Limited sampling models for CPT-11, SN-38, and SN-38 glucuronide

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Clinical Pharmacology
• Oncology Drug Development

Background:

• Irinotecan (CPT-11) is a crucial chemotherapy agent for advanced solid tumors.
• Accurate therapeutic drug monitoring of CPT-11 and its metabolites is essential for optimizing efficacy and minimizing toxicity.
• Traditional pharmacokinetic profiling requires frequent blood sampling, which can be burdensome for patients.

Purpose of the Study:

• To develop and validate limited sampling models (LSMs) for predicting the area under the curve (AUC) of irinotecan (CPT-11).
• To establish LSMs for predicting the AUC of key CPT-11 metabolites, SN-38 and SN-38 glucuronide (SN-38G).
• To assess the accuracy and feasibility of using minimal blood samples for pharmacokinetic assessments in clinical practice.

Main Methods:

• Regression models were developed using data from a Phase I clinical trial of 34 patients with advanced solid tumors receiving CPT-11.
• Multiple stepwise and all possible subsets regression analyses were employed to identify optimal predictor variables.
• Model validation included bootstrap simulation testing to assess the robustness and generalizability of the developed LSMs.

Main Results:

• Optimal LSMs for CPT-11 AUC utilized plasma concentrations at the end of infusion and 4 hours post-infusion, with an optional inclusion of a 7.5-hour time point.
• Predicting SN-38 and SN-38G AUC required an additional metabolite concentration measurement at 48 hours post-infusion.
• The developed LSMs demonstrated high accuracy, predicting most patient AUC values within 10% of the true calculated values.

Conclusions:

• Limited sampling models can accurately predict CPT-11 AUC using only two to three plasma concentration time-points.
• Various LSM alternatives offer comparable accuracy, suggesting clinical considerations and patient burden should guide model selection.
• These findings support the potential for simplified pharmacokinetic monitoring of irinotecan therapy in clinical settings.