Modeling plasma and saliva topotecan concentration time course using a population approach

Area of Science:

• Pharmacology
• Oncology
• Clinical Pharmacy

Background:

• Topotecan is a chemotherapy agent used for metastatic epithelial ovarian cancer.
• Accurate pharmacokinetic modeling is crucial for optimizing topotecan dosage and patient outcomes.
• Simultaneous analysis of drug concentrations in different biological fluids can enhance monitoring strategies.

Purpose of the Study:

• To develop a pharmacokinetic model that integrates topotecan concentrations in both plasma and saliva.
• To assess the utility of salivary topotecan levels for therapeutic drug monitoring.
• To establish a simplified sampling strategy for pharmacokinetic evaluation.

Main Methods:

• A three-compartment pharmacokinetic model was developed using nonlinear mixed-effects modeling.
• Data from 13 ovarian cancer patients receiving topotecan were analyzed.
• Interindividual and interoccasion variability were assessed, and a relationship between creatinine clearance and topotecan clearance was explored.

Main Results:

• The model successfully linked plasma (central compartment) and saliva (peripheral compartment) topotecan concentrations.
• A significant correlation was found between creatinine clearance and topotecan clearance, improving model fit.
• Large interindividual variability in topotecan clearance was observed (10.4-23 L/h), with limited interoccasion variability (6%).
• A validated limited sampling strategy using Bayesian estimation with two time points was developed.

Conclusions:

• Salivary topotecan concentrations provide a viable and effective means for drug monitoring.
• The developed pharmacokinetic model and limited sampling strategy can support optimized topotecan therapy.
• This approach may enhance therapeutic drug monitoring for topotecan in ovarian cancer patients.