A0683 - Modeling Gastric Luminal Rifabutin Concentrations: RHB-105 (Rifabutin 50mg Q8H) Provides More Favorable Exposure for H. pylori Eradication Than Generic Rifabutin 150mg BID or 300mg QD

Sunday, October 23, 2022

5:00 PM – 7:00 PM ET

Location: Crown Ballroom

Presenting Author(s)

Colin W. Howden, MD, FACG

University of Tennessee College of Medicine
Lake Forest, Illinois

Colin W. Howden, MD, FACG¹, Salil Pendse, MS², Mansi Jamindar, PharmD³, Kely L. Sheldon, PhD⁴
¹University of Tennessee College of Medicine, Lake Forest, IL; ²Allucent, Cary, NC; ³RedHill Biopharma Inc, Holly Springs, NC; ⁴RedHill Biopharma, Raleigh, NC

Introduction: H. pylori infection is a major risk factor for peptic ulcer and gastric cancer. Since the infection is predominantly extracellular, achieving and maintaining gastric luminal antibiotic concentrations above the relevant MIC₉₀ for H. pylori are important for successful eradication. RHB-105 is administered as 50mg rifabutin, 1000mg amoxicillin, and 40mg omeprazole, each dosed Q8H for 14 days. In two phase 3 clinical trials (NCT03198507/ NCT01980095), eradication rates were 89.4% (modified intention-to-treat) and 90.3% (in confirmed adherent subjects), respectively. In physiologically-based pharmacokinetic (PBPK) modeling, 50mg rifabutin Q8H provided ~3-fold longer time when gastric luminal concentration exceeded its MIC₉₀ (~93% of the day) compared to 150mg QD (~35% of the day). We have now applied this modeling to assess gastric luminal rifabutin concentrations with higher dose generic rifabutin regimens.

Methods: Plasma rifabutin pharmacokinetic (PK) data were obtained from published literature and clinical RHB-105 PK data. Chemical, biological, and formulation properties were obtained from literature or were calculated. The remaining parameters were estimated by fitting model predictions to a subset of the plasma PK data. The model was then used to simulate steady state gastric luminal rifabutin concentrations when dosed at 150mg BID or 300mg QD (each with omeprazole 20mg BID), compared to RHB-105, to predict the time above rifabutin's MIC₉₀ for H. pylori (0.008 µg/ml).

Results: Time with gastric luminal concentration above MIC₉₀ was 16.32±2.25 h for rifabutin 150mg BID (68% of day), and 8.51±1.86 h (35% of the day) for 300mg QD. Although both generic regimens contain twice the daily dose of rifabutin than RHB-105, both failed to achieve the prolonged gastric luminal rifabutin concentration time (22.25±1.08 h; 93% of the day) seen with RHB-105 (50mg Q8H; Figure 1).

Discussion: We previously showed that rifabutin 50mg Q8H (as in RHB-105) maintains gastric luminal concentrations above the MIC₉₀ nearly 3-times longer than 150mg QD. The current analysis further demonstrates that rifabutin dosed at 50mg Q8H provides more prolonged gastric luminal exposure (93% of the day) than dosing at 150mg BID (68% of the day) or 300mg QD (35% of the day). Rifabutin dosed 50mg Q8H (as in RHB-105) avoids unnecessarily high rifabutin doses that provide shorter periods of gastric luminal rifabutin exposure for successful H. pylori eradication.

Figure: Figure 1(A,B): Intragastric Rifabutin Concentration over 24 Hours with 50mg Q8H (RHB-105), 150mg BID and 300 mg QD

Disclosures:

Colin Howden: Allakos – Consultant. Alnylam – Speakers Bureau. Antibe – Stock-privately held company. Ironwood – Consultant. Neurogastrx – Consultant. Phathon Pharmaceuticals – Consultant, Speakers Bureau. RedHill Biopharma – Consultant, Speakers Bureau. Sanofi/Genzyme – Speakers Bureau.

Salil Pendse: Redhill Biopharma – Grant/Research Support.

Mansi Jamindar: RedHill Biopharma – Employee.

Kely Sheldon: RedHill Biopharma – Employee.

Colin W. Howden, MD, FACG¹, Salil Pendse, MS², Mansi Jamindar, PharmD³, Kely L. Sheldon, PhD⁴. A0683 - Modeling Gastric Luminal Rifabutin Concentrations: RHB-105 (Rifabutin 50mg Q8H) Provides More Favorable Exposure for H. pylori Eradication Than Generic Rifabutin 150mg BID or 300mg QD, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.