Nonlinear population pharmacokinetics of sirolimus in patients with advanced cancer

Area of Science:

• Pharmacology
• Clinical Pharmacology
• Pharmacometrics

Background:

• Sirolimus, a mammalian target of rapamycin inhibitor, demonstrates significant antitumor activity.
• Sirolimus exhibits nonlinear pharmacokinetic characteristics across a broad dose range (1-60 mg/week).

Purpose of the Study:

• To develop a population pharmacokinetic (PopPK) model to characterize the nonlinear pharmacokinetics of sirolimus.
• To identify covariates influencing sirolimus pharmacokinetics.

Main Methods:

• Analysis of whole blood concentration data from four Phase I clinical trials.
• Utilized nonlinear mixed-effects modeling (NONMEM) for PopPK model development.
• Assessed model robustness with nonparametric bootstrap and visual predictive checks.

Main Results:

• A two-compartment model with Michaelis-Menten saturable absorption best described the data.
• Hematocrit was identified as a significant covariate affecting sirolimus oral clearance.
• Visual predictive checks confirmed the model's adequate prediction of observed concentrations.

Conclusions:

• Sirolimus pharmacokinetics are nonlinear, primarily driven by saturable absorption.
• The developed PopPK model provides a robust framework for understanding sirolimus disposition.
• Hematocrit is a crucial factor to consider in sirolimus dosing strategies.