Changes of pharmacokinetics of rifampicin (RFP, Rifadin were investigated on endotoxin pretreated still not ruminant calves. The animals served as their own controls and drug administration twice in a 1-week interval gave the same results. Endotoxin 0.02 micrograms kg-1 given intravenously 1 h prior to the oral administration of RFP (20 mg kg-1) induced considerable pharmacokinetic changes. The serum levels of the total drug were significantly lower after the endotoxin administration. The pharmacokinetic analysis revealed significant changes mainly in the distribution phase. When both toxin and drug were administered intravenously, the drug levels were higher. The results are discussed with reference to the pathophysiological endotoxin changes. After the toxin administration the bioavailability of oral RFP was 4-fold lower.
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Antimicrob Agents Chemother
January 2025
Division of Infectious Diseases, Department of Medicine, University of Texas at Tyler School of Medicine, Tyler, Texas, USA.
The impact of heteroresistance on tuberculosis (TB) treatment outcomes is unclear, as is the role of different rifampin and isoniazid exposures on developing resistance mutations. Hollow fiber system model of TB (HFS-TB) units were inoculated with drug-susceptible () and treated with isoniazid and rifampin exposure identified in a clinical trial as leading to treatment failure and acquired drug resistance. Systems were sampled for drug concentration measurements, estimation of total and drug-resistant , and small molecule overlapping reads (SMOR) analysis for the detection of heteroresistance.
View Article and Find Full Text PDFClin Pharmacol Ther
January 2025
Certara Predictive Technologies Division, Certara UK Limited, Sheffield, UK.
Understanding cytokine-related therapeutic protein-drug interactions (TP-DI) is crucial for effective medication management in conditions characterized by elevated inflammatory responses. Recent FDA and ICH guidelines highlight a systematic, risk-based approach for evaluating these interactions, emphasizing the need for a thorough mechanistic understanding of TP-DIs. This study integrates the physiologically based pharmacokinetic (PBPK) model for TP (specifically interleukin-6, IL-6) with small-molecule drug PBPK models to elucidate cytokine-related TP-DI mechanistically.
View Article and Find Full Text PDFClin Pharmacol Ther
January 2025
Clinical Pharmacology, Pfizer R&D, Pfizer Inc, New York, New York, USA.
Rifampicin is a widely employed index inhibitor to assess the impact of organic anion transporting polypeptide 1B (OATP1B) inhibition on investigational drugs. The observation of nitrosamines in certain drug products, including rifampicin, has impacted the conduct of clinical drug-drug interaction (DDI) studies with rifampicin drug products. Cyclosporine is a recommended alternative to assess in vivo OATP1B activity; however, challenges exist in its use due to pharmacokinetic (PK) variability and non-selective inhibition of other drug disposition mechanisms.
View Article and Find Full Text PDFLancet Microbe
December 2024
Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU Munich, Germany; German Center for Infection Research, Munich Partner Site, Munich, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology, Infection, and Pandemic Research, Munich, Germany; Unit Global Health, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. Electronic address:
Background: The broad use of bedaquiline and pretomanid as the mainstay of new regimens to combat tuberculosis is a risk due to increasing bedaquiline resistance. We aimed to assess the safety, bactericidal activity, and pharmacokinetics of BTZ-043, a first-in-class DprE1 inhibitor with strong bactericidal activity in murine models.
Methods: This open-label, dose-expansion, randomised, controlled, phase 1b/2a trial was conducted in two specialised tuberculosis sites in Cape Town, South Africa.
Clin Infect Dis
January 2025
EPIUnit - Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal.
Background: Higher than standard doses of rifampicin could improve the treatment outcome of drug-susceptible tuberculosis without compromising the safety of patients.
Methods: We performed a systematic review of prospective clinical studies including adults with pulmonary and extrapulmonary TB receiving rifampicin doses above 10mg/kg/day. We extracted the data on overall adverse events (AE), hepatic AE, sputum culture conversion (SCC) at week 8, recurrence, mortality, and pharmacokinetics.
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