Pre-clinical development of a combination microbicide vaginal ring containing dapivirine and darunavir

Abstract

Objectives: 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 IC 50 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 104 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 IC 50 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.

Microbicide vaginal rings: Technological challenges and clinical development

“…Other examples include the EVA rings containing either MIV-150 [77] or MIV-160 developed by the Population Council [78], both of which exhibit partition-controlled release into an acetate buffer with surfactant system and the hot melt extruded polyether urethane ring containing UC781 [79]. Combination matrix-type rings containing more than one microbicide have also been investigated [80,81].…”

Precise engineering of dapivirine-loaded nanoparticles for the development of anti-HIV vaginal microbicides

“…46 1. Introduction 51 Recent years have seen an increasing interest in vaginal micro- 52 bicides as a potential prevention modality for sexual HIV transmis- 53 sion. This strategy, also commonly referred to as topical pre- 54 exposure prophylaxis (PrEP), comprises the use of vaginal products 55 containing anti-HIV compounds prior to or around the time of sex- 56 ual intercourse in order to avoid early transmission events at the 57 mucosal level [1].…”

Physiologically‐based pharmacokinetic model of vaginally administered dapivirine ring and film formulations

“…The simulated plasma concentration gradually increases to a C max of 0.0012 mg l –1 approximately 10 h after film insertion before steadily declining. The plasma concentration remains below the HIV EC99 and above the HIV IC50 (mean IC50 range of 0.09–0.14 ng ml –1 ) for approximately 200 h (panel B of Figure ). The simulated epithelium and stroma tissue concentrations accumulate very quickly, reaching C max approximately 1–3 h after film insertion respectively (panels C and D of Figure ).…”

“…After 28 days, animals were necropsied and the DPV concentration characterized in three samples of various tissues (vagina, cervix, uterus, rectum, female genital tract draining lymph nodes and distal lymph nodes). They found DPV was present in the vaginal tissue (1800 ng g -1 ), the cervix (94 ng g -1 ) and the rectum (40 ng g -1 ) but noted no detectable DPV in the uterus, axillary lymph nodes or iliac lymph nodes [49]. A study by Nuttall et al [57], determined drug concentration in the draining lymph nodes of rhesus macaques following once daily administration of [14C]DPV gel for 7 days.…”