期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 58, 期 9, 页码 5245-5252出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.03332-14
关键词
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资金
- ACTG CTU grant [U01-AI069439-01, U01-AI069502-01, 1U01AI069474-01, UL1TR001070, 1U01AI069465-01, UL1 TR001079]
- Vanderbilt CTSA grant from NCRR/NIH [UL1RR024975]
- UCSF CTSI grant [UL1TR000004]
- National Institute of Allergy and Infectious Diseases
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C]
- [U01 AI069465]
- [TR-000445]
- [AI-077505]
- [K23AI080842]
- [U01 AI068634]
- [UM1AI068636]
- [UM1AI68634]
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 (similar to 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 (C-max), area under the concentration- time curve from 0 to 24 h (AUC(0-24)), and trough concentration (C-min) 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.
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