Pharmacokinetics of continuous-infusion high-dose thiotepa

Area of Science:

• Pharmacology
• Oncology
• Clinical Pharmacy

Background:

• High-dose chemotherapy regimens, including thiotepa and cyclophosphamide with autologous bone marrow reinfusion, are used for advanced neoplasms.
• Understanding the pharmacokinetics of thiotepa is crucial for optimizing treatment and managing toxicity.

Purpose of the Study:

• To investigate the pharmacokinetics of thiotepa when administered as a continuous infusion over 4 days in patients with advanced neoplasms.
• To determine plasma concentrations, systemic clearance, and factors influencing thiotepa disposition.

Main Methods:

• A pharmacokinetic study involving 18 patients undergoing high-dose thiotepa and cyclophosphamide therapy.
• Plasma samples were collected during and after a 4-day continuous infusion of thiotepa.
• Thiotepa plasma concentrations were quantified using the method described by Egorin et al.

Main Results:

• Peak plasma thiotepa concentrations were observed within the first 24 hours of infusion in 72% of patients.
• Plasma thiotepa levels decreased by an average of 29% from peak by the end of the 96-hour infusion.
• Average total systemic clearance of thiotepa was 16.7 L/m2/hour, with an inverse correlation noted between clearance and thiotepa dose (P < 0.01).

Conclusions:

• Thiotepa exhibits concentration-dependent clearance in patients receiving high-dose therapy.
• The observed decline in plasma concentrations during infusion suggests potential non-linear pharmacokinetics or saturation of elimination pathways.
• These findings are important for dose individualization and therapeutic drug monitoring in high-dose thiotepa regimens.