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 #
1K23AI080842-01
Application #
7570796
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
2009-03-01
Budget End
2010-02-28
Support Year
1
Fiscal Year
2009
Total Cost
$133,574
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
McIlleron, Helen; Denti, Paolo; Cohn, Silvia et al. (2017) Prevention of TB using rifampicin plus isoniazid reduces nevirapine concentrations in HIV-exposed infants. J Antimicrob Chemother 72:2028-2034
Conde, Marcus B; Mello, Fernanda C Q; Duarte, Rafael Silva et al. (2016) A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis. PLoS One 11:e0154778
Hoffmann, Christopher J; Cohn, Silvia; Mashabela, Fildah et al. (2016) Treatment Failure, Drug Resistance, and CD4 T-Cell Count Decline Among Postpartum Women on Antiretroviral Therapy in South Africa. J Acquir Immune Defic Syndr 71:31-7
Svensson, Elin M; Murray, Stephen; Karlsson, Mats O et al. (2015) Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti-TB drug. J Antimicrob Chemother 70:1106-14
Denti, Paolo; Martinson, Neil; Cohn, Silvia et al. (2015) Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa. Antimicrob Agents Chemother 60:1234-41
Dooley, Kelly E; Savic, Radojka M; Park, Jeong-Gun et al. (2015) Novel dosing strategies increase exposures of the potent antituberculosis drug rifapentine but are poorly tolerated in healthy volunteers. Antimicrob Agents Chemother 59:3399-405
Dooley, Kelly E; Denti, Paolo; Martinson, Neil et al. (2015) Pharmacokinetics of efavirenz and treatment of HIV-1 among pregnant women with and without tuberculosis coinfection. J Infect Dis 211:197-205
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
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
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

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