title: Efavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Receiving Rifapentine and Isoniazid for Tuberculosis Prevention.
abstract: BACKGROUND
  Concomitant use of rifamycins to treat or prevent tuberculosis can result in subtherapeutic concentrations of antiretroviral drugs. We studied the interaction of efavirenz with daily rifapentine and isoniazid in human immunodeficiency virus (HIV)-infected individuals receiving a 4-week regimen to prevent tuberculosis.
  
  
  METHODS
  Participants receiving daily rifapentine and isoniazid with efavirenz had pharmacokinetic evaluations at baseline and weeks 2 and 4 of concomitant therapy. Efavirenz apparent oral clearance was estimated and the geometric mean ratio (GMR) of values before and during rifapentine and isoniazid was calculated. HIV type 1 (HIV-1) RNA was measured at baseline and week 8.
  
  
  RESULTS
  Eighty-seven participants were evaluable: 54% were female, and the median age was 35 years (interquartile range [IQR], 29-44 years). Numbers of participants with efavirenz concentrations ≥1 mg/L were 85 (98%) at week 0; 81 (93%) at week 2; 78 (90%) at week 4; and 75 (86%) at weeks 2 and 4. Median efavirenz apparent oral clearance was 9.3 L/hour (IQR, 6.42-13.22 L/hour) at baseline and 9.8 L/hour (IQR, 7.04-15.59 L/hour) during rifapentine/isoniazid treatment (GMR, 1.04 [90% confidence interval, .97-1.13]). Seventy-nine of 85 (93%) participants had undetectable HIV-1 RNA (<40 copies/mL) at entry; 71 of 75 (95%) participants had undetectable HIV-1 RNA at week 8. Two participants with undetectable HIV-1 RNA at study entry were detectable (43 and 47 copies/mL) at week 8.
  
  
  CONCLUSIONS
  The proportion of participants with midinterval efavirenz concentrations ≥1 mg/L did not cross below the prespecified threshold of >80%, and virologic suppression was maintained. Four weeks of daily rifapentine plus isoniazid can be coadministered with efavirenz without clinically meaningful reductions in efavirenz mid-dosing concentrations or virologic suppression.
  
  
  BACKGROUND
  NCT 01404312.
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Podany
authors.affiliation: Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Infectious Diseases, Internal Medicine, University of Nebraska Medical Center, Omaha.
authors.forename: Susan
authors.initials: S
authors.lastname: Swindells
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Chaisson
authors.affiliation: Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Janet W
authors.initials: JW
authors.lastname: Andersen
authors.affiliation: University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Thando
authors.initials: T
authors.lastname: Mwelase
authors.affiliation: Research Institute for Health Sciences and Faculty of Medicine, Chiang Mai University, Thailand.
authors.forename: Khuanchai
authors.initials: K
authors.lastname: Supparatpinyo
authors.affiliation: University of the Witwatersrand and Baragwanath Hospital, Soweto, South Africa.
authors.forename: Lerato
authors.initials: L
authors.lastname: Mohapi
authors.affiliation: Center for Clinical Global Health Education, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Amita
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Antiviral Research Center, University of California, San Diego.
authors.forename: Constance A
authors.initials: CA
authors.lastname: Benson
authors.affiliation: Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
authors.forename: Peter
authors.initials: P
authors.lastname: Kim
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha Infectious Diseases, Internal Medicine, University of Nebraska Medical Center, Omaha.
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000627:therapeutic use*; D048588:Benzoxazines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008297:Male; D012367:RNA, Viral / Q000032:analysis; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D012293:Rifampin / Q000031:analogs & derivatives / Q000627:therapeutic use; D014376:Tuberculosis / Q000517:prevention & control*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz; D007538:Isoniazid; D012293:Rifampin; C018421:rifapentine
keywords: HIV/AIDS; pharmacodynamics; pharmacokinetics; rifapentine; tuberculosis