Effect of Rifabutin on Ethambutol Pharmacokinetics in Healthy Volunteers

Breda, Massimo; Ms, Benedetti; Bani, Massimo; Pellizzoni, C.; Poggesi, Italo; Brianceschi, G; Rocchetti, Maurizio; Dolfi, L; Sassella, D; Rimoldi, R

doi:10.1006/phrs.1999.0526

Cited by 17 publications

(6 citation statements)

References 17 publications

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“…Genotype frequencies are summarised in Table 3 and Table 4. 9) 0 (0 93) 4 ( 7) 0 (0) The effect of CYP1A2 polymorphism on ethambutol pharmacokinetics was surprising due to the large fraction of ethambutol excreted unchanged via the kidneys (100). Ethambutol is a potent inhibitor of CYP1A2 and CYP2E1 (101).…”

Section: Genotypes (Paper II Paper Iii Paper Iv and Paper Vii)mentioning

confidence: 99%

Factors Affecting the Pharmacokinetics of Pyrazinamide and Its Metabolites in Patients Coinfected with HIV and Implications for Individualized Dosing

Sundell

Wijk

Bienvenu

et al. 2021

Antimicrob Agents Chemother

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Pyrazinamide is a first-line drug used in the treatment of tuberculosis. High exposure of pyrazinamide and its metabolites may result in hepatotoxicity whereas low exposure of pyrazinamide has been correlated to treatment failure by first-line antitubercular therapy. The aim of this study was to describe the pharmacokinetics and metabolism of pyrazinamide in patients co-infected with tuberculosis and HIV. We further aimed to identify demographic and clinical factors which affect the pharmacokinetics of pyrazinamide and its metabolites in order to suggest individualized dosing regimens. Plasma concentrations of pyrazinamide, pyrazinoic acid and 5-hydroxy pyrazinamide from 63 Rwandan patients co-infected with tuberculosis and HIV were determined by liquid chromatography tandem mass spectrometry followed by non-linear mixed effects modelling. Females had a close to 50% higher pyrazinamide bioavailability than males. The distribution volumes of pyrazinamide and both metabolites were lower in patients on concomitant efavirenz-based HIV therapy. Furthermore, there was a linear relationship between serum creatinine and oral clearance of pyrazinoic acid. Simulations indicated that increasing doses from 25 mg/kg to 35 mg/kg and 50 mg/kg in females and males, respectively would result in adequate exposure with regard to suggested thresholds and increase probability of target attainment to >0.9 for a minimal inhibitory concentration of 25 mg/L. Further, lowering the dose by 40% in patients with high serum creatinine would prevent accumulation of toxic metabolites. Individualized dosing is proposed to decrease variability in exposure to pyrazinamide and its metabolites. Reducing the variability in exposure may lower the risk of treatment failure and resistance development.

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Section: Genotypes (Paper II Paper Iii Paper Iv and Paper Vii)mentioning

confidence: 99%

Factors Affecting the Pharmacokinetics of Pyrazinamide and Its Metabolites in Patients Coinfected with HIV and Implications for Individualized Dosing

Sundell

Wijk

Bienvenu

et al. 2021

Antimicrob Agents Chemother

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“…EMB is eliminated mainly via renal filtration and active tubular secretion; approximately 50 to 70% and 70 to 84% of oral and intravenous doses, respectively, are recovered unchanged in the urine of subjects with normal renal function (6,18,19,25). EMB has a low plasma protein binding, with an unbound fraction of 70 to 80% (18).…”

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confidence: 99%

Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients

Jönsson

Davidse

Wilkins

et al. 2011

Antimicrob Agents Chemother

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Ethambutol, one of four drugs in the first-line antitubercular regimen, is used to protect against rifampin resistance in the event of preexisting resistance to isoniazid. The population pharmacokinetics of ethambutol in South African patients with pulmonary tuberculosis were characterized using nonlinear mixed-effects modeling. Patients from 2 centers were treated with ethambutol (800 to 1,500 mg daily) combined with standard antitubercular medication. Plasma concentrations of ethambutol were measured following multiple doses at steady state and were determined using a validated high-pressure liquid chromatography-tandem mass spectrometric method. The data comprised 189 patients (54% male, 12% HIV positive) weighing 47 kg, on average (range, 29 to 86 kg), and having a mean age of 36 years (range, 16 to 72 years). The estimated creatinine clearance was 79 ml/min (range, 23 to 150 ml/min). A two-compartment model with one transit compartment prior to first-order absorption and allometric scaling by body weight on clearance and volume terms was selected. HIV infection was associated with a 15% reduction in bioavailability. Renal function was not related to ethambutol clearance in this cohort. Interoccasion variability exceeded interindividual variability for oral clearance (coefficient of variation, 36 versus 20%). Typical oral clearance in this analysis (39.9 liters/h for a 50-kg individual) was lower than that previously reported, a finding partly explained by the differences in body weight between the studied populations. In summary, a population model describing the pharmacokinetics of ethambutol in South African tuberculosis patients was developed, but additional studies are needed to characterize the effects of renal function.In order to optimize treatment regimens, there is an urgent need to critically evaluate the pharmacokinetics and corresponding effects of the antituberculosis drugs among patients with tuberculosis. Population pharmacokinetic modeling is considered an efficient means to summarize data in terms of typical parameter estimates, effects of covariates (e.g., body weight, sex, and gender), and unexplained variability. Furthermore, population pharmacokinetic models are valuable for simulation purposes and enable alternative dose regimens for subpopulations aiming at specific pharmacokinetic target levels to be assessed to establish more effective treatment. The present analysis was designed to describe the population pharmacokinetics of ethambutol (EMB) in a South African patient population, including the characterization of interindividual variability (IIV) and interoccasion variability (IOV) and exploration of the causes of variability, which have not been addressed in previous models (27,39).EMB is a bacteriostatic agent with a mechanism of action that has been suggested to occur by inhibition of mycobacterial cell wall synthesis. The primary role of EMB in the first-line four-drug antitubercular regimen (i.e., EMB in combination with rifampin, isoniazid, and pyrazinamide) is to protect aga...

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“…The predictions of the model were validated using available drug concentration data. Simulated plasma concentrations for standard oral doses of rifampicin (600 mg), ethambutol (1200 mg), isoniazid (300 mg) and pyrazinamide (1500 mg) were plotted along with reported plasma concentration data 12,13,[18][19][20][21][22][23][24][25][26][27] for each drug dose respectively. At the start of the dosing regimen, there is a transient lasting several days when the average daily concentration increases and then reaches a steady state.…”

Section: Simulationmentioning

confidence: 99%

A Physiologically-Based Pharmacokinetic Model for Tuberculosis Drug Disposition at Extrapulmonary Sites

Ramachandran

Gadgil

2023

Preprint

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Tuberculosis (TB) is a leading cause of mortality due to an infectious agent. TB primarily targets the lungs but in about 16% cases can affect other organs as well, giving rise to extrapulmonary TB (EPTB). However, an optimal regimen for EPTB treatment is not defined. While the recommended treatment for most forms of EPTB is the same as pulmonary TB, pharmacokinetics of EPTB therapy are not as well-studied. To address this gap, we formulate a whole-body physiologically-based pharmacokinetic (PBPK) model for EPTB that for the first time includes the ability to simulate drug concentrations in the pleura and lymph node. Using this model, we estimate the time-dependent concentrations, at potential EPTB infection sites, of the 4 first-line anti-TB drugs: Rifampicin, Ethambutol, Isoniazid and Pyrazinamide. We utilise reported plasma concentration kinetics data to estimate model parameters for each drug, and validate our model using reported concentration data not used for model formulation or parameter estimation. Model predictions match the validation data and reported PK parameters (Cmax, tmax) for the drugs. The model also predicts Ethambutol, Isoniazid and Pyrazinamide concentrations in the pleura that match reported experimental values from an independent study. For each drug, the model is used to simulate the time-dependent drug concentrations at various EPTB sites. Predicted drug concentrations are compared to their critical concentration. Simulations suggest that while Rifampicin and Isoniazid concentrations are greater than critical concentration values at most EPTB sites, the concentrations of Ethambutol and Pyrazinamide are lower than their critical concentrations at most EPTB sites.

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Effect of Rifabutin on Ethambutol Pharmacokinetics in Healthy Volunteers

Cited by 17 publications

References 17 publications

Factors Affecting the Pharmacokinetics of Pyrazinamide and Its Metabolites in Patients Coinfected with HIV and Implications for Individualized Dosing

Factors Affecting the Pharmacokinetics of Pyrazinamide and Its Metabolites in Patients Coinfected with HIV and Implications for Individualized Dosing

Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients

A Physiologically-Based Pharmacokinetic Model for Tuberculosis Drug Disposition at Extrapulmonary Sites

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