Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors

Diane R. Mould, Nicholas H G Holford, Jan H M Schellens, Jos H. Beijnen, Paul R. Hutson, Hilde Rosing, Willem W. Ten Bokkel Huinink, Eric K. Rowinsky, Joan H. Schiller, Mark Russo, Graham Ross

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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/m2 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.

Original languageEnglish (US)
Pages (from-to)334-348
Number of pages15
JournalClinical Pharmacology and Therapeutics
Volume71
Issue number5
DOIs
StatePublished - 2002

Fingerprint

Topotecan
Pharmacokinetics
Neutropenia
Population
Neoplasms
Platinum
Logistic Models
Body Weight
Kidney
Intravenous Infusions
Area Under Curve
Therapeutics
Clinical Trials

ASJC Scopus subject areas

  • Pharmacology

Cite this

Mould, D. R., Holford, N. H. G., Schellens, J. H. M., Beijnen, J. H., Hutson, P. R., Rosing, H., ... Ross, G. (2002). Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. Clinical Pharmacology and Therapeutics, 71(5), 334-348. https://doi.org/10.1067/mcp.2002.123553

Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. / Mould, Diane R.; Holford, Nicholas H G; Schellens, Jan H M; Beijnen, Jos H.; Hutson, Paul R.; Rosing, Hilde; Ten Bokkel Huinink, Willem W.; Rowinsky, Eric K.; Schiller, Joan H.; Russo, Mark; Ross, Graham.

In: Clinical Pharmacology and Therapeutics, Vol. 71, No. 5, 2002, p. 334-348.

Research output: Contribution to journalArticle

Mould, DR, Holford, NHG, Schellens, JHM, Beijnen, JH, Hutson, PR, Rosing, H, Ten Bokkel Huinink, WW, Rowinsky, EK, Schiller, JH, Russo, M & Ross, G 2002, 'Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors', Clinical Pharmacology and Therapeutics, vol. 71, no. 5, pp. 334-348. https://doi.org/10.1067/mcp.2002.123553
Mould, Diane R. ; Holford, Nicholas H G ; Schellens, Jan H M ; Beijnen, Jos H. ; Hutson, Paul R. ; Rosing, Hilde ; Ten Bokkel Huinink, Willem W. ; Rowinsky, Eric K. ; Schiller, Joan H. ; Russo, Mark ; Ross, Graham. / Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. In: Clinical Pharmacology and Therapeutics. 2002 ; Vol. 71, No. 5. pp. 334-348.
@article{7fe9f18cc1a9486e8ca5aa5e9c9b9efa,
title = "Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors",
abstract = "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/m2 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.",
author = "Mould, {Diane R.} and Holford, {Nicholas H G} and Schellens, {Jan H M} and Beijnen, {Jos H.} and Hutson, {Paul R.} and Hilde Rosing and {Ten Bokkel Huinink}, {Willem W.} and Rowinsky, {Eric K.} and Schiller, {Joan H.} and Mark Russo and Graham Ross",
year = "2002",
doi = "10.1067/mcp.2002.123553",
language = "English (US)",
volume = "71",
pages = "334--348",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors

AU - Mould, Diane R.

AU - Holford, Nicholas H G

AU - Schellens, Jan H M

AU - Beijnen, Jos H.

AU - Hutson, Paul R.

AU - Rosing, Hilde

AU - Ten Bokkel Huinink, Willem W.

AU - Rowinsky, Eric K.

AU - Schiller, Joan H.

AU - Russo, Mark

AU - Ross, Graham

PY - 2002

Y1 - 2002

N2 - 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/m2 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.

AB - 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/m2 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.

UR - http://www.scopus.com/inward/record.url?scp=18344394148&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=18344394148&partnerID=8YFLogxK

U2 - 10.1067/mcp.2002.123553

DO - 10.1067/mcp.2002.123553

M3 - Article

C2 - 12011819

AN - SCOPUS:18344394148

VL - 71

SP - 334

EP - 348

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 5

ER -