Concentration-dependent blood binding: assessing implications through physiologically based Pharmacokinetic modeling...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Physiologically-Based Pharmacokinetic (PBPK) Modeling
• Drug-Red Blood Cell Interactions

Background:

• Concentration-dependent drug binding to red blood cells complicates pharmacokinetic assessments.
• Understanding how factors like hematocrit influence drug behavior is crucial for accurate dosing.

Purpose of the Study:

• To compare concentration-dependent and independent blood-to-plasma drug concentration ratios (B/P) using physiologically-based pharmacokinetic (PBPK) models.
• To evaluate the impact of hematocrit and dose on tacrolimus pharmacokinetics under different binding assumptions.

Main Methods:

• Developed and validated two PBPK models for tacrolimus: one with saturable blood binding and one with constant B/P.
• Simulated intravenous and oral dosing scenarios across a range of hematocrit and dose levels.
• Assessed differences in predicted drug concentrations (total and unbound) and area under the curve (AUC).

Main Results:

• Varying hematocrit (15-45%) for IV infusions predicted 6-9% differences in total blood AUC but 37-39% differences in unbound plasma AUC.
• Oral dosing showed substantial differences in trough (50-130%), peak (78-284%), and AUC (up to 125%) concentrations based on binding assumptions.
• Higher doses and hematocrit levels amplified the discrepancies between the two models.

Conclusions:

• PBPK models that ignore concentration-dependent binding may require compensatory parameter adjustments, limiting predictive accuracy.
• Accurate prediction of unbound drug concentrations and clinical outcomes necessitates accounting for saturable red blood cell binding.
• The choice of binding assumption in PBPK models significantly impacts predictions of drug exposure and variability.