Effect of Food Composition on the PK of Isoniazid Quantitatively Explained Using Physiologically Based Biopharmaceutics Modeling

This work shows the utilization of a physiologically based biopharmaceutics model (PBBM) to mechanistically explain the impact of diverse food types on the pharmacokinetics (PK) of isoniazid (INH) and acetyl-isoniazid (Ac-INH). The model was established and validated using published PK profiles for...

Full description

Saved in:
Bibliographic Details
Published in:The AAPS journal 2024-04, Vol.26 (3), p.54, Article 54
Main Authors: Pepin, Xavier J. H., Suarez-Sharp, Sandra
Format: Article
Language:English
Subjects:
Analysis
Antitubercular Agents - administration & dosage
Antitubercular Agents - pharmacokinetics
Arylamine N-Acetyltransferase - metabolism
Biochemistry
Biomedical and Life Sciences
Biomedicine
Biopharmaceutics - methods
Biotechnology
Enzymes
Food-Drug Interactions
Humans
Isoniazid
Isoniazid - administration & dosage
Isoniazid - pharmacokinetics
Models, Biological
Pharmacology/Toxicology
Pharmacy
Physiological aspects
Research Article
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:This work shows the utilization of a physiologically based biopharmaceutics model (PBBM) to mechanistically explain the impact of diverse food types on the pharmacokinetics (PK) of isoniazid (INH) and acetyl-isoniazid (Ac-INH). The model was established and validated using published PK profiles for INH along with a combination of measured and predicted values for the physico-chemical and biopharmaceutical propertied of INH and Ac-INH. A dedicated ontogeny model was developed for N-acetyltransferase 2 (NAT2) in human integrating Michaelis Menten parameters for this enzyme in the physiologically based pharmacokinetic (PBPK) model tissues and in the gut, to explain the pre-systemic and systemic metabolism of INH across different acetylator types. Additionally, a novel equation was proposed to calculate the luminal drug degradation related to the presence of reducing sugars, using individual sugar molar concentrations in the meal. By incorporating luminal degradation into the model, adjusting bile salt concentrations and gastric emptying according to food type and quantity, the PBBM was able to accurately predict the negative effect of carbohydrate-rich diets on the PK of INH. Graphical Abstract
ISSN:1550-7416
1550-7416
DOI:10.1208/s12248-024-00923-9