A Physiologically Based Pharmacokinetic Model for Capreomycin

Reisfeld, Brad; Metzler, C. P.; Lyons, Michael A.; Mayeno, Arthur N.; Brooks, Elizabeth J.; DeGroote, Mary Ann

doi:10.1128/aac.05180-11

Cited by 22 publications

(15 citation statements)

References 43 publications

(52 reference statements)

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“…We considered PBPK modeling appropriate to our objective, as it provides drug concentrations throughout the body with minimal use of free parameters and, with many examples of modeling complex chemical mixtures (55, 57), provides an established framework for addressing multidrug combinations. Although PBPK modeling has had limited application to anti-TB drugs thus far (58,59), it is well established in other areas of drug development and toxicological risk assessment (60); examples include anticancer (51) and immunosuppresive (61) drugs, monoclonal antibodies (62), nanoparticles (63), and a wide range of environmental toxicants (64). Empirical and semiphysiologically based pharmacokinetic models for rifampin, which include plasma and a tissue compartment such as liver (33) or lung (65,66), are available.…”

Section: Discussionmentioning

confidence: 99%

A Physiologically Based Pharmacokinetic Model of Rifampin in Mice

Lyons

Reisfeld

Yang

et al. 2013

Antimicrob Agents Chemother

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One problem associated with regimen-based development of antituberculosis (anti-TB) drugs is the difficulty of a systematic and thorough in vivo evaluation of the large number of possible regimens that arise from consideration of multiple drugs tested together. A mathematical model capable of simulating the pharmacokinetics and pharmacodynamics of experimental combination chemotherapy of TB offers a way to mitigate this problem by extending the use of available data to investigate regimens that are not initially tested. In order to increase the available mathematical tools needed to support such a model for preclinical anti-TB drug development, we constructed a preliminary whole-body physiologically based pharmacokinetic (PBPK) model of rifampin in mice, using data from the literature. Interindividual variability was approximated using Monte Carlo (MC) simulation with assigned probability distributions for the model parameters. An MC sensitivity analysis was also performed to determine correlations between model parameters and plasma concentration to inform future model development. Model predictions for rifampin concentrations in plasma, liver, kidneys, and lungs, following oral administration, were generally in agreement with published experimental data from multiple studies. Sensitive model parameters included those descriptive of oral absorption, total clearance, and partitioning of rifampin between blood and muscle. This PBPK model can serve as a starting point for the integration of rifampin pharmacokinetics in mice into a larger mathematical framework, including the immune response to Mycobacterium tuberculosis infection, and pharmacokinetic models for other anti-TB drugs.T uberculosis (TB), caused by Mycobacterium tuberculosis, is an infectious disease which continues to be a major cause of death in large parts of the world (1). While the current first-line therapy for drug-susceptible TB (composed of rifampin, isoniazid, pyrazinamide, and ethambutol) has been in clinical use for nearly 30 years, the emergence and spread of drug-resistant M. tuberculosis strains have motivated the search for new, more-effective combination regimens (2). Our interest here is the development of mathematical tools to supplement the animal studies necessary for the identification and testing of such new anti-TB drug regimens.The mouse is the primary animal species used for preclinical anti-TB drug development (3). Despite the differences between mice and humans, the activities of many anti-TB drugs against disease caused by M. tuberculosis are similar in both species (4, 5). Mice also provide for a range of TB susceptibility and pathology through a variety of outbred and inbred strains; a notable example is C3HeB/FeJ mice (6), which form necrotic pulmonary lesions similar to those observed in TB patients (7). The recent Critical Path to TB Drug Regimens (CPTR) Initiative (8) includes an added emphasis on the mouse for identification of new optimized three-drug regimens as a key step in advancing novel drug combinations into ...

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Section: Discussionmentioning

confidence: 99%

A Physiologically Based Pharmacokinetic Model of Rifampin in Mice

Lyons

Reisfeld

Yang

et al. 2013

Antimicrob Agents Chemother

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“…A number of plasma pharmacokinetic (PK) models for anti-TB antibiotics are available and range from one-compartment models to more complex physiology-based models[15, 24–26]. Combined PK-pharmacodynamics (PD) models for TB antibiotics have been built for RIF[27] and INH[28, 29] and nonspecific antibiotics[30].…”

Section: Introductionmentioning

confidence: 99%

A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment

Pienaar

Cilfone

Lin

et al. 2015

Journal of Theoretical Biology

161

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While active tuberculosis (TB) is a treatable disease, many complex factors prevent its global elimination. Part of the difficulty in developing optimal therapies is the large design space of antibiotic doses, regimens and combinations. Computational models that capture the spatial and temporal dynamics of antibiotics at the site of infection can aid in reducing the design space of costly and time-consuming animal pre-clinical and human clinical trials. The site of infection in TB is the granuloma, a collection of immune cells and bacteria that form in the lung, and new data suggest that penetration of drugs throughout granulomas is problematic. Here we integrate our computational model of granuloma formation and function with models for plasma pharmacokinetics, lung tissue pharmacokinetics and pharmacodynamics for two first line anti-TB antibiotics. The integrated model is calibrated to animal data. We make four predictions. First, antibiotics are frequently below effective concentrations inside granulomas, leading to bacterial growth between doses and contributing to the long treatment periods required for TB. Second, antibiotic concentration gradients form within granulomas, with lower concentrations toward their centers. Third, during antibiotic treatment, bacterial subpopulations are similar for INH and RIF treatment: mostly intracellular with extracellular bacteria located in areas non-permissive for replication (hypoxic areas), presenting a slowly increasing target population over time. Finally, we find that on an individual granuloma basis, pre-treatment infection severity (including bacterial burden, host cell activation and host cell death) is predictive of treatment outcome.

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“…In the few published clinical studies specifically evaluating alveolar lining fluid concentrations of aminoglycosides after systemic administration, alveolar concentrations ranged from 32% to 50% of the peak systemic concentration (9)(10)(11). Furthermore, preclinical studies of capreomycin pharmacokinetics in mice have shown that parenteral doses penetrate poorly into the lung (12). Since clinical effectiveness of the aminoglycosides and capreomycin is closely correlated with the ratio of C max to MIC, based on in vitro and in vivo studies with Gram-negative bacteria and with M. tuberculosis (13-15), one of the major challenges in TB chemotherapy is the ability to achieve both adequate lung compartmentspecific C max and systemic C max (for extrapulmonary sites of infection) while limiting or avoiding systemic toxicity.…”

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confidence: 99%

Phase I, Single-Dose, Dose-Escalating Study of Inhaled Dry Powder Capreomycin: a New Approach to Therapy of Drug-Resistant Tuberculosis

Dharmadhikari

Kabadi²,

Gerety³

et al. 2013

Antimicrob Agents Chemother

114

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dMultidrug-resistant tuberculosis (MDR-TB) threatens global TB control. The lengthy treatment includes one of the injectable drugs kanamycin, amikacin, and capreomycin, usually for the first 6 months. These drugs have potentially serious toxicities, and when given as intramuscular injections, dosing can be painful. Advances in particulate drug delivery have led to the formulation of capreomycin as the first antituberculosis drug available as a microparticle dry powder for inhalation and clinical study. Delivery by aerosol may result in successful treatment with lower doses. Here we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability in healthy subjects and measuring pharmacokinetic (PK) parameters. Twenty healthy adults (n ‫؍‬ 5 per group) were recruited to self-administer a single dose of inhaled dry powder capreomycin (25-mg, 75-mg, 150-mg, or 300-mg nominal dose) using a simple, handheld delivery device. Inhalations were well tolerated by all subjects. The most common adverse event was mild to moderate transient cough, in five subjects. There were no changes in lung function, audiometry, or laboratory parameters. Capreomycin was rapidly absorbed after inhalation. Systemic concentrations were detected in each dose group within 20 min. Peak and mean plasma concentrations of capreomycin were dose proportional. Serum concentrations exceeded 2 g/ml (MIC for Mycobacterium tuberculosis) following the highest dose; the half-life (t 1/2 ) was 4.8 ؎ 1.0 h. A novel inhaled microparticle dry powder formulation of capreomycin was well tolerated. A single 300-mg dose rapidly achieved serum drug concentrations above the MIC for Mycobacterium tuberculosis, suggesting the potential of inhaled therapy as part of an MDR-TB treatment regimen. M ultidrug-resistant tuberculosis (MDR-TB) is difficult to treat and readily spread and threatens global tuberculosis control, especially where HIV coinfection is common. According to the WHO, an estimated 440,000 new cases of MDR-TB occur each year (1, 2), but only a small fraction are receiving qualityassured treatment (1). In most public health treatment programs, 18 to 24 months of therapy with four or more second-line drugs are required. Second-line drugs are less efficacious, more toxic, and associated with treatment success rates of only 40 to 80% (1, 3-6). According to current WHO MDR-TB treatment guidelines, at least one injectable antibiotic (kanamycin, amikacin, or capreomycin) is an essential part of the 6-month intensive phase of treatment. These 3-to 7-times-per-week injections are painful for patients, especially for children and those with little muscle mass. Injections require skilled health care staff and place them at risk of needle stick injuries and infections (3). Treatment with injectable drugs is associated with systemic toxicity, including nephrotoxicity, which is typically mild and reversible, and ototoxicity, which can be significant and irreversible. Dosing must also be adjusted in individuals with preexisting renal...

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A Physiologically Based Pharmacokinetic Model for Capreomycin

Cited by 22 publications

References 43 publications

A Physiologically Based Pharmacokinetic Model of Rifampin in Mice

A Physiologically Based Pharmacokinetic Model of Rifampin in Mice

A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment

Phase I, Single-Dose, Dose-Escalating Study of Inhaled Dry Powder Capreomycin: a New Approach to Therapy of Drug-Resistant Tuberculosis

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