title: Pre-clinical development of a combination microbicide vaginal ring containing dapivirine and darunavir.
abstract: OBJECTIVE
  Combination microbicide vaginal rings may be more effective than single microbicide rings at reducing/preventing sexual transmission of HIV. Here, we report the pre-clinical development and macaque pharmacokinetics of matrix-type silicone elastomer vaginal rings containing dapivirine and darunavir.
  
  
  METHODS
  Macaque rings containing 25 mg dapivirine, 100 mg dapivirine, 300 mg darunavir or 100 mg dapivirine+300 mg darunavir were manufactured and characterized by differential scanning calorimetry. In vitro release was assessed into isopropanol/water and simulated vaginal fluid. Macaque vaginal fluid and blood serum concentrations for both antiretrovirals were measured during 28 day ring use. Tissue levels were measured on day 28. Ex vivo challenge studies were performed on vaginal fluid samples and IC50 values were calculated.
  
  
  RESULTS
  Darunavir caused a concentration-dependent reduction in the dapivirine melting temperature in both solid drug mixes and in the combination ring. In vitro release from rings was dependent on drug loading, the number of drugs present and the release medium. In macaques, serum concentrations of both microbicides were maintained between 10(1) and 10(2) pg/mL. Vaginal fluid levels ranged between 10(3) and 10(4) ng/g and between 10(4) and 10(5) ng/g for dapivirine and darunavir, respectively. Both dapivirine and darunavir showed very similar concentrations in each tissue type; the range of drug tissue concentrations followed the general rank order: vagina (1.8 × 10(3)-3.8 × 10(3) ng/g)  > cervix (9.4 × 10(1)-3.9 × 10(2) ng/g)  > uterus (0-108 ng/g)  > rectum (0-40 ng/g). Measured IC50 values were >2 ng/mL for both compounds.
  
  
  CONCLUSIONS
  Based on these results, and in light of recent clinical progress of the 25 mg dapivirine ring, a combination vaginal ring containing dapivirine and darunavir is a viable second-generation HIV microbicide candidate.
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
authors.forename: Diarmaid J
authors.initials: DJ
authors.lastname: Murphy
authors.affiliation: CEA, Division of Immuno-Virology, DSV/iMETI, IDMIT Center, 18 route du Panorama, F92265 Fontenay-aux-Roses, France UMR-E1, Paris Sud University-11, Orsay, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Desjardins
authors.affiliation: CEA, Division of Immuno-Virology, DSV/iMETI, IDMIT Center, 18 route du Panorama, F92265 Fontenay-aux-Roses, France UMR-E1, Paris Sud University-11, Orsay, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dereuddre-Bosquet
authors.affiliation: CEA, Division of Immuno-Virology, DSV/iMETI, IDMIT Center, 18 route du Panorama, F92265 Fontenay-aux-Roses, France UMR-E1, Paris Sud University-11, Orsay, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Brochard
authors.affiliation: CEA, Division of Immuno-Virology, DSV/iMETI, IDMIT Center, 18 route du Panorama, F92265 Fontenay-aux-Roses, France UMR-E1, Paris Sud University-11, Orsay, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Perrot
authors.affiliation: Commissariat à l'Energie Atomique, iBiTecS, SPI, Laboratoire d'Etude du Métabolisme des Médicaments, F-91191 Gif-sur-Yvette, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Pruvost
authors.affiliation: CEA, Division of Immuno-Virology, DSV/iMETI, IDMIT Center, 18 route du Panorama, F92265 Fontenay-aux-Roses, France UMR-E1, Paris Sud University-11, Orsay, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Le Grand
authors.affiliation: Janssen Diagnostics, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Ole
authors.initials: O
authors.lastname: Lagatie
authors.affiliation: Janssen Diagnostics, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Vanhooren
authors.affiliation: Janssen Diagnostics, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Maxim
authors.initials: M
authors.lastname: Feyaerts
authors.affiliation: Janssen Diagnostics, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Jens
authors.initials: J
authors.lastname: van Roey
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
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001826:Body Fluids / Q000737:chemistry; D002584:Cervix Uteri / Q000737:chemistry; D003274:Contraceptive Devices, Female; D000069454:Darunavir; D004195:Disease Models, Animal; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D020128:Inhibitory Concentration 50; D008251:Macaca; D065129:Pre-Exposure Prophylaxis / Q000379:methods*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012007:Rectum / Q000737:chemistry; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014599:Uterus / Q000737:chemistry; D014621:Vagina / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D011743:Pyrimidines; D013449:Sulfonamides; C481671:Dapivirine; D000069454:Darunavir
keywords: HIV microbicides; cynomolgus macaques; pharmacokinetics; silicone elastomer vaginal rings