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.