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Patient adherence is vital for Helicobacter pylori eradication. Simplifying therapy dosing schedules may promote patient adherence, enhance treatment success rates, and help mitigate the development of antibiotic resistance. We aimed to assess plasma and intragastric rifabutin, amoxicillin, and omeprazole concentrations comparing two dosing schedules of RHB‐105 (every 8 h and a more flexible three‐times daily schedule, at 8 a.m., 12 p.m., and 6 p.m.) using a validated physiologically based pharmacokinetic (PBPK) model. Leveraging in vitro and in vivo information on the pharmacokinetics of the three components of RHB‐105, we developed mechanistic absorption PBPK models to predict plasma and intragastric concentration–time profiles for each component. There were only negligible differences in the area under the concentration–time curves (AUC) for plasma and the intragastric compartment, and maximal concentration (Cmax) with only up to a 1.1‐fold difference for rifabutin, amoxicillin, and omeprazole between dosing schedules. Overlapping 90% confidence intervals for both AUC and Cmax support that overall exposures are comparable regardless of dosing every 8 h or three‐times daily for all three drugs. Drug exposure was highly similar for rifabutin, amoxicillin, and omeprazole with each dosing schedule. Novel mechanistic absorption PBPK modeling supports the approval and use of the more flexible dosing schedule for RHB‐105, simplifying patient experience and potentially increasing adherence. [ABSTRACT FROM AUTHOR]