Investigating the critical variables of azithromycin oral absorption using in vitro tests and PBPK Modeling

Mariana Guimaraes Sa Correia, Pascal Somville, Maria Vertzoni, Nikoletta Fotaki

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Abstract

Azithromycin is an antibiotic listed in the essential list of medicines for adults and pediatrics. Conflicting evidence has been found regarding azithromycin classification according to the Biopharmaceutics classification system (BCS). The purpose of this study was to identify the critical variables that influence the oral absorption of azithromycin in adults and pediatrics.

Azithromycin solubility and dissolution studies (oral suspension) were performed in buffers and biorelevant media simulating the fasted and fed gastrointestinal tract. A PBPK model was developed for azithromycin for healthy adult volunteers and pediatrics (Simcyp® v18.2) informed by in vitro solubility and dissolution studies to predict drug performance after administration of azithromycin as an oral suspension.

The developed PBPK model predicted azithromycin plasma concentrations-time profiles after administration of an oral suspension to adults and pediatrics. Sensitivity analysis of solubility vs dose suggests that absorption is independent of solubility within the therapeutic dose range in both adults and pediatrics. The developed PBPK model for adults and pediatrics was consistent with the mechanism of permeation through the intestinal membrane (passive and active processes) being the rate-limiting step of azithromycin's absorption.

The physiologically based approach proposed was shown to be useful to determine the factors controlling drug absorption in adults and pediatrics.
Original languageEnglish
Pages (from-to)3874-3888
JournalJournal of Pharmaceutical Sciences
Volume110
Issue number12
Early online date13 Sept 2021
DOIs
Publication statusPublished - 31 Dec 2021

Bibliographical note

Funding Information:
The authors would like to thank Certara for providing the academic license for the Simcyp® simulator. Part of this work was presented at AAPS PharmSci Virtual Conference from October 26th to November 5th, 2020. This work was supported by the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No 674909 (PEARRL), www.pearrl.eu .

Publisher Copyright:
© 2021 American Pharmacists Association

Keywords

  • Absorption
  • Biopharmaceutics classification system (BCS)
  • Pediatric
  • Permeability
  • Physiologically Based Pharmacokinetic (PBPK) modeling
  • Solubility

ASJC Scopus subject areas

  • Pharmaceutical Science

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