Understanding the Oral Absorption of Irbesartan Using Biorelevant Dissolution Testing and PBPK Modeling

AAPS PharmSciTech
Navpreet KaurArvind Kumar Bansal

Abstract

Poorly soluble weak bases form a significant proportion of the drugs available in the market thereby making it imperative to understand their absorption behavior. This work aims to mechanistically understand the oral absorption behavior for a weakly basic drug, Irbesartan (IRB), by investigating its pH dependent solubility, supersaturation, and precipitation behavior. Simulations performed using the equilibrium solubility could not accurately predict oral absorption. A multi-compartmental biorelevant dissolution testing model was used to evaluate dissolution in the stomach and duodenal compartment and mimic oral drug administration. This model exhibited sustained intestinal supersaturation (2-4-fold) even upon varying flow rates (4 mL/min, 7 mL/min, and mono-exponential transfer) from gastric to intestinal compartment. Simulation of oral absorption using GastroPlus™ and dissolution data collectively predicted plasma exposure with higher accuracy (% prediction error values within ± 15%), thereby indicating that multi-compartment dissolution testing enabled an improved prediction for oral pharmacokinetics of Irbesartan. Additionally, precipitates obtained in the intestinal compartment were characterized to determine the factors u...Continue Reading

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Methods Mentioned

BETA
Differential
X-Ray
light microscopy

Software Mentioned

Simulations Plus
TA Universal Analysis®
PKPlus
DIFFRAC plus EVA
[UNK]

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