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Summary: 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 concentrations 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. [ABSTRACT FROM AUTHOR]

Tubulin was recently found to be a uniquely potent regulator of the voltage-dependent anion channel (VDAC), the most abundant channel of the mitochondrial outer membrane, which constitutes a major pathway for ATP/ADP and other metabolites across this membrane. Dimeric tubulin induces reversible blockage of VDAC reconstituted into a planar lipid membrane and dramatically reduces respiration of isolated mitochondria. Here we show that VDAC phosphorylation is an important determinant of its interaction with dimeric tubulin. We demonstrate that in vitro phosphorylation of VDAC by either glycogen synthase kinase-3β (GSK3β) or cAMP-dependent protein kinase A (PKA), increases the on-rate of tubulin binding to the reconstituted channel by orders of magnitude, but only for tubulin at the cis side of the membrane. This and the fact the basic properties of VDAC, such as single-channel conductance and selectivity, remained unaltered by phosphorylation allowed us to suggest the phosphorylation regions positioned on the cytosolic loops of VDAC and establish channel orientation in our reconstitution experiments. Experiments on human hepatoma cells HepG2 support our conjecture that VDAC permeability for the mitochondrial respiratory substrates is regulated by dimeric tubulin and channel phosphorylation. Treatment of HepG2 cells with colchicine prevents microtubule polymerization, thus increasing dimeric tubulin availability in the cytosol. Accordingly, this leads to a decrease of mitochondrial potential measured by assessing mitochondrial tetramethylrhodamine methyester uptake with confocal microscopy. Inhibition of PKA activity blocks and reverses mitochondrial depolarization induced by colchicine. Our findings suggest a novel functional link between serine/threonine kinase signaling pathways, mitochondrial respiration, and the highly dynamic microtubule network which is characteristic of cancerogenesis and cell proliferation. [ABSTRACT FROM AUTHOR]

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]