Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of Paclitaxel in patients with solid tumors.
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.


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-micromol 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.
Joerger
Markus
M
Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
Huitema
Alwin D R
AD
van den Bongard
Desiree H J G
DH
Schellens
Jan H M
JH
Beijnen
Jos H
JH
D000367:Age Factors; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D049628:Body Size; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011153:Population; D012737:Sex Factors
D000970:Antineoplastic Agents; D017239:Paclitaxel