Population pharmacokinetics of topotecan: intraindividual variability in total drug.
The inter- and intraindividual variabilities in topotecan clearance (CL) were explored using a population pharmacokinetic approach. Total (lactone + hydroxy acid) topotecan plasma concentrations were obtained in 31 women with metastatic epithelial ovarian cancer treated by the 30-min intravenous infusion on 5 subsequent days. The data corresponding to three occasions (days 1 and 5 of cycle 1, and day 1 of cycle 2), were analyzed using the nonlinear mixed effect model program. A large interindividual variability was observed, with CL varying from 9.1 to 42.51 per hour (mean 21.0). Topotecan CL was related to serum creatinine level, and age. A close relationship was also observed between topotecan CL and creatinine clearance. Intraindividual variability both within cycle 1 and between the two first cycles was limited, with a mean variation of -2+/-17%, and + 5+/-20%, respectively. A limited sampling strategy using Bayesian estimation based on two samples (5 min before the end of the 30-min infusion, and 4 h after the end of infusion) was developed. The results of this study combine relationships between topotecan pharmacokinetic parameters and patient covariates that may be useful for a priori dose adjustment, and convenient sampling procedure that can be used for further studies and drug monitoring.
Montazeri
A
A
Institut Claudius-Regaud, Toulouse, France.
Boucaud
M
M
Lokiec
F
F
Pinguet
F
F
Culine
S
S
Déporte-Féty
R
R
Albin
N
N
Laguerre
B
B
Goupil
A
A
Bugat
R
R
Canal
P
P
Chatelut
E
E
D000368:Aged; D000465:Algorithms; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D005260:Female; D006801:Humans; D008875:Middle Aged; D011153:Population; D012189:Retrospective Studies; D019772:Topotecan / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D019772:Topotecan