Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model

Abstract

Preexposure prophylaxis (PrEP) using FDA-approved antiretroviral (ARV) drugs is emerging as a promising strategy for the prevention of sexual HIV infection. There is growing consensus that a combination of ARV agents, analogous to highly active antiretroviral therapy (HAART), likely is essential for optimally effective PrEP (1, 2). Oral administration of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) (Truvada; Gilead Sciences, Inc.) is the first regimen approved by the FDA to reduce the risk of HIV infection in uninfected individuals (http://www.fda.gov/NewsEvents/Newsroom /PressAnnouncements/ucm312210.htm). Three recent clinical trials demonstrated that oral ARV regimens using the combination of TDF and FTC can be effective in susceptible men, women, and partners of HIV-infected individuals (3-5). However, the relative risk reduction in these trials varied widely (from 44 to 75%), and a study in which women used a daily oral TDF-FTC regimen was stopped early due to futility. A critical factor driving success in these trials appears to involve sustaining high levels of adherence to frequent dosing (6).It is well established across different delivery methods that adherence to therapy is inversely related to the dosing period (7-10). Controlled topical delivery of ARV drugs using intravaginal rings (IVRs) is thought to improve adherence (11) and to provide sustained mucosal levels independent of coitus and daily dosing (12). The delivery of two or more ARV drugs from conventional IVR designs involves significant technological and manufacturing hurdles. To meet these challenges, we have developed a novel IVR technology, the pod-IVR (13), that enables rapid development of devices capable of delivering multiple agents over a wide range of target delivery rates and aqueous solubilities (14-16). We recently published the design and 28-day pharmacokinetic (PK) evaluation in sheep of a five-drug pod-IVR as a proof-of-concept, advanced multipurpose prevention technology (MPT), combining three ARV drugs from different mechanistic classes (tenofovir [TFV], nevirapine, and saquinavir) with a proven estrogen-progestogen contraceptive for prevention of HIV infection and unintended pregnancy (17).Here we present the first report of an IVR delivering TDF and FTC, as well as the first report of a triple-combination IVR delivering TDF, FTC, and maraviroc (MVC) (an entry inhibitor/antagonist of chemokine receptor 5 [CCR5]). Preliminary local safety and pharmacokinetic (PK) findings for these devices were determined in pig-tailed macaques, which are considered by many to represent the most relevant animal model for HIV vaginal PrEP studies (15,18,19). Steady-state drug levels for all three ARV agents in vaginal fluids were sustained over the 28-day study period, with corresponding vaginal tissue concentrations suggesting putative efficacy in preventing HIV infection.

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

“…Proinflammatory cytokine levels in the CVL fluid samples as a function of time during PK1 and PK2 did not show statistically significant changes as a result of IVR use except for IL-18 levels in the PK1 low-releasing group, which decreased from those at the baseline upon ring insertion. These results indicate that neither the pod-IVR nor the VRC01-N itself leads to an increased inflammatory response, as has been observed previously for pod-IVRs delivering antiretrovirals (ARVs) in pig-tailed macaques (48,55).…”

“…Because each pod is a separate delivery device, pod-IVRs can deliver multiple MAbs simultaneously with the independent control of release rates. Pod-IVRs for macaques (48,49) are significantly smaller than those for humans (44,45) and limit the total drug loading and capacity to deliver multiple MAbs at efficacious rates. The macaque pod-IVRs used here accommodate a maximum of six 25-mg pods, providing a maximum MAb loading of 75 mg from a formulation that contains 50% MAb.…”

“…The release rate from pod-IVRs is determined by the additive effect of the MAb solubility and three independently variable parameters: the composition and thickness of the pod's polymer membrane coating, the size and number of delivery channels through the ring exposing each individual pod to the vaginal fluid, and the number of pods in the ring. The pod-IVR design has been used for the delivery of relatively hydrophilic small-molecule antiretroviral drugs singly and in combination (43,44,48) and of ovine IgG as a model for human MAb (45). Formulation and in vitro release of VRC01-N.…”

Fórum PrEP: um debate on-line sobre uso da profilaxia pré-exposição no Brasil

“…Entre as atuais estratégias de prevenção biomédica contra a infecção pelo HIV, a profilaxia pré-exposição (PrEP), vem se destacando pela eficácia apresentada nos ensaios clínicos desenvolvidos, com redução no risco de infecção que varia de 92% 1 a 100% 2 , a depender da adesão à terapêutica 3 . Seu uso é particularmente recomendado para populações-chave vulneráveis a infecção, dentre os quais se destacam homens que fazem sexo com homens (HSH) 1 .…”

“…Embora atualmente somente essa combinação esteja aprovada para uso, estudos sobre a PrEP utilizando outros medicamentos e vias de administração vêm sendo desenvolvidos 3 .…”