title: Phase I safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin.
abstract: There is an urgent need for new antituberculosis (anti-TB) drugs, including agents that are safe and effective with concomitant antiretrovirals (ARV) and first-line TB drugs. PA-824 is a novel antituberculosis nitroimidazole in late-phase clinical development. Cytochrome P450 (CYP) 3A, which can be induced or inhibited by ARV and antituberculosis drugs, is a minor (∼20%) metabolic pathway for PA-824. In a phase I clinical trial, we characterized interactions between PA-824 and efavirenz (arm 1), lopinavir/ritonavir (arm 2), and rifampin (arm 3) in healthy, HIV-uninfected volunteers without TB disease. Participants in arms 1 and 2 were randomized to receive drugs via sequence 1 (PA-824 alone, washout, ARV, and ARV plus PA-824) or sequence 2 (ARV, ARV with PA-824, washout, and PA-824 alone). In arm 3, participants received PA-824 and then rifampin and then both. Pharmacokinetic sampling occurred at the end of each dosing period. Fifty-two individuals participated. Compared to PA-824 alone, plasma PA-824 values (based on geometric mean ratios) for maximum concentration (Cmax), area under the concentration-time curve from 0 to 24 h (AUC0-24), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz, 13%, 17%, and 21% with lopinavir-ritonavir (lopinavir/r) and 53%, 66%, and 85% with rifampin, respectively. Medications were well tolerated. In conclusion, lopinavir/r had minimal effect on PA-824 exposures, supporting PA-824 use with lopinavir/r without dose adjustment. PA-824 exposures, though, were reduced more than expected when given with efavirenz or rifampin. The clinical implications of these reductions will depend upon data from current clinical trials defining PA-824 concentration-effect relationships. (This study has been registered at ClinicalTrials.gov under registration no. NCT01571414.).
authors: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA kdooley1@jhmi.edu.
authors: Kelly E
authors: KE
authors: Dooley
authors: University of California, San Francisco, California, USA.
authors: Anne F
authors: AF
authors: Luetkemeyer
authors: Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Jeong-Gun
authors: JG
authors: Park
authors: Social & Scientific Systems, Inc., Silver Spring, Maryland, USA.
authors: Reena
authors: R
authors: Allen
authors: Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Yoninah
authors: Y
authors: Cramer
authors: Global Alliance for TB Drug Development, New York, New York, USA.
authors: Stephen
authors: S
authors: Murray
authors: Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Deborah
authors: D
authors: Sutherland
authors: University of California, San Francisco, California, USA.
authors: Francesca
authors: F
authors: Aweeka
authors: Ohio State University, Columbus, Ohio, USA.
authors: Susan L
authors: SL
authors: Koletar
authors: University of California, San Francisco, California, USA.
authors: Florence
authors: F
authors: Marzan
authors: Henry M. Jackson Foundation, Division of AIDS, National Institutes of Health, Bethesda, Maryland, USA.
authors: Jing
authors: J
authors: Bao
authors: University of California, San Francisco, California, USA.
authors: Rada
authors: R
authors: Savic
authors: Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: David W
authors: DW
authors: Haas
mesh_terms: D000328:Adult; D000480:Alkynes; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003521:Cyclopropanes; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D061466:Lopinavir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010597:Pharmacogenetics; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000480:Alkynes; D000995:Antitubercular Agents; D000998:Antiviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004338:Drug Combinations; D009593:Nitroimidazoles; C558899:lopinavir-ritonavir drug combination; C410767:pretomanid; D061466:Lopinavir; C098320:efavirenz; D019438:Ritonavir; D012293:Rifampin