University of Tennessee College of Medicine White, TN, United States
Colin W. Howden, MD, FACG1, Salil N. Pendse, MS2, Mark A. Bush, PhD2, June S. Almenoff, MD, PhD3, Kely L. Sheldon, PhD3 1University of Tennessee College of Medicine, Germantown, TN; 2Nuventra, Inc., Durham, NC; 3RedHill Biopharma, Raleigh, NC
Introduction: H. pylori infection is common and has potentially serious sequalae. Topical gastric antibiotic exposure is important for successful eradication. Variable success has been reported with rifabutin (RIF) when used off-label (typically dosed at 150 mg QD) as a component of treatment. In two phase 3 trials in treatment-naïve subjects, RHB-105 (50 mg rifabutin, 1000 mg amoxicillin, 40 mg omeprazole Q8H for 14 days) demonstrated eradication rates of 89.4% (NCT03198507; modified intention-to-treat) and 83.8% ITT (NCT01980095; 90.3% in confirmed adherent subjects). Our objective was to use physiologically based pharmacokinetic (PBPK) modeling to assess how dosing affects gastric RIF concentrations and any potential impact on H. pylori eradication.
Methods: Plasma RIF pharmacokinetic (PK) data were obtained from literature and RHB-105 clinical studies. Key chemical and biological properties of the formulations were obtained from literature or calculated using quantitative structure‑activity relationship models. The remaining parameters were estimated by fitting model predictions to a subset of the plasma PK data. The final parameterized PBPK model was validated against the plasma PK data not used for fitting. The model was then used to simulate steady state gastric concentrations for RIF 150 mg QD and 50 mg Q8H to predict time above the RIF MIC90 for H. pylori (0.008 µg/ml) for each regimen.
Results: Predicted plasma PK parameters were consistent with those observed in RHB-105 clinical studies. Based on steady-state simulations, time above MIC90 for RIF was 7.8 ± 2.7 h with 50 mg Q8H and 2.5 ± 1.0 h with 150 mg QD (3.12-fold difference). There was no impact of intragastric pH on predicted gastric lumen concentrations.
Discussion: Key determinants of gastric RIF concentrations are its gastrointestinal transit time, time required for systemic absorption, and dosing frequency. RIF 50 mg Q8H (as in RHB-105) maintains gastric RIF concentrations above its MIC90 3.12-fold longer than 150 mg QD. With 150 mg QD dosing, the longer time that gastric RIF levels are below the MIC90 could explain its lower eradication rates than RHB-105 and could contribute to the emergence of RIF resistance. This analysis suggests there may be a link between sustained gastric RIF exposure with 50 mg Q8H and high eradication rates seen with RHB-105. It also demonstrates that 150 mg QD cannot replicate the effect of dosing at 50 mg Q8H.
Figure: Figure 1: Gastric lumen rifabutin concentrations of 50 mg Q8H vs. 150 mg QD over time
Colin W. Howden, MD, FACG1, Salil N. Pendse, MS2, Mark A. Bush, PhD2, June S. Almenoff, MD, PhD3, Kely L. Sheldon, PhD3. P2029 - RHB-105 Q8H Rifabutin Dosing Provides Favorable Exposure for Helicobacter pylori Eradication, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.