title: Single and multiple dose pharmacokinetics of dolutegravir in the genital tract of HIV-negative women.
abstract: BACKGROUND
  Antiretrovirals that achieve adequate concentrations in anatomical sites of transmission are of interest for HIV prevention. A Phase I open-label pharmacokinetic (PK) study was performed to describe first dose (PK1) and steady-state (PK2) PKs of the integrase inhibitor dolutegravir (DTG) in blood plasma (BP), cervicovaginal fluid (CVF), cervical tissue (CT) and vaginal tissue (VT) in HIV type-1-negative women.
  
  
  METHODS
  A total of 8 healthy females given DTG 50 mg daily for 5-7 days had 11 paired BP and CVF samples collected over 24 h following the first dose (PK1) and multiple dosing (PK2). Each woman underwent CT and VT biopsies at 1/4 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analysed by validated liquid chromatography-tandem mass spectrometry methods. Non-compartmental PK analysis was performed and Spearman rank correlations determined between matrices.
  
  
  RESULTS
  BP areas under the concentration-time curve (AUCs) were similar to previous reports and concentrations remained greater than the protein-adjusted (PA) 90% inhibitory concentration (IC90) for wild-type HIV (64 ng/ml). CVF exposures were approximately 6% of BP with low inter-individual variability. CT and VT exposures were 7% of BP at PK1, and 9-10% of BP at PK2 with 94% of samples >PA-IC90. CT and VT concentrations were correlated to each other (ρ=0.70, P=0.003), and to CVF at steady state (ρ=0.52, P=0.04). Accumulation of DTG from PK1 to PK2 occurred in BP, CT and VT, but only marginally in CVF.
  
  
  CONCLUSIONS
  DTG BP PK were consistent with previously published values. CVF, CT and VT exposures were highly correlated. At PK2, DTG accumulated to a greater extent in tissue than in BP or CVF, suggesting increased tissue affinity.
authors.affiliation: University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Adams
authors.forename: Kristine B
authors.initials: KB
authors.lastname: Patterson
authors.forename: Heather M A
authors.initials: HM
authors.lastname: Prince
authors.forename: Craig
authors.initials: C
authors.lastname: Sykes
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Greener
authors.forename: Julie B
authors.initials: JB
authors.lastname: Dumond
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002584:Cervix Uteri / Q000187:drug effects*; D005260:Female; D015658:HIV Infections / Q000517:prevention & control; D019428:HIV Integrase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics*; D006801:Humans; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D014621:Vagina / Q000187:drug effects*; D055815:Young Adult; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir
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