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

AAPS PharmSciTech volume 21, Article number: 102 (2020) Cite this article

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 underlying intestinal supersaturation of Irbesartan. The solid form of these precipitates was amorphous with considerable particle size reduction. This indicated that following gastric transit, precipitate formation in the amorphous form coupled with an approximately 10 times particle size reduction could be potential factors leading to the generation and sustenance of intestinal drug supersaturation.

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Abbreviations

ACAT:

Advanced compartmental absorption and transit model

API:

Active pharmaceutical ingredient

AUC:

Area under the curve

BCS:

Biopharmaceutics classification system

Cmax :

Maximal concentration

CR:

Complete release

DSC:

Differential scanning calorimetry

G+:

GastroPlus™

GIT:

Gastrointestinal tract

HPLC:

High pressure liquid chromatography

IRB:

Irbesartan

IVIVC:

In vitro in vivo correlation

IVISIV:

In vitro-in silico-in vivo

Ksp :

Solubility product constant

PBPK:

Physiologically based pharmacokinetics

PK:

Pharmacokinetics

pKa :

pH corresponding to 50% ionization

PE:

Prediction error

PXRD:

Powder X-ray diffraction

S:

Solubility (ionized + unionized form)

SO :

Intrinsic solubility

SEM:

Scanning electron microscopy

SGF:

Simulated gastric fluid

SIF:

Simulated intestinal fluid

Tg :

Glass transition temperature

Tm :

Melting point

Tmax :

Time of maximal concentration

USP:

United States Pharmacopeia

Vd :

Volume of distribution

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Author information

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, University of Minnesota-Twin Cities, Minneapolis, Minnesota, 55455, USA

    Navpreet Kaur

  2. Novartis Healthcare Private Limited, Hyderabad, 500081, India

    Poonam Singh Thakur

  3. Lupin Limited (Research Park), Pune, Maharashtra, 412115, India

    Ganesh Shete

  4. Glenmark Pharmaceuticals Limited, Navi Mumbai, Maharashtra, 400026, India

    Rahul Gangwal

  5. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, (Mohali), Punjab, 160062, India

    Abhay T. Sangamwar & Arvind Kumar Bansal

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  1. Navpreet Kaur
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  2. Poonam Singh Thakur
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Correspondence to Arvind Kumar Bansal.

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Kaur, N., Thakur, P.S., Shete, G. et al. Understanding the Oral Absorption of Irbesartan Using Biorelevant Dissolution Testing and PBPK Modeling. AAPS PharmSciTech 21, 102 (2020). https://doi.org/10.1208/s12249-020-01643-x

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  • DOI: https://doi.org/10.1208/s12249-020-01643-x

KEY WORDS

  • weak base
  • biorelevant
  • PBPK modeling
  • GastroPlus™