title: Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects.
abstract: BACKGROUND
  The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone.
  
  
  METHODS
  Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. On day 14 of each phase, blood was sampled for pharmacokinetic studies, and the area under the concentration-time curve (AUCτ) and average concentration (C avg) were calculated and compared using an unpaired t test.
  
  
  RESULTS
  Twenty-nine subjects completed both dosing cohorts. Subjects receiving EFV-based cART had 47% and 44% lower atovaquone AUCτ than subjects not receiving cART at atovaquone doses of 750 mg BID and 1500 mg BID, respectively (P≤ .01). Only 5 of 10 subjects receiving EFV-based cART plus atovaquone 750 mg BID had an atovaquone C avg>15 µg/mL, which has previously been associated with successful treatment of Pneumocystis jirovecipneumonia. AUCτ and Cavg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone C avg>18.5 µg/mL, a concentration that has previously been associated with successful treatment of Toxoplasmaencephalitis (TE).
  
  
  CONCLUSIONS
  These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV.
  
  
  BACKGROUND
  NCT01479361.
authors.affiliation: Pharmacy Department, National Institutes of Health (NIH) Clinical Center, Bethesda.|Leidos Biomedical Research, Inc, National Cancer Institute at Frederick.
authors.forename: Mónica M
authors.initials: MM
authors.lastname: Calderón
authors.affiliation: Pharmacy Department, National Institutes of Health (NIH) Clinical Center, Bethesda.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Penzak
authors.affiliation: National Institute of Allergy and Infectious Diseases, NIH.
authors.forename: Alice K
authors.initials: AK
authors.lastname: Pau
authors.affiliation: Pharmacy Department, National Institutes of Health (NIH) Clinical Center, Bethesda.
authors.forename: Parag
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Leidos Biomedical Research, Inc, National Cancer Institute at Frederick.
authors.forename: Maryellen
authors.initials: M
authors.lastname: McManus
authors.affiliation: Pharmacy Department, National Institutes of Health (NIH) Clinical Center, Bethesda.
authors.forename: Raul M
authors.initials: RM
authors.lastname: Alfaro
authors.affiliation: Critical Care Medicine Department, NIH Clinical Center, Bethesda, Maryland.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kovacs
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000890:Anti-Infective Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000069446:Atazanavir Sulfate / Q000009:adverse effects / Q000627:therapeutic use; D053626:Atovaquone / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D048588:Benzoxazines / Q000009:adverse effects / Q000627:therapeutic use*; D003521:Cyclopropanes; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000009:adverse effects; D004660:Encephalitis / Q000188:drug therapy / Q000517:prevention & control; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy / Q000517:prevention & control; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D019438:Ritonavir / Q000009:adverse effects / Q000627:therapeutic use*; D016781:Toxoplasmosis, Cerebral / Q000188:drug therapy / Q000517:prevention & control; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D000069446:Atazanavir Sulfate; C098320:efavirenz; D019438:Ritonavir; D053626:Atovaquone
keywords: Pneumocystis jiroveci pneumonia; atovaquone; drug interaction; efavirenz; toxoplasma encephalitis