: +41 7 1494 1111

E-mail: markus.joerger@...

Abstract

What is already known about this subject

• There are few data about the safety of paclitaxel in patients with

clinically significant liver impairment. A study by Venook and colleagues (J

Clin Oncol 1998; 16: 1811–19) studied paclitaxel pharmacokinetics (PK) and

pharmacodynamics (PD) in patients with liver impairment. The results were

mainly descriptive, as detailed PK–PD data were available for only a

subgroup of patients.

• Another study by and colleagues found a correlation between tumour

involvement of the liver, aspartate aminotransferase and total bilirubin

concentrations and reduced paclitaxel clearance in 48 patients with advanced

breast cancer in an early combined Phase I/II study (J Clin Oncol 1994; 12:

1621–9).

• Finally, the study by Huizing and colleagues (Ann Oncol 1995; 6: 699–704)

described two advanced breast cancer patients with liver impairment who

experienced higher paclitaxel AUC concentrations and more severe

neuropathywhen exposed to paclitaxel 250 mg m2 as a 3-h infusion.

• Liver impairment has been studied as a covariate within population models

of paclitaxel in patients with normal or mildly impaired liver function

(Henningsson et al. Eur JCancer 2003; 39: 1105–14; Joerger et al. Clin

Cancer Res 2006; 12: 2150–7). Both studies found a negative correlation

between total bilirubin concentrations and paclitaxel elimination.

What this study adds

• A direct relationship between liver impairment, paclitaxel elimination

and susceptibility to neutropenia/thrombopenia.

• As a result of PK–PD simulations, suggestions could be made for (further)

dose adaptations for patients with more severe liver impairment.

AimsTo assess quantitatively the safety and pharmacology of paclitaxel in

patients with moderate to severe hepatic impairment.

MethodsSolid tumour patients were enrolled into five liver function cohorts

as defined by liver transaminase and total bilirubin concentrations.

Paclitaxel was administered as a 3-h intravenous infusion at doses ranging

from 110 to 175 mg m2, depending on liver impairment. Covariate and

semimechanistic pharmacokinetic–pharmacodynamic (PK–PD) population modelling

was used to describe the impact of liver impairment on the pharmacology and

safety of paclitaxel.

ResultsThirty-five patients were included in the study, and PK data were

assessed for 59 treatment courses. Most patients had advanced breast cancer

(n = 22). Objective responses to paclitaxel were seen in four patients

(11%). Patients in higher categories of liver impairment had a significantly

lower paclitaxel elimination capacity (R2 = & #8722;0.38, P = 0.05), and

total bilirubin was a significant covariate to predict decreased elimination

capacity with population modelling (P = 0.002). Total bilirubin was also a

significant predictor of increased haematological toxicity within the

integrated population PK–PD model (P < 104). Data simulations were used to

calculate safe initial paclitaxel doses, which were lower than the

administered doses for liver impairment cohorts III–V.

ConclusionsTotal bilirubin is a good predictor of paclitaxel elimination

capacity and of individual susceptibility to paclitaxel-related

myelosuppression in cancer patients with moderate to severe liver

impairment. The proposed, adapted paclitaxel doses need validation in

prospective trials.

http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2125.2007.02956.x

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