The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides

Abstract

dWhen 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. With an estimated 2.3 million new human immunodeficiency virus type 1 (HIV-1) infections in 2012 (1) and a total number of people living with HIV estimated at 35.3 million in the same year, the need for effective prevention strategies remains critical. Although barrier prevention strategies, such as male and female condoms, are effective, and behavioral programs teaching the benefits of monogamy and abstinence have shown some success (2-4), they have not significantly impacted the epidemic. One area of key concern is sub-Saharan Africa, where 57% of HIV-infected people are women (1). In order to provide prevention strategies to women in this high-risk population, locally (vaginally or rectally) applied products containing potent antiretroviral drugs are being developed by many different groups. These microbicides represent one of the most promising prophylactic strategies currently being developed in terms of being simple to self-administer, relatively easy to produce, and by virtue of the lower drug levels required compared to those with systemic approaches, the potential to be within reach of the health system and nongovernmental organization (NGO) budgets in the developing world. A key advantage to the topical microbicide approach is also that the same targeted active ingredient...

Microbicide vaginal rings: Technological challenges and clinical development

“…As a result, the current version of the DPV-releasing VR, a 28-day matrix-type device containing 25 mg micronised DPV (Ring-004), is fabricated using an addition-cure silicone elastomer that produces no cure by-product. Compared with core-type rings (Figure 2 [156]. DPV plasma and vaginal fluid levels were lower than those measured in previous ring clinical studies [56,76,85,157].…”

Engineering highly multivalent sperm-binding IgG antibodies for potent non-hormonal female contraception

“…Clinical PCT studies have proven to be highly predictive of contraceptive efficacy in contraceptive effectiveness clinical trials [38][39][40][41][42][43] . The sheep vagina is physiologically and anatomically very similar to the human vagina 44,45 , making it the gold standard for assessing vaginal products. We instilled PBS, IgG, FIF or FFIFF into the…”

Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES

“…Previously, we have reported the pharmacokinetics of 5P12-RANTES in sheep following vaginal administration of a 5P12-RANTES aqueous gel formulation and a 5P12-RANTES vaginal ring (McBride et al, 2019(McBride et al, , 2017. Also, Holt et al, have previously Ring-004) (Holt et al, 2015). The sheep model is particularly useful for pharmacokinetic testing of vaginal rings, since, unlike macaques, sheep can be fitted with the same size of ring used in women.…”

“…Several papers have previously reported pharmacokinetic data for the 25 mg matrix-type dapivirine ring (Ring-004), either in sheep or in women Holt et al, 2015;A. M. Nel et al, 2014).…”