The Hollow Fiber System Model in the Nonclinical Evaluation of Antituberculosis Drug Regimens

Tuberculosis remains a serious public health challenge, with the global prevalence of active disease estimated at 8.6 million and the mortality rate at 1.3 million deaths per year [1]. In 2012, the Centers for Disease Control and Prevention reported approximately 10 000 cases in the United States, of which approximately 1% were resistant to both rifampin and isoniazid [2]. These epidemiologic data highlight the need for new antituberculosis drugs, encompassing novel mechanisms of action, improved safety profiles, and fewer drug–drug interactions. New combination regimens will be of particular importance in improving the management and control of tuberculosis globally. A pathway for bringing new antituberculosis drugs and drug combinations efficiently and promptly into laterstage clinical trials is a critical public health goal. Among recent advances in drug therapy for tuberculosis, shortened treatment regimens have had a dramatic public health impact. Instead of the mid-20th-century practice of administering singleor dual-drug treatments for 1 year or longer, the standard of care today for patients with susceptible tuberculosis is the 6-month 2HRZE/4HR regimen, consisting of 2 months of treatment with isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E) followed by 4 months of isoniazid and rifampin. The 2HRZE/4HR regimen was developed, primarily by the British Medical Research Council [3], during 1970–1982, through many earlystage phase 2 clinical trials, in which multiple variations of combination drug regimens were investigated. This development process was highly laborious, underscoring the need for tools to inform regimen development, including more efficiently designed, later-stage phase 2 clinical trials. In this supplement of Clinical Infectious Diseases, authors from the Critical Path to TB Drug Regimens (CPTR) and academia present an in vitro model to evaluate drug activity against Mycobacterium tuberculosis; specifically, the authors posit that the hollow fiber system model of tuberculosis (HFS-TB) might be used to identify promising regimens appropriate for testing in laterstage phase 2 clinical trials. The HFS-TB can be used to simulate many pharmacokinetic characteristics of antimycobacterial drugs and allows for the exploration of concentration–effect relationships potentially relevant to the treatment of tuberculosis in the clinical setting. In contrast, the clinical identification of such relationships (ie, prior to later-stage clinical trial evaluations) may take several years. In addition, the HFS-TB can model the emergence of resistance by reiterating microbial dynamics (eg, dormancy of bacilli subpopulations). The effective use of the hollowfiber systemmodel (HFS) in the course of developing individual antibacterial drugs has allowed investigators to predict pharmacodynamic characteristics and thereby determine dosing regimens for clinical trials more efficiently. For example, it was used to predict exposure and efficacy of amoxicillin for the prophylaxis of inhalational anthrax in children and pregnant women [4]. In concert with mathematic Correspondence: Joseph G. Toerner, MD, MPH, Office of Antimicrobial Products, CDER/Office of New Drugs, US Food and Drug Administration, 10903 New Hampshire Ave, White Oak Bldg 22, Rm 6244, Silver Spring, MD 20993 (joseph.toerner@ fda.hhs.gov). Clinical Infectious Diseases 2015;61(S1):S32–3 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/cid/civ460