Revising Pharmacokinetics of Oral Drug Absorption: II Bioavailability-Bioequivalence Considerations

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Pharmacometrics and Mathematical Modeling

Background:

• Physiologically based pharmacokinetic (PBFTPK) models offer a mechanistic approach to understanding drug disposition.
• Finite time PBFTPK models, specifically first-order (PBFTPK)1 and zero-order (PBFTPK)0, provide a framework for analyzing drug absorption over time.
• Assessing bioavailability and bioequivalence is crucial for drug development and therapeutic efficacy.

Purpose of the Study:

• To investigate the application of (PBFTPK)1 and (PBFTPK)0 models in bioavailability and bioequivalence assessments.
• To develop a novel methodology for estimating absolute bioavailability (F) using only oral drug administration data.
• To compare the performance of these models against traditional methods like the Bateman equation.

Main Methods:

• Simulated concentration-time data were generated using the Bateman equation and compared with data from (PBFTPK)1 and (PBFTPK)0 models.
• Key parameters such as blood concentration at the end of absorption (Cb(τ)) and maximum concentration (Cmax) were analyzed.
• The utility of specific mathematical expressions ([Formula: see text] and [Formula: see text]) for bioequivalence was explored, and equations for calculating F from oral data were derived.

Main Results:

• (PBFTPK)0 models demonstrated complex absorption dynamics, while both models showed Cmax ≥ Cb(τ) for rapidly and non-rapidly absorbed drugs.
• Cb(τ) and τ were identified as meaningful parameters for drug exposure rate in non-rapidly absorbed cases.
• The parameter [Formula: see text] proved useful for assessing the extent of absorption in rapidly absorbed drugs, with an estimated F close to unity for theophylline.

Conclusions:

• The (PBFTPK)1 and (PBFTPK)0 models provide a more realistic representation of in vivo drug absorption processes.
• Absolute bioavailability (F) can be reliably estimated exclusively from oral drug administration data using these models.
• These findings support the utility of finite time PBFTPK models in pharmacokinetic assessments.