There are only nine FDA-approved drugs for the treatment of tuberculosis (TB). Most of the pharmacokinetic and pharmacodynamic data available for them are limited in scope, and were acquired with outdated techniques. Since there are no revolutionary antituberculosis drugs on the horizon, we must optimize our use of the available drugs. Mounting evidence points to definable relationships between the antituberculosis drug serum concentrations achieved in patients and their responses to treatment. If we are to improve the nearly 50% treatment failure rates for patients with multidrug-resistant tuberculosis (MDR-TB), it is critical that we define and exploit these relationships. Clearly defined therapeutic ranges for the antituberculosis drugs would allow clinicians to control and optimize the treatment of TB and especially MDR-TB. The overall goal of this study is to define the pharmacokinetic parameter values and key drug interactions for the antituberculosis drug. We will also determine how these values are altered by the host response to TB infection, concurrent illnesses, and extremes of age. This basic research will lead to maximum aposteriori probability (MAP) Bayesian and """"""""multiple model"""""""" (MM) stochastic dosage design strategies for the individualization, adaptive control, and optimization of drug therapy for patients with TB and MDR-TB. It will also define relationships between the serum concentrations achieved and the clinical and bacteriological outcomes of treatment. We will research two specific areas. Project No. 1: We will perform randomized, cross-over pharmacokinetic studies in healthy volunteers. This will allow us to control a large number of variables that cannot be controlled in patients with TB. Subjects will receive (a) drugs taken in the fasted state, (b) drugs taken with food, and (c) drugs taken with antacids. Population pharmacokinetic models will be constructed for each antituberculosis drug using the USC*PACK software. We will determine six important endpoints: (1) true normal serum concentrations, (2) normal population pharmacokinetic parameter values, (3) the degree of intrasubject and intersubject variability in these values, and accurate recommendations regarding (4) which drugs must be taken on an empty stomach, (5) which drugs should be taken with food, and (6) which drugs must not be taken with antacids. Project No. 2: There are practically no data regarding the pharmacokinetics of the antituberculosis drugs in neonates and children, and the data for adults is sparse and does not address intermittent therapy. We will perform pharmacokinetic studies in neonates, children, and adults infected with TB and MDR-TB. Population pharmacokinetic mode's will be constructed as above. We will describe any changes in the parameter values caused by the host response to TB infection. We will seek to define unique subpopulations of TB patients based on age, selected concurrent illness, such as gastrointestinal, hepatic, or renal dysfunction, or AIDS. We will develop MAP Bayesian and MM stochastic dosage design strategies for the individualization and adaptive control of drug therapy for patients with TB and MDR-TB. We will also define relationships between the serum concentrations achieved and the clinical and bacteriological outcomes of treatment.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (SRC (49))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Jewish Health
United States
Zip Code
Chideya, Sekai; Winston, Carla A; Peloquin, Charles A et al. (2009) Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana. Clin Infect Dis 48:1685-94
Brandt, Curtis R; Akkarawongsa, Radeekorn; Altmann, Sharon et al. (2007) Evaluation of a theta-defensin in a Murine model of herpes simplex virus type 1 keratitis. Invest Ophthalmol Vis Sci 48:5118-24
Tappero, Jordan W; Bradford, Williamson Z; Agerton, Tracy B et al. (2005) Serum concentrations of antimycobacterial drugs in patients with pulmonary tuberculosis in Botswana. Clin Infect Dis 41:461-9
Zhu, M; Burman, W J; Starke, J R et al. (2004) Pharmacokinetics of ethambutol in children and adults with tuberculosis. Int J Tuberc Lung Dis 8:1360-7
Nix, D E David E; Adam, R D Rodney D; Auclair, Barbara et al. (2004) Pharmacokinetics and relative bioavailability of clofazimine in relation to food, orange juice and antacid. Tuberculosis (Edinb) 84:365-73
Yasin, Bushra; Wang, Wei; Pang, Mabel et al. (2004) Theta defensins protect cells from infection by herpes simplex virus by inhibiting viral adhesion and entry. J Virol 78:5147-56
Zhu, M; Namdar, R; Stambaugh, J J et al. (2002) Population pharmacokinetics of ethionamide in patients with tuberculosis. Tuberculosis (Edinb) 82:91-6
Stambaugh, J J; Berning, S E; Bulpitt, A E et al. (2002) Ofloxacin population pharmacokinetics in patients with tuberculosis. Int J Tuberc Lung Dis 6:503-9
Burman, W J; Gallicano, K; Peloquin, C (2001) Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. Clin Pharmacokinet 40:327-41
Auclair, B; Nix, D E; Adam, R D et al. (2001) Pharmacokinetics of ethionamide administered under fasting conditions or with orange juice, food, or antacids. Antimicrob Agents Chemother 45:810-4

Showing the most recent 10 out of 20 publications