title: Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques.
abstract: OBJECTIVE
  To investigate the pharmacokinetics (PK) of maraviroc, a CCR5-targeted HIV-1 entry inhibitor, in rhesus macaques following vaginal administration of various maraviroc-loaded aqueous hydroxyethylcellulose (HEC) gels, and to correlate the PK data with efficacy in a single high-dose vaginal SHIV-162P3 challenge model.
  
  
  METHODS
  Maraviroc concentrations in vaginal fluid (Weck-Cel(®) sponge), vaginal tissue (punch biopsy) and plasma were assessed over 72 h following single-dose vaginal application of various maraviroc-loaded HEC gels. The range of maraviroc gel concentrations was sufficiently broad (0.003%-3.3% w/w) that test gels included both fully solubilized and predominantly dispersed formulations. The efficacy of the HEC gels against a single high-dose vaginal SHIV-162P3 challenge was also measured, and correlated with the PK concentrations.
  
  
  RESULTS
  Maraviroc concentrations in vaginal fluid (range 10(4)-10(7) ng/mL), vaginal tissue (100-1200 ng/g) and plasma (<10(2) ng/mL) were highly dependent on maraviroc gel loading, irrespective of the form of the maraviroc component within the gel (solubilized versus dispersed). Fluid and plasma concentrations were generally highest 0.5 or 2 h after gel application, before declining steadily through to 72 h. Maraviroc concentrations in the various biological compartments correlated strongly with the extent of protection against vaginal SHIV-162P3 challenge. Complete protection was achieved with a 3.3% w/w maraviroc gel.
  
  
  CONCLUSIONS
  A high degree of correlation between PK and efficacy was observed. Based on the data obtained with the 3.3% w/w maraviroc gel, maintenance of vaginal fluid and tissue levels in the order of 10(7) ng/mL and 10(3) ng/g, respectively, are required for complete protection with this compound.
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK. k.malcolm@qub.ac.uk
authors.forename: R Karl
authors.initials: RK
authors.lastname: Malcolm
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Forbes
authors.forename: Leslie
authors.initials: L
authors.lastname: Geer
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Veazey
authors.forename: Laurie
authors.initials: L
authors.lastname: Goldman
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D001826:Body Fluids / Q000737:chemistry; D003510:Cyclohexanes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D000077592:Maraviroc; D010949:Plasma / Q000737:chemistry; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014621:Vagina / Q000737:chemistry; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage*
chemical_list: D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D014230:Triazoles; D014622:Vaginal Creams, Foams, and Jellies; D000077592:Maraviroc