Phase 1 Pharmacokinetic Trial of 2 Intravaginal Rings Containing Different Dose Strengths of Vicriviroc (MK-4176) and MK-2048

Abstract

Background: Vaginal rings (VRs) are a promising approach for sustained delivery of antiretroviral (ARV) medication to prevent human immunodeficiency virus (HIV) infection in women. Combination ARV VRs could increase efficacy.

Methods: MTN-028, a phase 1 trial in 19 HIV-uninfected women, evaluated 2 VRs containing vicriviroc (VCV) and MK-2048. Participants were randomized 2:1 to a low-dose (VCV, 91 mg; MK-2048, 10 mg) or original-dose (VCV, 182 mg; MK-2048, 30 mg) ring used for 28 days. Safety was assessed by documenting adverse events (AEs). Drug concentrations were evaluated in plasma, cervicovaginal fluid (CVF), and cervical tissue samples.

Results: 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.

Conclusions: In this first study evaluating 2 doses of a combination VCV/MK-2048 VR, both rings were found to be safe and well tolerated. VCV and MK-2048 were detectable in plasma, CVF, and cervical tissue samples, and drug release and plasma drug exposure were higher for the original-dose than for the low-dose ring.

Trial registration: ClinicalTrials.gov NCT02419456.

Keywords: MK-2048; microbicide; pharmacokinetic; vaginal rings; vicriviroc.

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Study visit schedule. Abbreviations: ENR, enrollment; SCR, screening; V, visit.

Figure 2.

Flowchart of participants in the low-dose and original-dose vaginal ring (VR) groups. The participant with early termination was replaced after being on a product hold, by investigator decision; data before withdrawal were included in safety but not pharmacokinetic (PK) analyses.

Figure 3.

Geometric mean vicriviroc (VCV) and MK-2048 plasma and cervicovaginal fluid (CVF) concentrations over time. A, Plasma VCV concentrations. B, CVF VCV concentrations. C, Plasma MK-2048 concentrations. D, CVF MK-2048 concentrations.