Kinetics of oral ethambutol in the normal subject

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...

Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 82%

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Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients

Jönsson

Davidse

Wilkins

et al. 2011

“…For the rifamycins, clarithromycin and linezolid, the MIC values measured in liquid medium (7H9 broth) were at least one dilution above the values measured on solid medium (7H11 agar). For the drugs most commonly recommended to treat MAC infection (clarithromycin, rifampin, ethambutol, and amikacin), the MIC values were close to or greater than the peak serum concentration obtained at the standard doses in humans (19)(20)(21)(22)(23)(24)(25). The MIC value for clarithromycin was one dilution lower on Mueller-Hinton agar (pH 7.3) than on 7H11 agar (pH 6.6), i.e., 1 mg/liter compared to 2 mg/liter, while the MIC value for amikacin was 16 mg/liter on both types of agar.…”

Section: ϫ5mentioning

confidence: 88%

Characterization of Mouse Models of Mycobacterium avium Complex Infection and Evaluation of Drug Combinations

Andréjak

Almeida

Tyagi

et al. 2015

dThe Mycobacterium avium complex is the most common cause of nontuberculous mycobacterial lung disease worldwide; yet, an optimal treatment regimen for M. avium complex infection has not been established. Clarithromycin is accepted as the cornerstone drug for treatment of M. avium lung disease; however, good model systems, especially animal models, are needed to evaluate the most effective companion drugs. We performed a series of experiments to evaluate and use different mouse models (comparing BALB/c, C57BL/6, nude, and beige mice) of M. avium infection and to assess the anti-M. avium activity of single and combination drug regimens, in vitro, ex vivo, and in mice. In vitro, clarithromycin and moxifloxacin were most active against M. avium, and no antagonism was observed between these two drugs. Nude mice were more susceptible to M. avium infection than the other mouse strains tested, but the impact of treatment was most clearly seen in M. avium-infected BALB/c mice. The combination of clarithromycin-ethambutol-rifampin was more effective in all infected mice than moxifloxacin-ethambutolrifampin; the addition of moxifloxacin to the clarithromycin-containing regimen did not increase treatment efficacy. Clarithromycin-containing regimens are the most effective for M. avium infection; substitution of moxifloxacin for clarithromycin had a negative impact on treatment efficacy. P ulmonary disease due to nontuberculous mycobacteria (NTM) is on the rise worldwide (1, 2), and in several areas, including the United States and Canada, the incidence rate of such disease is higher than that of tuberculosis (3, 4). The most common cause of pulmonary NTM disease is infection with bacilli from the Mycobacterium avium complex (MAC). Although presentation and severity of MAC infections are varied and poorly understood, progressive cavitary disease can lead to extensive lung destruction and respiratory failure within a few years if left untreated (5).Unfortunately, treatment of pulmonary MAC infection is not straightforward. As with other NTM infections, the evidence base for treatment is very limited, and current treatment guidelines are largely based on expert opinion and a limited number of small, and sometimes contradictory, studies. The effectiveness of the macrolide clarithromycin has clearly been established for MAC infections; however, this drug must be given as part of a combination regimen to prevent the selection of clarithromycin-resistant bacilli (5, 6). The most complementary and efficacious companion drugs, as well as the optimal regimen and duration of the multidrug administration, are unknown. The current therapy guidelines for MAC lung disease recommend the combination of a macrolide (clarithromycin or azithromycin) with ethambutol and a rifamycin (usually rifampin), with or without an initial phase including an aminoglycoside (streptomycin or amikacin), administered for a minimum of 12 months after sputum culture conversion; this recommended regimen is considered successful in approximately 50 to 60% of patie...

“…Each volunteer had 10 ml of blood drawn at each of the seven time points: t ϭ 0 h (predose) and 2, 6, 11, 18, and 24 h following ethambutol administration. This sampling scheme was based on the ␣ and ␤ half-lives of ethambutol in previous studies (24,25,35,46). The blood was spun down for serum separation, and the serum was stored at Ϫ80°C until transport for measurement of the ethambutol concentration.…”

Section: Methodsmentioning

confidence: 99%

Ethambutol Pharmacokinetic Variability Is Linked to Body Mass in Overweight, Obese, and Extremely Obese People

Hall

Swancutt

Meek

et al. 2012

We conducted a prospective study of 18 adult volunteers (male-to-female ratio of 1) whose body mass index fell into categories of <25, 25 to 40, or >40 kg/m 2 , who received a single oral dose of 1,600 mg ethambutol. Only individuals with normal renal function were recruited. The minimum body mass (M) was 45.6 kg, the median was 90.8 kg, and the maximum weight was 160.4 kg. Ethambutol pharmacokinetics were best described by a two-compartment model. Inclusion of weight as a covariate dramatically improved the model, with a relative likelihood approaching infinity. The typical clearance was 42.6 liters/h. Ethambutol systemic clearance was proportional to (M/45.6) 3/4 and thus obeyed fractal geometry-based laws. This means that the area under the concentration-time curve (AUC) actually decreased for obese patients compared to that for leaner patients, reducing chances of concentration-dependent toxicity. On the other hand, such reduced AUCs could lead to therapy failure. Thus, new and individualized ethambutol dosing regimens need to be designed for obese and extremely obese patients. Mycobacterial diseases remain a significant cause of morbidity and mortality worldwide. Tuberculosis (TB) is responsible for approximately two million deaths per year. TB has historically been regarded as a thin man's disease. Yet in our studies in Texas, a considerable proportion of the patients have been overweight and obese (33, 34). In addition, other studies have demonstrated that patients with diabetes mellitus, who are often overweight as part of metabolic syndrome, are at an increased risk of developing active pulmonary TB (20,30). This is a problem given that the "average" American's weight has increased by 10 kg in the last 4 decades, so that 2 in every 3 Americans are now overweight (body mass index [BMI] Ն 25 kg/m 2 ), 1 in 3 are obese (BMI Ն 30 kg/ m 2 ), and 6% are morbidly obese (BMI Ն 40 kg/m 2 ) (10, 32). In high-burden TB countries in southern Africa and South America, obesity has also become a major problem, rivaling even that in the United States, with considerable proportions of overweight/obese people and underweight/malnourished people coexisting within the same populations (9, 23). In Egypt, for example, obesity rates among women are Ͼ45%, while in the Pacific Islands of Samoa and Tonga they are 60 to 70% (39). Approximately 1.3 billion out of the 6 billion humans are at least overweight, so clearly the entire species is becoming obese (31). This is a major challenge, given that anti-TB dosing regimens were designed decades ago for an underweight population of patients with "consumption."Body mass (M) or weight is a physical phenomenon. Physical phenomena occur on a large range of scales. As an example, the mass of living things can vary from about ϳ6 ϫ 10 Ϫ16 kg for a bacterium to ϳ6 ϫ 10 4 kg for a sperm whale, a span of 10 20 . Scaling biochemical relationships using linear relationships across such a large span is often inaccurate. Second, the shapes of most natural objects, such as human organs, trees, mou...