title: The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides.
abstract: When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring.
authors.affiliation: International Partnership for Microbicides, Silver Spring, Maryland, USA jholt@ipmglobal.org.
authors.forename: Jonathon D S
authors.initials: JD
authors.lastname: Holt
authors.affiliation: Huntingdon Life Sciences, Huntingdon Research Centre, Huntingdon, Cambridgeshire, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Cameron
authors.affiliation: Huntingdon Life Sciences, Huntingdon Research Centre, Huntingdon, Cambridgeshire, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dias
authors.affiliation: Huntingdon Life Sciences, Huntingdon Research Centre, Huntingdon, Cambridgeshire, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Holding
authors.affiliation: ABL B.V., Assen, The Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Muntendam
authors.affiliation: ABL B.V., Assen, The Netherlands.
authors.forename: Freddy
authors.initials: F
authors.lastname: Oostebring
authors.affiliation: ABL B.V., Assen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Dreier
authors.affiliation: University of Pittsburgh, Magee Women's Research Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rohan
authors.affiliation: International Partnership for Microbicides, Silver Spring, Maryland, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nuttall
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D003274:Contraceptive Devices, Female; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000009:adverse effects; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000517:prevention & control / Q000635:transmission; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D012756:Sheep; D000068698:Tenofovir / Q000493:pharmacokinetics; D014621:Vagina / Q000187:drug effects; D014622:Vaginal Creams, Foams, and Jellies / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D004337:Drug Carriers; D011743:Pyrimidines; D014622:Vaginal Creams, Foams, and Jellies; D000068698:Tenofovir; C481671:Dapivirine
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