Prednisolone: limited sampling strategies for estimating pharmacokinetic parameters

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Clinical Pharmacology
• Bioequivalence Studies

Background:

• Accurate estimation of pharmacokinetic parameters like area under the concentration-time curve (AUC) and maximum concentration (Cmax) is crucial for drug development and bioequivalence studies.
• Traditional pharmacokinetic assessments require multiple blood samples, which can be burdensome for participants and resource-intensive.
• Limited-sampling strategies (LSS) offer a potential solution by estimating key parameters from a minimal number of samples.

Purpose of the Study:

• To develop and validate limited-sampling strategy (LSS) models for estimating prednisolone's area under plasma concentration versus time curve (AUC(0-infinity)), maximum plasma concentration (Cmax), and total oral clearance (CL/F).
• To assess the utility of these LSS models in determining bioequivalence between different prednisone formulations.

Main Methods:

• Developed LSS models using linear regression analysis of pharmacokinetic parameters against plasma prednisolone concentrations from a bioequivalence study (n=24) involving prednisone (20 mg PO).
• Validated the LSS models using data from the test formulation and simulated data sets generated by ADAPT II software.
• Assessed bioequivalence using LSS-derived AUC(0-infinity) and Cmax values compared to original values.

Main Results:

• Single-point LSS models (1.5h for Cmax, 7h for AUC(0-infinity)/CL/F) accurately estimated pharmacokinetic parameters (R2=0.84-0.97, bias <1%, precision <10%) for the reference formulation.
• Validation on test formulations showed precise estimates (R2>0.83, bias <3%, precision <10%) with single-point models.
• Two-point LSS models (1.5h and 7h) were required for accurate estimation from simulated data (R2>0.87, bias <6%, precision <8%).
• Bioequivalence assessment results using LSS-derived parameters were identical to those obtained using original data.

Conclusions:

• One- and two-point LSS models provide accurate estimates of prednisolone's key pharmacokinetic parameters after oral prednisone administration.
• These LSS models enable reliable bioequivalence assessment between prednisone formulations, reducing the need for extensive blood sampling.
• The developed LSS models are valuable tools for efficient pharmacokinetic analysis in clinical studies.