Impact Of Rifampicin Research Articles

2538. The Impact of Rifampicin on Blood Pressure in Patients Receiving Nifedipine: A Retrospective Study

Abstract Background No comparative study has been published to date to evaluate the impact of drug-drug interaction (DDI) between rifampin (CYP3A4 inducer) and nifedipine on clinical outcomes. The aim of this study was to investigate the change in systolic blood pressure (SBP) after rifampin initiation in hypertensive patients who were receiving oral nifedipine. Methods This retrospective cohort study was conducted at King Abdulaziz University Hospital. We included hospitalized adults ≥18 years who were started on rifampin while they were receiving oral nifedipine for hypertension. Patients with uncontrolled hypertension (baseline SBP of >140 mmHg) and those receiving beta-blockers were excluded. The study outcomes were SBP changes by day 8 after rifampin initiation, which were compared by Chi-squared test. Results A total of 16 patients were included. The median maximum increase in SBP from baseline after starting rifampin was 24 [17.75 - 29] mmHg. The median SBP did not increase significantly on the second day (135 [128.5-141.5]; P=0.147) but the increases were significant on the following days. The median SBP was 146.5 [140.5-154.25] (P=0.002) on the third day, 142.5 [132.75-160.5] (P=0.009) on the fourth day, 149.5 [136-159.75] (P=0.005) on the fifth day, 146.5 [134.25-159.5] (P=0.012) on the sixth day, 149 [143.25-154.5] (P=0.007) on the seventh day, 151.5 [143.75-163] (P=0.007) on the eighth day. Conclusion Initiation of rifampin in hypertensive nifedipine-treated patients was associated with a statistically and clinically significant increase in SBP starting from day 3 of rifampin. This supports the need to avoid nifedipine use in patients taking rifampin. Disclosures Khalid Eljaaly, PharmD, MS, BCPS, BCIDP, FCCP, Reckitt Benckiser Healthcare International Ltd, UK: Member of the Global Respiratory Infection Partnership, supported by unrestricted educational grant from Reckitt Benckiser Healthcare Ltd

Physiologically Based Pharmacokinetic Modeling to Simulate CYP3A4-Mediated Drug-Drug Interactions for Pyrotinib.

Pyrotinib is a newly developed tyrosine kinase inhibitor whose in vivo clearance relies heavily on cytochrome P450 3A4 (CYP3A4) activity. Clinical trials are ongoing to explore the effects of coadministration with CYP3A4 perpetrators on pyrotinib exposure. The present study aims to utilize physiologically based pharmacokinetic (PBPK) modeling to predict CYP3A4-based drug interactions of pyrotinib. Pyrotinib PBPK model was developed in the PK-Sim® multicompartmental physiology structure. Physiochemical parameters were obtained from the literature, and clearance-related parameters were optimized by fitting clinical single-dose pharmacokinetic data. Pharmacokinetic parameters from the model output were compared with the observed data to validate the model predictive performance. Using validated CYP3A4 perpetrator models, we conducted PBPK simulations for drug interactions in a virtual population to explore the impacts of comedication with these perpetrators. The PBPK model accurately describes pyrotinib single- and multi-dose pharmacokinetics. The model also predicts dramatic exposure change of pyrotinib in the presence of itraconazole and rifampicin, though the impact of rifampicin is somewhat underestimated. According to model predictions, coadministration with typical potent or moderate CYP3A4 perpetrators increases pyrotinib concentration by over sixfold, extinguishing the possibility of dose adjustment for pyrotinib. A weak CYP3A4 inhibitor has minimal influence on pyrotinib pharmacokinetics. PBPK modeling provides valuable information to avoid irrational medication when receiving pyrotinib chemotherapy.

Systemic Antimicrobial Treatment of Chronic Osteomyelitis in Adults: A Narrative Review.

Chronic osteomyelitis in adults is a complex condition that requires prolonged and intensive antimicrobial therapy, but evidence on optimal selection and duration of antibiotics is limited. A review of PubMed and Ovid Embase databases was conducted to identify systematic reviews, meta-analyses, retrospective and randomised controlled trials (RCTs) on antibiotic treatment outcomes in adults with chronic osteomyelitis. Three main areas of interest were investigated: short-term versus long-term antibiotic therapy, oral versus parenteral antibiotic therapy, and combination antibiotic therapy with rifampicin versus without rifampicin. A total of 36 articles were identified and findings were synthesised using a narrative review approach. The available literature suffers from limitations, including a lack of high-quality studies, inconsistent definitions, and varying inclusion/exclusion criteria among studies. Most studies are open-labelled and lack blinding. Limited high-quality evidence exists that oral therapy is non-inferior to parenteral therapy and that shorter antibiotic duration might be appropriate in low-risk patients. Studies on the impact of rifampicin are inconclusive. Further well-designed studies are needed to provide more robust evidence in these areas.

Impact of rifampicin on the pharmacokinetics of clarithromycin and 14-hydroxy clarithromycin in patients with multidrug combination therapy for pulmonary Mycobacterium avium complex infection

IntroductionClarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) combination therapy is used to treat pulmonary Mycobacterium avium complex (MAC) infection; however, serum CAM concentration decreases due to RFP-mediated induction of CYP3A activity. Therefore, we investigated the pharmacokinetics of CAM, 14-hydroxy clarithromycin (14-OH CAM), EB, and RFP in patients receiving this three-drug combination therapy. MethodsCAM monotherapy was started, EB was added 2 weeks later, and RFP was added 2 weeks after that. Serum CAM, 14-OH CAM, EB, and RFP concentrations were measured before and at 2, 4, 6, and 12 or 24 h after administration on days 14, 28, and 42, and pharmacokinetic parameters were calculated. ResultsMedian area under the curve (AUC) of CAM decreased by 92.1% from 0 to 12 h after concomitant administration of RFP compared with CAM monotherapy [1.7 (interquartile range [IQR], 1.4–1.8) μg·h/mL vs. 21.5 (IQR, 17.7–32.3) μg·h/mL, respectively]. In contrast, median AUC of 14-OH CAM was not significantly different between concomitant administration of RFP [9.1 (IQR, 7.9–10.9) μg·h/mL] and CAM monotherapy [8.2 (IQR, 6.3–9.3) μg·h/mL]. AUCs of CAM and 14-OH CAM did not change in CAM+EB combination therapy. ConclusionsWhen RFP is combined with CAM in the treatment of pulmonary MAC infection, the blood concentration of CAM significantly decreased and that of the active metabolite 14-OH CAM increased, but not significantly. Our results suggest that combination therapy with CAM and RFP needs to be reconsidered and may require dose modification in the treatment of pulmonary MAC infection.

Impact of rifampicin-inhibitable transport on the liver distribution and tissue kinetics of erlotinib assessed with PET imaging in rats

BackgroundErlotinib is an epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor approved for treatment of non-small cell lung cancer. The wide inter-individual pharmacokinetic (PK) variability of erlotinib may impact treatment outcome and/or toxicity. Recent in vivo studies reported a nonlinear uptake transport of erlotinib into the liver, suggesting carrier-mediated system(s) to mediate its hepatobiliary clearance. Erlotinib has been identified in vitro as a substrate of organic anion-transporting polypeptide (OATP) transporters which expression does not restrict to hepatocytes and may impact the tissue uptake of erlotinib in vivo.ResultsThe impact of rifampicin (40 mg/kg), a potent OATP inhibitor, on the liver uptake and exposure to tissues of 11C-erlotinib was investigated in rats (4 animals per group) using positron emission tomography (PET) imaging. Tissue pharmacokinetics (PK) and corresponding exposure (area under the curve, AUC) were assessed in the liver, kidney cortex, abdominal aorta (blood pool) and the lungs. The plasma PK of parent 11C-erlotinib was also measured using arterial blood sampling to estimate the transfer rate constant (kuptake) of 11C-erlotinib from plasma into different tissues.PET images unveiled the predominant distribution of 11C-erlotinib-associated radioactivity to the liver, which gradually moved to the intestine, thus highlighting hepatobiliary clearance. 11C-erlotinib also accumulated in the kidney cortex. Rifampicin did not impact AUCaorta but reduced kuptake, liver (p < 0.001), causing a significant 27.3% decrease in liver exposure (p < 0.001). Moreover, a significant decrease in kuptake, kidney with a concomitant decrease in AUCkidney (− 30.4%, p < 0.001) were observed. Rifampicin neither affected kuptake, lung nor AUClung.ConclusionsOur results suggest that 11C-erlotinib is an in vivo substrate of rOATP transporters expressed in the liver and possibly of rifampicin-inhibitable transporter(s) in the kidneys. Decreased 11C-erlotinib uptake by elimination organs did not translate into changes in systemic exposure and exposure to the lungs, which are a target tissue for erlotinib therapy.

Leveraging of Rifampicin-Dosed Cynomolgus Monkeys to Identify Bile Acid 3-O-Sulfate Conjugates as Potential Novel Biomarkers for Organic Anion-Transporting Polypeptides.

In the search for novel bile acid (BA) biomarkers of liver organic anion-transporting polypeptides (OATPs), cynomolgus monkeys received oral rifampicin (RIF) at four dose levels (1, 3, 10, and 30 mg/kg) that generated plasma-free Cmax values (0.06, 0.66, 2.57, and 7.79 µM, respectively) spanning the reported in vitro IC50 values for OATP1B1 and OATP1B3 (≤1.7 μM). As expected, the area under the plasma concentration-time curve (AUC) of an OATP probe drug (i.v. 2H4-pitavastatin, 0.2 mg/kg) was increased 1.2-, 2.4-, 3.8-, and 4.5-fold, respectively. Plasma of RIF-dosed cynomolgus monkeys was subjected to a liquid chromatography-tandem mass spectrometry method that supported the analysis of 30 different BAs. Monkey urine was profiled, and we also determined that the impact of RIF on BA renal clearance was minimal. Although sulfated BAs comprised only 1% of the plasma BA pool, a robust RIF dose response (maximal ≥50-fold increase in plasma AUC) was observed for the sulfates of five BAs [glycodeoxycholate (GDCA-S), glycochenodeoxycholate (GCDCA-S), taurochenodeoxycholate, deoxycholate (DCA-S), and taurodeoxycholate (TDCA-S)]. In vitro, RIF (≤100 μM) did not inhibit cynomolgus monkey liver cytosol-catalyzed BA sulfation and cynomolgus monkey hepatocyte-mediated uptake of representative sulfated BAs (GDCA-S, GCDCA-S, DCA-S, and TDCA-S) was sodium-independent and inhibited (≥70%) by RIF (5 μM); uptake of taurocholic acid was sensitive to sodium removal (74% decrease) and relatively refractory to RIF (≤21% inhibition). We concluded that sulfated BAs may serve as sensitive biomarkers of cynomolgus monkey OATPs and that exploration of their utility as circulating human OATP biomarkers is warranted.