title: Pharmacokinetic profile of raltegravir, elvitegravir and dolutegravir in plasma and mucosal secretions in rhesus macaques.
abstract: OBJECTIVE
  Pharmacokinetic studies in animal models are important for assessing the prophylactic potential of antiretroviral drugs for HIV prevention. This study sought to identify clinically relevant doses of the marketed integrase inhibitors raltegravir, elvitegravir and dolutegravir in macaques and investigate drug penetration and antiviral activity in mucosal secretions.
  
  
  METHODS
  Macaques received one oral dose of raltegravir, elvitegravir or dolutegravir alone or in combination with emtricitabine and tenofovir disoproxil fumarate followed by drug level measurements in blood and rectal and vaginal secretions. Antiviral activity was investigated in TZM-bl cells exposed to SHIV162p3 in the presence of rectal secretions collected from treated animals.
  
  
  RESULTS
  Plasma drug concentrations with 50 mg/kg raltegravir or elvitegravir were within the range seen in humans receiving 400-800 mg of raltegravir or 800 mg of unboosted elvitegravir but lower than with 150 mg of elvitegravir boosted with cobicistat. AUC0-24 values for dolutegravir increased proportionally with the dose, with a calculated human-equivalent dose of 20 mg/kg. Elvitegravir showed the highest penetration in rectal and vaginal fluids despite the absence of pharmacological boosting, followed by raltegravir and dolutegravir. Rectal secretions collected at 24 h from treated macaques blocked infection of TZM-bl cells by 50% at dilutions of 1/1000 (raltegravir), 1/800 (dolutegravir) and >1/30 000 (elvitegravir).
  
  
  CONCLUSIONS
  We defined macaque doses of HIV integrase inhibitors that recapitulate human clinical doses, which will facilitate efficacy and dose escalation studies in macaques. High and sustained drug concentrations and activity in mucosal secretions suggest that integrase inhibitors are promising candidates for HIV prevention.
authors: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA.
authors: Ivana
authors: I
authors: Massud
authors: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA.
authors: Amy
authors: A
authors: Martin
authors: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA.
authors: Chuong
authors: C
authors: Dinh
authors: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA.
authors: James
authors: J
authors: Mitchell
authors: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA.
authors: Leecresia
authors: L
authors: Jenkins
authors: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA.
authors: Walid
authors: W
authors: Heneine
authors: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA.
authors: Chou-Pong
authors: CP
authors: Pau
authors: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA ggarcia-lerma@cdc.gov.
authors: J Gerardo
authors: JG
authors: García-Lerma
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012634:Bodily Secretions / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D009092:Mucous Membrane / Q000737:chemistry*; D010078:Oxazines; D010879:Piperazines; D010949:Plasma / Q000737:chemistry*; D011728:Pyridones; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012007:Rectum / Q000737:chemistry; D053719:Tandem Mass Spectrometry; D014621:Vagina / Q000737:chemistry; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir
keywords: antiviral activity; integrase inhibitors; non-human primates
references: J Acquir Immune Defic Syndr. 2000 Aug 1;24(4):297-309
references: 11015145
references: J Pharm Sci. 1986 Sep;75(9):852-7
references: 3465954
references: Science. 1995 Nov 17;270(5239):1197-9
references: 7502044
references: J Virol. 1998 May;72(5):4265-73
references: 9557716
references: J Acquir Immune Defic Syndr. 2006 Sep;43(1):1-5
references: 16936557
references: Drug Metab Dispos. 2007 Sep;35(9):1657-63
references: 17591678
references: PLoS Med. 2008 Feb;5(2):e28
references: 18254653
references: FASEB J. 2008 Mar;22(3):659-61
references: 17942826
references: J Acquir Immune Defic Syndr. 2009 Aug 15;51(5):546-53
references: 19546811
references: Antimicrob Agents Chemother. 2010 Jan;54(1):254-8
references: 19884365
references: Sci Transl Med. 2010 Jan 13;2(14):14ra4
references: 20371467
references: Retrovirology. 2010;7:21
references: 20233398
references: J Acquir Immune Defic Syndr. 2010 Nov;55(3):323-9
references: 20683270
references: N Engl J Med. 2010 Dec 30;363(27):2587-99
references: 21091279
references: Antimicrob Agents Chemother. 2011 Feb;55(2):813-21
references: 21115794
references: Antimicrob Agents Chemother. 2011 Jun;55(6):3018-21
references: 21444705
references: J Acquir Immune Defic Syndr. 2011 Dec 15;58(5):450-7
references: 21926632
references: N Engl J Med. 2012 Aug 2;367(5):411-22
references: 22784040
references: Curr Opin HIV AIDS. 2012 Sep;7(5):390-400
references: 22789987
references: Sci Transl Med. 2012 Sep 12;4(151):151ra125
references: 22972843
references: Curr Opin HIV AIDS. 2012 Nov;7(6):505-13
references: 22964889
references: Clin Pharmacokinet. 2011 Apr;50(4):229-44
references: 21348537
references: J Antimicrob Chemother. 2011 Jun;66(6):1340-5
references: 21406434
references: PLoS One. 2012;7(12):e50632
references: 23226529
references: J Virol. 2013 Aug;87(16):8952-61
references: 23740994
references: Infect Control Hosp Epidemiol. 2013 Sep;34(9):875-92
references: 23917901
references: AIDS. 2013 Jun 1;27(9):1413-9
references: 23945503
references: J Acquir Immune Defic Syndr. 2013 Sep 1;64(1):39-44
references: 23945251
references: J Med Primatol. 2013 Oct;42(5):237-46
references: 24025078
references: Antimicrob Agents Chemother. 2012 Mar;56(3):1627-9
references: 22183173
references: Antimicrob Agents Chemother. 2012 Jun;56(6):3101-6
references: 22430964
references: N Engl J Med. 2012 Aug 2;367(5):399-410
references: 22784037
references: N Engl J Med. 2012 Aug 2;367(5):423-34
references: 22784038
references: Antivir Ther. 2013;18(8):1005-13
references: 23899439
references: Science. 2014 Mar 7;343(6175):1151-4
references: 24594934
references: Sci Transl Med. 2014 Mar 12;6(227):227ra35
references: 24622515
references: Clin Pharmacokinet. 2014 Jul;53(7):611-24
references: 24859035
references: Nature. 2014 Aug 7;512(7512):74-7
references: 25042999
references: J Antimicrob Chemother. 2014 Sep;69(9):2470-6
references: 24862094
references: J Infect Dis. 2011 May 15;203(10):1484-90
references: 21502084