StephanSchaller
commented
1 year ago Aliment Pharmacol Ther. 2023 Apr 20. doi: https://10.1111/apt.17526 (https://pubmed.ncbi.nlm.nih.gov/37081832/)
Physiologically based pharmacokinetic modelling to predict intragastric rifabutin concentrations in the treatment of Helicobacter pylori infection Colin W Howden 1, Shailja Shah 2, Salil N Pendse 3, Elliot Offman 4, June S Almenoff 5, Kely L Sheldon 5
Abstract Background: Sustained intragastric antibiotic exposure is important for Helicobacter pylori eradication, yet little is known about gastric pharmacology of commonly used H. pylori regimens. For rifabutin, differing intragastric concentration based on dosing regimen may account for differences in reported eradication rates.
Aim: To compare intragastric rifabutin concentrations between low-dose rifabutin (50 mg three time daily; as in RHB-105) and generically dosed rifabutin 150 mg once daily, 150 mg twice daily, and 300 mg once daily using a validated physiologically based pharmacokinetic (PBPK) model.
Methods: We obtained plasma pharmacokinetic data from the RHB-105 clinical development programs and used it to develop and validate a whole-body PBPK model using PK-SIM software. We modified the existing rifabutin model to include the impact of omeprazole on gastric pH and emptying time. Modelled intragastric rifabutin exposure was expressed as the time that each regimen maintained its concentration ≥MIC90 .
Results: Rifabutin 50 mg three times daily achieved significantly longer times with intragastric concentration above MIC90 (22.3 ± 1.1 h) than 150 mg once daily (8.3 ± 1.7 h), 150 mg twice daily (16.3 ± 2.3 h), or 300 mg once daily (8.5 ± 1.9 h) while providing the lowest mean maximal plasma concentration and mean area under the plasma concentration-time curve of all regimens studied.
Conclusions: PBPK modelling showed rifabutin 50 mg three times daily had higher intragastric exposure times than 150 mg once daily or twice daily, or 300 mg once daily. This low-dose rifabutin regimen provides the highest potential for H. pylori eradication while minimising systemic rifabutin exposure.
Keywords: H. pylori < topics; acidity (intragastric) < topics; enteric infections < disease-based; gastric cancer < disease-based; stomach and duodenum < organ-based.
© 2023 RedHill Biopharma. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.