Dosing of thioTEPA for myeloablative therapy

Area of Science:

• Pharmacology and Toxicology
• Hematology and Oncology
• Clinical Pharmacy

Background:

• High-dose thioTEPA is a standard component of myeloablative regimens for marrow transplantation.
• The pharmacokinetic profile and optimal dosing of thioTEPA in obese patients remain underexplored.
• Obesity may influence drug distribution and clearance, potentially impacting efficacy and toxicity.

Purpose of the Study:

• To determine the pharmacokinetics of thioTEPA and its metabolite TEPA in adult patients undergoing marrow transplantation.
• To evaluate the correlation between thioTEPA/TEPA exposure and regimen-related toxicity (RRT).
• To assess the impact of body weight on thioTEPA pharmacokinetics and toxicity, and to propose dosing strategies for obese patients.

Main Methods:

• Pharmacokinetic analysis of thioTEPA and TEPA in 15 adults receiving thioTEPA (150-250 mg/m2) daily for 3 days with busulfan and cyclophosphamide.
• Plasma samples collected over 24 hours, concentrations measured by gas chromatography.
• Correlation analysis between drug concentrations (peak, AUC), pharmacokinetic parameters (Vc, t1/2, clearance), and RRT grades; comparison of RRT in obese vs. non-obese patients.

Main Results:

• Mean plasma concentrations of thioTEPA and TEPA were determined at 22-24 hours post-infusion.
• Significant association found between RRT grades 2-4 and TEPA peak concentration (>1.75 µg/ml) or combined thioTEPA/TEPA AUC (>30 mg h/L).
• ThioTEPA volume of central compartment (Vc) correlated significantly with adjusted body weight (r=0.74, P=0.0015); obese patients dosed on ideal weight had higher RRT than those dosed on adjusted weight.

Conclusions:

• Drug exposure (TEPA peak, combined AUC) is a key determinant of toxicity in thioTEPA-based regimens.
• ThioTEPA pharmacokinetics, particularly Vc, are influenced by body weight.
• Dosing thioTEPA based on adjusted body weight is recommended for obese patients to mitigate toxicity.