Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors.
OBJECTIVE
Our objective was to describe the pharmacokinetics and pharmacodynamics of topotecan in patients.


METHODS
Data were pooled from 9 clinical trials. Topotecan, as a single-agent therapy, was administered as a daily 30-minute intravenous infusion for 5 days on a 3-week cycle. Doses of 0.2 to 2.0 mg/m(2) were studied; concentration and neutropenic event data were obtained on multiple occasions. The pharmacokinetics were characterized with use of hierarchical nonlinear regression. The relationship between severity of neutropenia and exposure was characterized with use of logistic regression.


RESULTS
The pharmacokinetics of topotecan were described with a linear 2-compartment model. Compromised renal function, low body weight, and poor Eastern Cooperative Oncology Group performance status were determinants of lower clearance, resulting in elevated exposure. Application of covariates reduced interpatient variability in clearance. Logistic regression showed that topotecan area under the concentration-time curve from 0 to 24 hours was predictive of the severity of neutropenia; the only other significant covariate was the number of courses of previous treatment with platinum-based regimens.


CONCLUSIONS
Patients with compromised renal function, low body weight, or poor performance status had low topotecan clearance. Patients with high topotecan AUC had an increased probability of experiencing severe neutropenia, which was greater if the patient had been pretreated with platinum-based agents. The use of covariates to individualize dose would result in less variability in exposure, reducing the likelihood of severe neutropenia and potentially improving treatment benefit.
Mould
Diane R
DR
Projections Research Inc., 535 Springview Lane, Phoenixville, PA 19460, USA.
Holford
Nicholas H G
NH
Schellens
Jan H M
JH
Beijnen
Jos H
JH
Hutson
Paul R
PR
Rosing
Hilde
H
ten Bokkel Huinink
Willem W
WW
Rowinsky
Eric K
EK
Schiller
Joan H
JH
Russo
Mark
M
Ross
Graham
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D016001:Confidence Intervals; D005260:Female; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009503:Neutropenia / Q000139:chemically induced; D011336:Probability; D019772:Topotecan / Q000009:adverse effects* / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D019772:Topotecan