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.

• Authors: Albert Y Liu, Jingyang Zhang, Peter L Anderson, Theresa Wagner, Zhenyu Pan, Melissa Peda, Kailazarid Gomez, May Beamer, Cindy Jacobson, Julie Strizki, Charlene S Dezzutti, Jeanna M Piper, MTN-028 Protocol Team for the Microbicide Trials Network
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 68 Issue 7 Pg. 1129-1135 (03 19 2019) ISSN: 1537-6591 [Electronic] United States
• PMID: 30289444 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)
• Copyright: © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

Chemical References

• Anti-Retroviral Agents
• Piperazines
• Pyrimidines
• vicriviroc

Topics

• Adolescent
• Adult
• Anti-Retroviral Agents (administration & dosage, adverse effects, pharmacokinetics)
• Body Fluids (chemistry)
• Contraceptive Devices, Female
• Drug-Related Side Effects and Adverse Reactions (epidemiology)
• Female
• Healthy Volunteers
• Humans
• Middle Aged
• Piperazines (administration & dosage, adverse effects, pharmacokinetics)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• Single-Blind Method
• Young Adult