Pharmacokinetics and Preliminary Safety of Pod-Intravaginal Rings Delivering the Monoclonal Antibody VRC01-N for HIV Prophylaxis in a Macaque Model

Abstract

The broadly neutralizing antibody (bNAb) VRC01, capable of neutralizing 91% of known human immunodeficiency virus type 1 (HIV-1) isolates in vitro, is a promising candidate microbicide for preventing sexual HIV infection when administered topically to the vagina; however, accessibility to antibody-based prophylactic treatment by target populations in sub-Saharan Africa and other underdeveloped regions may be limited by the high cost of conventionally produced antibodies and the limited capacity to manufacture such antibodies. Intravaginal rings of the pod design (pod-IVRs) delivering Nicotiana-manufactured VRC01 (VRC01-N) over a range of release rates have been developed. The pharmacokinetics and preliminary safety of VRC01-N pod-IVRs were evaluated in a rhesus macaque model. The devices sustained VRC01-N release for up to 21 days at controlled rates, with mean steady-state VRC01-N levels in vaginal fluids in the range of 10 2 to 10 3 g g Ϫ1 being correlated with in vitro release rates. No adverse safety indications were observed. These findings indicate that pod-IVRs are promising devices for the delivery of the candidate topical microbicide VRC01-N against HIV-1 infection and merit further preclinical evaluation.

In vitro release testing methods for drug-releasing vaginal rings

“…Interest in vaginal ring technology for drug delivery applications has piqued in recent years, driven primarily by a surge of innovation around the use of new ring designs and new polymeric materials for fabrication of rings. In fact, much of this innovation has stemmed directly from efforts to develop antiretroviral-releasing rings for prevention of HIV infection and multi-purpose prevention technologies the combine HIV prevention with contraception and prevention of other sexually transmitted infections [1][2][3]10,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. In particular, great advances have been made in extending ring technology beyond conventional low molecular weight and relatively hydrophobic drugs to the formulation and release of hydrophilic drugs, biomolecular drugs and drug combinations.…”

Stabilization and Sustained Release of HIV Inhibitors by Encapsulation in Silk Fibroin Disks

“…These amounts are satisfactory as initial proof of concept from a pharmacological perspective. Recent reports describe intravaginal rings that are manufactured with much higher quantities of small molecule and antibody inhibitors, showing release in the mg range [61][62][63] . We are also pursuing larger amounts of protein in the context of larger disks, films, and inserts.…”

Efficacy of silk fibroin biomaterial vehicle for in vivo mucosal delivery of Griffithsin and protection against HIV and SHIV infection ex vivo

“…The use of insertable gels containing ARVs in clinical trials led to moderate success in the CAPRISA 004 study [7], and disappointing outcomes in the VOICE [6] and FACTS 001 trials, largely due to inconsistent adherence, especially among young women [6,7,9,10,60]. More recently, vaginal rings or infusions are being studied for the delivery of multiple anti-viral drugs, bNAbs or the viral entry inhibitor, 5P12-RANTES [61][62][63][64][65][66][67][68]. However, infusions will require the engagement of medical assistance and may not be easily accessible to women in different settings and geographic locations.…”