Phase I safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin.

TitlePhase I safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin.
Publication TypeJournal Article
Year of Publication2014
AuthorsDooley KE, Luetkemeyer AF, Park J-G, Allen R, Cramer Y, Murray S, Sutherland D, Aweeka F, Koletar SL, Marzan F, Bao J, Savic R, Haas DW
Corporate AuthorsAIDS Clinical Trials Group A5306 Study Team
JournalAntimicrob Agents Chemother
Volume58
Issue9
Pagination5245-52
Date Published2014 Sep
ISSN1098-6596
KeywordsAdult, Antitubercular Agents, Antiviral Agents, Benzoxazines, Drug Combinations, Drug Therapy, Combination, Female, Humans, Lopinavir, Male, Middle Aged, Nitroimidazoles, Pharmacogenetics, Rifampin, Ritonavir, Young Adult
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.).

DOI10.1128/AAC.03332-14
Alternate JournalAntimicrob. Agents Chemother.
PubMed ID24957823
PubMed Central IDPMC4135849
Grant List1U01AI069465-01 / AI / NIAID NIH HHS / United States
1U01AI069474-01 / AI / NIAID NIH HHS / United States
AI-077505 / AI / NIAID NIH HHS / United States
HHSN272200800014C / / PHS HHS / United States
K23AI080842 / AI / NIAID NIH HHS / United States
P30 AI027763 / AI / NIAID NIH HHS / United States
TR-000445 / TR / NCATS NIH HHS / United States
U01 AI068634 / AI / NIAID NIH HHS / United States
U01 AI069465 / AI / NIAID NIH HHS / United States
U01-AI069439-01 / AI / NIAID NIH HHS / United States
U01-AI069502-01 / AI / NIAID NIH HHS / United States
UL1 TR000004 / TR / NCATS NIH HHS / United States
UL1 TR001070 / TR / NCATS NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
UL1RR024975 / RR / NCRR NIH HHS / United States
UL1TR000004 / TR / NCATS NIH HHS / United States
UL1TR001070 / TR / NCATS NIH HHS / United States
UM1 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States
UM1 AI069439 / AI / NIAID NIH HHS / United States
UM1 AI069494 / AI / NIAID NIH HHS / United States
UM1 AI069496 / AI / NIAID NIH HHS / United States
UM1 AI106701 / AI / NIAID NIH HHS / United States
UM1AI068636 / AI / NIAID NIH HHS / United States
UM1AI68634 / AI / NIAID NIH HHS / United States