title: Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application.
abstract: OBJECTIVE
  This study measured and compared the pharmacokinetics of CMPD167, a small molecule antiretroviral CCR5 inhibitor with potential as an HIV microbicide, following vaginal, rectal and oral administration in rhesus macaques.
  
  
  METHODS
  A vaginal hydroxyethylcellulose (HEC) gel, a rectal HEC gel, a silicone elastomer matrix-type vaginal ring and an oral solution, each containing CMPD167, were prepared and administered to rhesus macaques pretreated with Depo-Provera. CMPD167 concentrations in vaginal fluid, vaginal tissue (ring only), rectal fluid and blood plasma were quantified by HPLC-mass spectrometry.
  
  
  RESULTS
  CMPD167 concentrations measured in rectal fluid, vaginal fluid and blood plasma were highly dependent on both the route of administration and the formulation type. Although rectal and vaginal fluid concentrations were highest when CMPD167 was administered locally (via either gel or ring), lower concentrations of the drug were also measured in these compartments following administration at the remote mucosal site or orally. CMPD167 levels in the vaginal and rectal fluid following oral administration were relatively low compared with local administration.
  
  
  CONCLUSIONS
  The study provides clear evidence for vaginal-rectal and rectal-vaginal drug transfer pathways and suggests that oral pre-exposure prophylaxis with CMPD167 may be less efficacious at preventing sexual transmission of HIV-1 than topically applied products.
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
authors.forename: R Karl
authors.initials: RK
authors.lastname: Malcolm
authors.forename: Deborah
authors.initials: D
authors.lastname: Lowry
authors.forename: Peter
authors.initials: P
authors.lastname: Boyd
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: P J
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D000282:Administration, Intravaginal; D000284:Administration, Oral; D000285:Administration, Rectal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001826:Body Fluids / Q000737:chemistry; D065100:CCR5 Receptor Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D008253:Macaca mulatta; D008297:Male; D013058:Mass Spectrometry; D011720:Pyrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015728:Receptors, HIV / Q000037:antagonists & inhibitors*; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; C480490:CMPD 167; D011720:Pyrazoles; D015728:Receptors, HIV; D014633:Valine
keywords: CMPD167; HIV microbicides; PrEP; pre-exposure prophylaxis; rectal gels; vaginal HEC gels; vaginal rings