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

• Published in: Clinical cancer research Vol. 12; no. 7; pp. 2150 - 2157
• Main Authors: JOERGER, Markus, HUITEMA, Alwin D. R, VAN DEN BONGARD, Desiree H. J. G, SCHELLENS, Jan H. M, BEIJNEN, Jos H
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-04-2006
• Subjects: Age Factors; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Body Size; drug elimination; Female; gender; Humans; immunohistochemistry; Liver - drug effects; Liver - metabolism; Liver Function Tests; Male; Medical sciences; Middle Aged; Models, Biological; Neoplasms - drug therapy; Paclitaxel - pharmacokinetics; Paclitaxel - therapeutic use; Pharmacology. Drug treatments; Population; population modeling; Sex Factors; SITES AND TUMOR TYPES; toxicity; Antineoplastic agent; Human; Solid tumor; Population pharmacokinetics; Sex; Corporal biometry; Malignant tumor; Liver function; Taxane derivatives; Body size; Paclitaxel; Antimitotic; Age; Quantitative analysis
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-2069

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 with VM 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-μmol 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.