Home
Resources
Publications
Advances and Challenges in PBPK modeling--Analysis of Factors Contributing to the Oral Absorption of Atazanavir, a Poorly Soluble Weak Base

Advances and Challenges in PBPK modeling--Analysis of Factors Contributing to the Oral Absorption of Atazanavir, a Poorly Soluble Weak Base

Mark Berlin, Aaron Ruff, Filippos Kesisoglou, Wei Xu, Michael Hong Wang, Jennifer B Dressman

Eur J Pharm Biopharm. 2015 Jun;93:267-80.

PMID: 25872159

Abstract:

Many active pharmaceutical ingredients (APIs) exhibit a highly variable pharmacokinetic (PK) profile. This behavior may be attributable to pre-absorptive, absorptive and/or post-absorptive factors. Pre-absorptive factors are those related to dosage form disintegration, drug dissolution, supersaturation, precipitation and gastric emptying. Absorptive factors are involved with drug absorption and efflux mechanisms, while drug distribution and clearance are post-absorptive factors. This study aimed to investigate the relative influence of the aforementioned parameters on the pharmacokinetic profile of atazanavir, a poorly soluble weakly basic compound with highly variable pharmacokinetics. The pre-absorptive behavior of the drug was examined by applying biorelevant in vitro tests to reflect upper gastrointestinal behavior in the fasted and fed states. The in vitro results were implemented, along with permeability and post-absorptive data obtained from the literature, into physiologically based pharmacokinetic (PBPK) models. Sensitivity analysis of the resulting plasma profiles revealed that the pharmacokinetic profile of atazanavir is affected by an array of factors rather than one standout factor. According to the in silico model, pre-absorptive and absorptive factors had less impact on atazanavir bioavailability compared to post-absorptive parameters, although active drug efflux and extraction appear to account for the sub-proportional pharmacokinetic response to lower atazanavir doses in the fasted state. From the PBPK models it was concluded that further enhancement of the formulation would bring little improvement in the pharmacokinetic response to atazanavir. This approach may prove useful in assessing the potential benefits of formulation enhancement of other existing drug products on the market.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP162537113	Atazanavir Related Compound A		162537-11-3	Price

As a specialist in analytical chemical Products, Alfa Chemistry offers consumers a wealth of raw materials and a full range of technologies and services.

QUICK LINKS

HEADQUARTERS

Tel:

Fax:

Email: