- Assess local pharmacokinetics (PK) of vicriviroc (MK-4176) and MK-2048 during and after 28-days of continuous use of two MK-2048A IVRs containing different dose strengths
MTN-028 was a single-site, single-blind, two-arm, randomized Phase 1 safety and PK trial of two IVRs containing a combination of a CCR5-receptor antagonist, VCV (MK-4176), with an integrase inhibitor, MK-2048. The two rings tested in MTN-028 were formulated with different dose strengths. The study enrolled 18 evaluable healthy, 18-45-year-old HIV-uninfected, non-pregnant, sexually abstinent women who were using adequate contraception. Women were randomized to one of two study regimens in a 2:1 ratio (low dose: original dose). The IVR was used continuously for approximately 28 consecutive days. Two different formulations of the MK-2048A combination IVR were developed and evaluated in MTN-028 to inform in vitro and in vivo modeling to further optimize the drug release profiles of an IVR containing VCV and MK-2048 for use in future studies, including the potential development of a combination antiretroviral/contraceptive ring. MTN-027 and MTN-028 were the first clinical trials to test an integrase inhibitor as a microbicide.
MTN-028 completed follow-up on March 22, 2016. The primary manuscript, the only paper from this study, was published in Clinical Infectious Diseases in March 2019.
The two doses/formulations of a combination VCV/MK-2048 IVR were safe and well-tolerated. All AEs reported were grade 1 or 2, with no statistically significant differences in related genitourinary AEs or grade ≥2 AEs observed between arms (P = >.99). VCV/MK-2048 concentrations rose rapidly, with higher plasma area under the concentration-time curve (AUC) in the original-dose arm (geometric mean ratio, 3.29 for VCV and 1.49 for MK-2048) and similar AUCs across arms for CVF samples. Cervical tissue concentrations were higher in the original-dose arm (geometric mean ratio, 7.94 for VCV and 6.45 for MK-2048), with greater drug released based on residual drug levels. Plasma and CVF concentrations for both drugs fell rapidly after ring removal.
US Eunice Kennedy Shriver National Institute of Child Health and Human Development
US National Institute of Mental Health
US National Institutes of Health
Phase I, single-site, two-arm, randomized (2:1), single-blind trial