Conflicting Findings on an Intermediate Dose of Rifampicin for Pulmonary Tuberculosis.
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ABSTRACT:
SUBMITTER: Te Brake LHM
PROVIDER: S-EPMC6515878 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
Publications
Conflicting Findings on an Intermediate Dose of Rifampicin for Pulmonary Tuberculosis.
Te Brake Lindsey H M LHM Boeree Martin J MJ Aarnoutse Robert E RE
American journal of respiratory and critical care medicine 20190501 9
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Project description:Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.
| S-EPMC10583668 | biostudies-literature
Project description:BackgroundRecent evidence suggests that higher rifampicin doses may improve tuberculosis (TB) treatment outcome.MethodsIn this observational cohort study we evaluated all TB patients who were treated with high-dose rifampicin (> 10 mg/kg daily) in our reference centre, from January 2008 to May 2018. Indications, achieved plasma rifampicin exposures, safety and tolerability were evaluated.ResultsEighty-eight patients were included. The main indications were low plasma concentrations (64.7%) and severe illness (29.5%), including central nervous system TB. Adjusted rifampicin dosages ranged from 900 mg to a maximum of 2400 mg (corresponding to 32 mg/kg) per day. Patients with severe illness received high-dose rifampicin immediately, the others had a higher dosage guided by therapeutic drug monitoring. Four patients developed hepatotoxicity, of which two were proven due to isoniazid. Re-introduction of high-dose rifampicin was successful in all four. Eighty-seven patients tolerated high-dose rifampicin well throughout treatment. Only one patient required a dose reduction due to gastro-intestinal disturbance.ConclusionHigh-dose rifampicin, used in specific groups of patients in our clinical setting, is safe and well-tolerated for the whole treatment duration. Measurement of drug exposures could be used as a tool/guide to increase rifampicin dosage if a reduced medication absorption or a poor treatment outcome is suspected. We suggest to administer high-dose rifampicin to patients with severe manifestations of TB or low rifampicin exposure to improve treatment outcome.
| S-EPMC6417786 | biostudies-literature
Project description: Not available
| S-EPMC7301730 | biostudies-literature
Project description:This is the first clinical implementation of the Multistate Tuberculosis Pharmacometric (MTP) model describing fast-, slow-, and nonmultiplying bacterial states of Mycobacterium tuberculosis. Colony forming unit data from 19 patients treated with rifampicin were analyzed. A previously developed rifampicin population pharmacokinetic (PK) model was linked to the MTP model previously developed using in vitro data. Drug effect was implemented as exposure-response relationships tested at several effect sites, both alone and in combination. All MTP model parameters were fixed to in vitro estimates except Bmax . Drug effect was described by an on/off effect inhibiting growth of fast-multiplying bacteria in addition to linear increase of the stimulation of the death rate of slow- and nonmultiplying bacteria with increasing drug exposure. Clinical trial simulations predicted well three retrospective clinical trials using the final model that confirmed the potential utility of the MTP model in antitubercular drug development.
| S-EPMC4873565 | biostudies-literature
Project description:AimsTo propose new exposure targets for Bayesian dose optimisation suited for high-dose rifampicin and to apply them using measured plasma concentrations coupled with a Bayesian forecasting algorithm allowing predictions of future doses, considering rifampicin's auto-induction, saturable pharmacokinetics and high interoccasion variability.MethodsRifampicin exposure targets for Bayesian dose optimisation were defined based on literature data on safety and anti-mycobacterial activity in relation to rifampicin's pharmacokinetics i.e. highest plasma concentration up to 24 hours and area under the plasma concentration-time curve up to 24 hours (AUC0-24h ). Targets were suggested with and without considering minimum inhibitory concentration (MIC) information. Individual optimal doses were predicted for patients treated with rifampicin (10 mg/kg) using the targets with Bayesian forecasting together with sparse measurements of rifampicin plasma concentrations and baseline rifampicin MIC.ResultsThe suggested exposure target for Bayesian dose optimisation was a steady state AUC0-24h of 181-214 h × mg/L. The observed MICs ranged from 0.016-0.125 mg/L (mode: 0.064 mg/L). The predicted optimal dose in patients using the suggested target ranged from 1200-3000 mg (20-50 mg/kg) with a mode of 1800 mg (30 mg/kg, n = 24). The predicted optimal doses when taking MIC into account were highly dependent on the known technical variability of measured individual MIC and the dose was substantially lower compared to when using the AUC0-24h -only target.ConclusionsA new up-to-date exposure target for Bayesian dose optimisation suited for high-dose rifampicin was derived. Using measured plasma concentrations coupled with Bayesian forecasting allowed prediction of the future dose whilst accounting for the auto-induction, saturable pharmacokinetics and high between-occasion variability of rifampicin.
| S-EPMC6783589 | biostudies-literature
Project description:BackgroundRifampicin (RMP) and its major metabolite, desacetyl rifampicin (dRMP), can interfere with urine dipstick tests (UDTs) in patients with tuberculosis (TB) who receive oral RMP. This study sought to examine the effects of RMP and dRMP on UDTs using 2 different urine dipsticks (i.e., Arkray's Aution Sticks 10EA and GIMA's Combi-Screen 11SYS Plus sticks).MethodsUrine colorimetry was applied to measure RMP concentrations and determine the range of total RMP concentration in the urine within 2-6 and 12-24 h of oral administration of RMP. In vitro interference assays and confirmatory tests were performed to evaluate the effects of RMP and dRMP on the analytes.ResultsThe total RMP concentration in the urine of the 40 TB patients analyzed as urine sample was 88-376 µg/mL within 2-6 h and 22-112 µg/mL within 12-24 h of oral administration of RMP. Interference was observed for different analytes at consistent or varied RMP concentrations between the in vitro interference assays and the confirmatory tests, including 75 patients [Aution Sticks 10EA: 250, 250 µg/mL for protein (PRO); 400, 300 µg/mL for leukocyte esterase (LEU); Combi-Screen 11SYS Plus: 125, 150 µg/mL for ketones (KET); 500, 350 µg/mL for nitrite (NIT); 200, 300 µg/mL for PRO; 125, 150 µg/mL for LEU].ConclusionsRMP and dRMP interfered with the analytes of the UDTs using the 2 urine dipsticks in different levels. The in vitro interference assay is not an ideal substitute for the confirmatory test. The collection of urine samples within 12-24 h of administration of RMP can prevent the interference caused by RMP and dRMP.
| S-EPMC10267930 | biostudies-literature
Project description:Background: Rifampicin resistance (RR) is a major challenge in the clinical management of tuberculosis (TB), but data on its prevalence are still sparse in many countries. Our study aimed at estimating the prevalence of RR-TB in Kajiado County, Kenya. Secondary objectives were to estimate the incidence of pulmonary TB in adults and the rate of HIV-TB coinfection. Methods: We conducted an observational study in the context of the ATI-TB Project, carried out in Kajiado. The project was based on an active-case-finding campaign implemented with the aid of village chiefs, traditional healers and community health volunteers. Diagnosis relied on Xpert MTB/RIF, including a mobile machine that could be used to cover areas where testing would otherwise be difficult. Results: In sum, 3840 adults were screened for active TB during the campaign. RR cases among all TB diagnoses were 4.6%. The annual incidence of pulmonary TB among adults was 521 cases per 100,000 population. The rate of HIV coinfection was 22.2% among pulmonary TB diagnoses. Conclusion: The prevalence of RR-TB was four times that what could be inferred from official notifications in Kajiado, and higher than overall prevalence in Kenya. In addition, our estimate of incidence of pulmonary TB in adults in Kajiado significantly differed from cases notified in the same area. In contrast, the rate of HIV coinfection was in line with national and regional data. TB diagnostic capability must be strengthened in Kajiado to improve patients’ management and public health interventions.
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Project description:BackgroundWe estimated the incidence of acquired isoniazid and rifampicin resistance in rifampicin-susceptible tuberculosis in a setting of high human immunodeficiency virus type 1 (HIV-1) infection and tuberculosis coprevalence.MethodsGeneXpert MTB/RIF-confirmed patients with rifampicin-susceptible tuberculosis were recruited at antituberculosis treatment initiation in Khayelitsha, South Africa. Liquid culture and adherence assessment were performed at 2 and 5-6 months. MTBDRplus was performed on mycobacteria-positive cultures to ascertain acquired drug resistance (ADR). Spoligotyping and whole-genome sequencing were performed to ascertain homogeneity between baseline isolates and isolates with ADR. Baseline isolates were retrospectively tested for isoniazid monoresistance. An electronic database review was performed to ascertain tuberculosis recurrences.ResultsA total of 306 participants (62% with HIV-1 coinfection, of whom 71% received antiretroviral therapy) were recruited. Ascertainment of outcomes was complete for 284 participants. Five acquired a resistant Mycobacterium tuberculosis strain during or subsequent to treatment. One strain was confirmed to have ADR, 2 were confirmed as causing exogenous reinfection, and 2 were unrecoverable for genotyping. Incident ADR was estimated to have ranged from 0.3% (95% confidence interval [CI], .1%-1.9%; 1 of 284 participants) to 1% (95% CI, .2%-3%; 3 of 284 participants). Seventeen of 279 baseline isolates (6.1%; 95% CI, 3.6%-9.6%) had isoniazid monoresistance (13 of 17 had an inhA promoter mutation), but 0 of 17 had amplified resistance.ConclusionsTreatment with standardized antituberculosis regimens dosed daily throughout, high uptake of antiretroviral therapy, and low prevalence of isoniazid monoresistance were associated with a low frequency of ADR.
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Project description:Ultrasound reports of 102 children with microbiologically confirmed or clinically diagnosed pulmonary tuberculosis (TB) showed that 23 of 37 (64%) and 23 of 65 (36%) had TB suggestive abdominal lymphadenopathy, and 16 of 37 (44%) and 8 of 65 (13%) had splenic microabscesses, respectively. Splenic microabscesses were associated with HIV infection (P = 0.041). These data suggest that pulmonary TB is often complicated by abdominal TB in children.
| S-EPMC5610051 | biostudies-literature
Project description:Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability. Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise. Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified. Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.
| S-EPMC8275874 | biostudies-literature