Nonlinear population pharmacokinetics of sirolimus in patients with advanced cancer

K. Wu, E. E W Cohen, L. K. House, J. Ramírez, W. Zhang, M. J. Ratain, Robert Bies

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Sirolimus, the prototypical inhibitor of the mammalian target of rapamycin, has substantial antitumor activity. In this study, sirolimus showed nonlinear pharmacokinetic characteristics over a wide dose range (from 1 to 60 mg/week). The objective of this study was to develop a population pharmacokinetic (PopPK) model to describe the nonlinearity of sirolimus. Whole blood concentration data, obtained from four phase I clinical trials, were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach. The influence of potential covariates was evaluated. Model robustness was assessed using nonparametric bootstrap and visual predictive check approaches. The data were well described by a two-compartment model incorporating a saturable Michaelis?Menten kinetic absorption process. A covariate analysis identified hematocrit as influencing the oral clearance of sirolimus. The visual predictive check indicated that the final pharmacokinetic model adequately predicted observed concentrations. The pharmacokinetics of sirolimus, based on whole blood concentrations, appears to be nonlinear due to saturable absorption.

Original languageEnglish
Article numbere17
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume1
Issue number1
DOIs
StatePublished - 2012

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Pharmacokinetics
Sirolimus
Cancer
Population
Blood
Covariates
Neoplasms
Absorption
Model Robustness
Phase I Trial
Nonparametric Bootstrap
Compartment Model
Mixed Effects
Nonlinear Effects
Clearance
Clinical Trials
Inhibitor
Dose
Clinical Trials, Phase I
Kinetics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Nonlinear population pharmacokinetics of sirolimus in patients with advanced cancer. / Wu, K.; Cohen, E. E W; House, L. K.; Ramírez, J.; Zhang, W.; Ratain, M. J.; Bies, Robert.

In: CPT: Pharmacometrics and Systems Pharmacology, Vol. 1, No. 1, e17, 2012.

Research output: Contribution to journalArticle

Wu, K. ; Cohen, E. E W ; House, L. K. ; Ramírez, J. ; Zhang, W. ; Ratain, M. J. ; Bies, Robert. / Nonlinear population pharmacokinetics of sirolimus in patients with advanced cancer. In: CPT: Pharmacometrics and Systems Pharmacology. 2012 ; Vol. 1, No. 1.
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