Safety and Pharmacokinetics of Quick-Dissolving Polymeric Vaginal Films Delivering the Antiretroviral IQP-0528 for Preexposure Prophylaxis

Abstract

dFor human immunodeficiency virus (HIV) prevention, microbicides or drugs delivered as quick-dissolving films may be more acceptable to women than gels because of their compact size, minimal waste, lack of an applicator, and easier storage and transport. This has the potential to improve adherence to promising products for preexposure prophylaxis. Vaginal films containing IQP-0528, a nonnucleoside reverse transcriptase inhibitor, were evaluated for their pharmacokinetics in pigtailed macaques. Polymeric films (22 by 44 by 0.1 mm; providing 75% of a human dose) containing IQP-0528 (1.5%, wt/wt) with and without poly(lactic-co-glycolic acid) (PLGA) nanoparticle encapsulation were inserted vaginally into pigtailed macaques in a crossover study design (n ‫؍‬ 6). With unencapsulated drug, the median ( In the absence of an effective vaccine, preexposure prophylaxis (PrEP) with antiretroviral (ARV) drugs is currently a very promising biomedical intervention to control the human immunodeficiency virus (HIV) epidemic (1, 2). PrEP involves the use of ARV by high-risk HIV-negative individuals to prevent HIV acquisition. Many ARVs that have traditionally been used for HIV treatment have advanced as PrEP agents due to their safety and potency profiles (1,(3)(4)(5). Of the available ARVs, tenofovir disoproxil fumarate (TDF), a nucleoside reverse transcriptase inhibitor (NRTI) used widely in HIV treatment, has been studied extensively in animals and humans as a PrEP agent (3, 5). The success with oral TDF and Truvada, TDF in combination with emtricitabine (FTC), in inhibiting HIV infection in nonhuman primates led to the clinical trials in humans with TDF and Truvada (1, 6-11). In stark contrast to the success of TDF and Truvada in clinical trials in men who have sex with men and heterosexual HIV-discordant couples, two large clinical trials in women with oral Truvada, VOICE and FEM-PrEP, have demonstrated no protection due to a lack of adherence (12, 13).Providing optimal dosage forms of potent HIV PrEP agents for women has the potential to improve product adherence (14,15). Topical dosage forms can be effective in reducing HIV infection, as demonstrated by the CAPRISA 004 vaginal 1% tenofovir (TFV) gel trial, where per-protocol use of the gel before and after sex with no more than 2 doses in 24 h (BAT-24) reduced HIV acquisition by 39% (2). As observed in the oral PrEP trials, greater efficacy was reported among the high adherers in CAPRISA 004 (54% versus 28% in the low adherers) (2). Subsequent trials with 1% TFV gel, such as FACTS 001, employing the BAT-24 regimen used in CAPRISA-004, and the VOICE trial, with a daily application of 1% TFV gel, were not effective in protecting women against HIV acquisition (12, 16). It was estimated based on the returned used applicators that only 13% of the FACTS 001 trial participants were able to use the gel in Ն80% of sex acts per month (16). Neither the noncoital daily application of the TFV gel with VOICE nor the pericoital vaginal dosing regimen with FACTS 001 demonstrated effecti...

Vaginal Formulations for Prevention of Sexual Transmission of HIV

“…Both formulations released a higher amount than required to exceed IC50 and showed no toxicity or alterations in vaginal microbiota. The drug release profile from nanoparticle-based films was some orders of magnitude greater than for films containing the free drug [42].…”

“…Films are thin, soft, flexible sheets obtained by the solvent-casting method (Figure 3) orless frequently-by hot-melt extrusion. Films are typically designed to disintegrate within a few minutes on contact with vaginal fluids, so the drugs are released promptly [41,42]. Vaginal films are well accepted by women as they are discreet and easy to use and carry around due to their low weight and size, and suitable for the design of new microbicides [39].…”

“…However, films also have some disadvantages that must be taken into account when developing these systems. Due to their small size and weight they can incorporate only a small amount of drug, generally less than 50% of the total weight of the formulation [42]. The limited volume of vaginal fluid may condition the disintegration process and hence the release of the drug.…”

“…Plasticizers such as glycerol or polyethylene glycols are also included to give the film flexibility and facilitate handling and administration [44]. Other components are frequently included in addition to matrix-forming polymers and plasticizers; for example preservatives or disintegrants [42]. Work is currently underway to obtain controlled release and long-term efficacy and stability [45].…”

Nanotechnologies for early diagnosis, in situ disease monitoring, and prevention

“…A few studies detailing on NPs in films as potential microbicide products have been described (Table 1.2.2). [128][129][130][131] For example, our group demonstrated the versatility and potential usefulness of NPs-in-film systems for delivering a combination of hydrophobic (efavirenz) and hydrophilic (tenofovir) antiretroviral drugs. 131 Efavirenz-loaded PLGA NPs and tenofovir were incorporated into the polymer matrix during manufacturing by solvent casting.…”