Tuberculosis (TB) is the second-leading cause of death by infection. Novel strategies are critically needed to shorten treatment duration and treat multidrug resistant (MDR) and extensively drug-resistant (XDR) TB. The applicant is pursuing joint training in Clinical Pharmacology and Infectious Diseases and will combine her expertise in these areas to lead the rational development of new treatments for TB. The K23 award would provide the ideal vehicle for her to complete her education and training so she may launch an independent career in academic clinical research focused on TB therapeutics. The overall goal of this proposal is to evaluate pharmacokinetic and pharmacodynamic (PK/PD) parameters of two promising new TB treatments. First, moxifloxacin- and rifapentine- (RPT) containing regimens are strikingly effective in mice. Defining the PK/PD parameters that predict treatment response in humans will be essential for developing rational dosing regimens. Rifamycin hypersensitivity, however, may occur with high-dose, intermittent RPT and impact its safety. Second, TMC207 is a new agent being developed for TB treatment that is active against MDR TB. It is metabolized by the cytochrome P450 isoenzyme 3A4 (CYP3A4), so drug interactions with agents used to treat human immunodeficiency virus (HIV) are likely. We propose:
AIM 1 : To identify, for RPT and moxifloxacin, the PK/PD parameters that correlate most strongly with treatment response. We will perform a PK study nested in a Phase II randomized trial comparing a moxifloxacin- and RPT-based regimen to standard therapy during intensive phase TB treatment in Brazil.
AIM 2 : To investigate the incidence and immunopathogenesis of rifamycin hypersensitivity syndrome in patients receiving high-dose, intermittent RPT in the context of the Phase II trial.
AIM 3 : To determine the impact of antiviral drugs (ARVs), beginning with efavirenz (EFV), on the steady state pharmacokinetics of TMC207 in healthy volunteers. These studies will be performed at Johns Hopkins University with AIDS Clinical Trials Group (ACTG) support. Through these studies, we will better understand the pharmacology of moxifloxacin- and RPT-based regimens, allowing for optimization of this potent new regimen which may shorten TB treatment. This work will also provide crucial information that will impact the treatment of TB/HIV coinfected patients worldwide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI080842-04
Application #
8230582
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Mason, Robin M
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$134,325
Indirect Cost
$9,950
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cherkaoui, Imad; Sabouni, Radia; Ghali, Iraqi et al. (2014) Treatment default amongst patients with tuberculosis in urban Morocco: predicting and explaining default and post-default sputum smear and drug susceptibility results. PLoS One 9:e93574
Dooley, Kelly E; Luetkemeyer, Anne F; Park, Jeong-Gun et al. (2014) Phase I safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin. Antimicrob Agents Chemother 58:5245-52
Savic, Radojka M; Lu, Yanhui; Bliven-Sizemore, Erin et al. (2014) Population pharmacokinetics of rifapentine and desacetyl rifapentine in healthy volunteers: nonlinearities in clearance and bioavailability. Antimicrob Agents Chemother 58:3035-42
Parsons, Teresa L; Marzinke, Mark A; Hoang, Thuy et al. (2014) Quantification of rifapentine, a potent antituberculosis drug, from dried blood spot samples using liquid chromatographic-tandem mass spectrometric analysis. Antimicrob Agents Chemother 58:6747-57
Svensson, Elin M; Dooley, Kelly E; Karlsson, Mats O (2014) Impact of lopinavir-ritonavir or nevirapine on bedaquiline exposures and potential implications for patients with tuberculosis-HIV coinfection. Antimicrob Agents Chemother 58:6406-12
Dooley, Kelly E; Nuermberger, Eric L; Diacon, Andreas H (2013) Pipeline of drugs for related diseases: tuberculosis. Curr Opin HIV AIDS 8:579-85
Svensson, Elin M; Aweeka, Francesca; Park, Jeong-Gun et al. (2013) Model-based estimates of the effects of efavirenz on bedaquiline pharmacokinetics and suggested dose adjustments for patients coinfected with HIV and tuberculosis. Antimicrob Agents Chemother 57:2780-7
Dooley, Kelly E; Obuku, Ekwaro A; Durakovic, Nadza et al. (2013) World Health Organization group 5 drugs for the treatment of drug-resistant tuberculosis: unclear efficacy or untapped potential? J Infect Dis 207:1352-8
Dooley, Kelly E; Park, Jeong-Gun; Swindells, Susan et al. (2012) Safety, tolerability, and pharmacokinetic interactions of the antituberculous agent TMC207 (bedaquiline) with efavirenz in healthy volunteers: AIDS Clinical Trials Group Study A5267. J Acquir Immune Defic Syndr 59:455-62
Dooley, K E; Bliven-Sizemore, E E; Weiner, M et al. (2012) Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers. Clin Pharmacol Ther 91:881-8

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