Application of in Silico Tools in Clinical Practice using Ketoconazole as a Model Drug

Authors

  • Daniela Amaral Silva Department of Pharmacy, Faculty of Pharmaceutical Sciences, Universidade de São Paulo, Av. Prof. Lineu Prestes, 580, Cidade Universitária, 05508-000, Butantã, SP, Brazil. Faculty of Pharmacy & Pharmaceutical Sciences, Katz Centre for Pharmacy & Health Research, University of Alberta, Canada.
  • Marcelo Dutra Duque Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo - UNIFESP, Brazil.
  • Neal M Davies Faculty of Pharmacy & Pharmaceutical Sciences, Katz Centre for Pharmacy & Health Research, University of Alberta, Canada.
  • Raimar Löbenberg Faculty of Pharmacy & Pharmaceutical Sciences, Katz Centre for Pharmacy & Health Research, University of Alberta, Canada.
  • Humberto Gomes Ferraz Department of Pharmacy, Faculty of Pharmaceutical Sciences, Universidade de São Paulo, Av. Prof. Lineu Prestes, 580, Cidade Universitária, 05508-000, Butantã, SP, Brazil.

DOI:

https://doi.org/10.18433/jpps30227

Abstract

Hypochlorhydria is a condition where the production of hydrochloric acid in the stomach is decreased. As a result, the intragastric pH is elevated. This condition can be due to a series of causes, such as disease (gastric mucosal infection caused by Helicobacter pylori and is prominent in AIDS patients), ethnicity, age and also the use of antisecretory agents. This may significantly impact the absorption of other drugs that have pH-dependent solubility, such as ketoconazole, a weak base. Within this context, the purpose of this study was to demonstrate how GastroPlusTM – a physiological based software program- can be used to predict clinical pharmacokinetics of ketoconazole in a normal physiological state vs. elevated gastric pH. A simple physiologically based pharmacokinetic model was built and validated to explore the impact that different physiologic conditions in the stomach (hypochlorhydria, drug administered with water and Coca Cola®) had on ketoconazole’s bioavailability. The developed model was able to accurately predict the impact of increased pH and beverage co-administration on dissolution and absorption of the drug, and confirmed that complete gastric dissolution is essential. Particle size only mattered in hypochlorhydric conditions due to the incomplete gastric dissolution, as its absorption would depend on intestinal dissolution, which corroborates with previous studies. Therefore, in silico approaches are a potential tool to assess a pharmaceutical product’s performance and efficacy under different physiological and pathophysiological states supporting the assessment of different dosing strategies in clinical practice.

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Published

2018-10-23

How to Cite

Silva, D. A., Duque, M. D., Davies, N. M., Löbenberg, R., & Ferraz, H. G. (2018). Application of in Silico Tools in Clinical Practice using Ketoconazole as a Model Drug. Journal of Pharmacy &Amp; Pharmaceutical Sciences, 21(1s), 242s–253s. https://doi.org/10.18433/jpps30227

Issue

Section

Pharmaceutical Sciences; Original Research Articles