title: MTN-001: randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments.
abstract: BACKGROUND
  Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development.
  
  
  OBJECTIVE
  MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design.
  
  
  RESULTS
  We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03).
  
  
  CONCLUSIONS
  Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00592124.
authors: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA. chendrix@jhmi.edu
authors: Craig W
authors: CW
authors: Hendrix
authors: Beatrice A
authors: BA
authors: Chen
authors: Vijayanand
authors: V
authors: Guddera
authors: Craig
authors: C
authors: Hoesley
authors: Jessica
authors: J
authors: Justman
authors: Clemensia
authors: C
authors: Nakabiito
authors: Robert
authors: R
authors: Salata
authors: Lydia
authors: L
authors: Soto-Torres
authors: Karen
authors: K
authors: Patterson
authors: Alexandra M
authors: AM
authors: Minnis
authors: Sharavi
authors: S
authors: Gandham
authors: Kailazarid
authors: K
authors: Gomez
authors: Barbra A
authors: BA
authors: Richardson
authors: Namandje N
authors: NN
authors: Bumpus
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D005260:Female; D015658:HIV Infections / Q000517:prevention & control; D006801:Humans; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D010757:Phosphorous Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D010766:Phosphorylation; D012007:Rectum / Q000378:metabolism; D013607:Tablets; D000068698:Tenofovir; D014621:Vagina / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D014622:Vaginal Creams, Foams, and Jellies; D055815:Young Adult
chemical_list: C574165:9-(2-((bis(pivaloyloxymethoxy)phosphinoyl)methoxy)propyl)adenine; D019380:Anti-HIV Agents; D063065:Organophosphonates; D010757:Phosphorous Acids; D013607:Tablets; D014622:Vaginal Creams, Foams, and Jellies; D000068698:Tenofovir; D000225:Adenine
references: Lab Invest. 1957 May-Jun;6(3):241-50
references: 13429844
references: Clin Pharmacokinet. 2004;43(9):595-612
references: 15217303
references: Antimicrob Agents Chemother. 2009 May;53(5):1937-43
references: 19273671
references: AIDS. 2007 Sep 12;21(14):1899-907
references: 17721097
references: Sci Transl Med. 2011 Dec 7;3(112):112re4
references: 22158861
references: Antimicrob Agents Chemother. 2001 Oct;45(10):2733-9
references: 11557462
references: J Acquir Immune Defic Syndr. 2005 Aug 1;39(4):406-11
references: 16010161
references: Antimicrob Agents Chemother. 2011 Jun;55(6):2976-8
references: 21402849
references: Clin Diagn Lab Immunol. 1997 Sep;4(5):624-6
references: 9302218
references: Biol Reprod. 2011 Jul;85(1):97-104
references: 21471299
references: Acta Cytol. 1961 Jan-Feb;5:17-29
references: 13740082
references: Clin Diagn Lab Immunol. 1995 Jan;2(1):57-61
references: 7719914
references: AIDS. 2002 Nov 8;16(16):2159-63
references: 12409737
references: Lancet. 2011 Jul 16;378(9787):279-81
references: 21763939
references: Antimicrob Agents Chemother. 2012 Jan;56(1):103-9
references: 21986823
references: N Engl J Med. 2012 Aug 2;367(5):423-34
references: 22784038
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Nov 7;843(2):147-56
references: 16828350
references: J Biol Chem. 1994 Apr 29;269(17):12633-8
references: 8175673
references: N Engl J Med. 2012 Aug 2;367(5):411-22
references: 22784040
references: N Engl J Med. 2010 Dec 30;363(27):2587-99
references: 21091279
references: PLoS One. 2011 Jan 25;6(1):e16475
references: 21283552
references: Pharmacotherapy. 2003 Jun;23(6):695-701
references: 12820810
references: J Clin Microbiol. 2011 Feb;49(2):735-6
references: 21106793
references: J Antimicrob Chemother. 2011 Feb;66(2):240-50
references: 21118913
references: PLoS One. 2011;6(10):e25974
references: 22039430
references: Antimicrob Agents Chemother. 1998 Mar;42(3):612-7
references: 9517941
references: N Engl J Med. 2012 Aug 2;367(5):399-410
references: 22784037
references: J Infect Dis. 2012 Oct 1;206(7):993-1001
references: 22829639
references: AIDS Behav. 2013 Feb;17(2):737-47
references: 23065145
references: Science. 2010 Sep 3;329(5996):1168-74
references: 20643915