Human isoniazid (INH) fast and slow acetylator PBPK models:

The human PBPK models of fast and slow isoniazid acetylators were built with the PBPK modeling software PK-Sim® (Version 7.1.0; Bayer AG, 2017). Model parameter identification was performed in MATLAB and MoBi®. The latest versions of PK-Sim® and MoBi® are freely available under the GPLv2 License (https://github.com/Open-Systems-Pharmacology).

Physicochemical compound properties (lipophilicity, water solubility, molecular weight, and pKa values) of all modeled compounds were estimated with MarvinSketch (Version 15.11.30.0; ChemAxon Kft., Budapest, Hungary) and used to parameterize the basic distribution model in PK-Sim®. The PBPK model of isoniazid and its metabolites can be used to simulate the pharmacokinetics of a single or multiple oral administration of isoniazid for human fast and slow acetylators.

The detailed development of the fast and slow PBPK models of isoniazid and its metabolites as well as their validation is described in Cordes et al. 2016 (http://aac.asm.org/content/60/10/6134.long). The here presented isoniazid PBPK models were updated for a hepatic hydrazine clearance reaction (NOS2; UniProtKB: P35228).