Safety and Pharmacokinetics of Intravaginal Rings Delivering Tenofovir in Pig-Tailed Macaques

Abstract

Antiretroviral-based microbicides applied topically to the vagina may play an important role in protecting women from HIV infection. Incorporation of the nucleoside reverse transcriptase inhibitor tenofovir (TFV) into intravaginal rings (IVRs) for sustained mucosal delivery may lead to increased microbicide product adherence and efficacy compared with those of conventional vaginal formulations. Formulations of a novel "pod IVR" platform spanning a range of IVR drug loadings and daily release rates of TFV were evaluated in a pig-tailed macaque model. The rings were safe and exhibited sustained release at controlled rates over 28 days. Vaginal secretion TFV levels were independent of IVR drug loading and were able to be varied over 1.5 log units by changing the ring configuration. Mean TFV levels in vaginal secretions were 72.4 ؎ 109 g ml ؊1 (slow releasing) and 1.84 ؎ 1.97 mg ml ؊1 (fast releasing). The mean TFV vaginal tissue concentration from the slow-releasing IVRs was 76.4 ؎ 54.8 g g ؊1 and remained at steady state 7 days after IVR removal, consistent with the long intracellular half-life of TFV. Intracellular tenofovir diphosphate (TFV-DP), the active moiety in defining efficacy, was measured in vaginal lymphocytes collected in the study using the fast-releasing IVR formulation. Mean intracellular TFV-DP levels of 446 ؎ 150 fmol/10 6 cells fall within a range that may be protective of simian-human immunodeficiency virus strain SF162p3 (SHIV SF162p3 ) infection in nonhuman primates. These data suggest that TFV-releasing IVRs based on the pod design have potential for the prevention of transmission of human immunodeficiency virus type 1 (HIV-1) and merit further clinical investigation.

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).…”

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

“…The study timeline and biological sample collection points are shown in Fig. 2 and employed published protocols (15,24). Briefly, six sexually mature female pig-tailed macaques (Macaca nemestrina) were used; three received TDF-FTC IVRs (Table 1), and three received TDF-FTC-MVC IVRs.…”

“…Macaquesized (21) polydimethylsiloxane (PDMS) (silicone) pod-IVRs were prepared in a multistep process that has been described in detail elsewhere (13,15). Six pods per combination IVR were used in two different formulations, i.e., one containing three pods each of TDF and FTC and another containing two pods each of TDF, FTC, and MVC (Table 1 and Fig.…”

“…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.…”

“…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)(15)(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).…”