PMID- 30289444
OWN - NLM
STAT- MEDLINE
DCOM- 20200506
LR  - 20200506
IS  - 1537-6591 (Electronic)
IS  - 1058-4838 (Print)
IS  - 1058-4838 (Linking)
VI  - 68
IP  - 7
DP  - 2019 Mar 19
TI  - Phase 1 Pharmacokinetic Trial of 2 Intravaginal Rings Containing Different Dose 
      Strengths of Vicriviroc (MK-4176) and MK-2048.
PG  - 1129-1135
LID - 10.1093/cid/ciy652 [doi]
AB  - 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.
CI  - (c) 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.
FAU - Liu, Albert Y
AU  - Liu AY
AD  - Bridge HIV, San Francisco Department of Public Health, California.
FAU - Zhang, Jingyang
AU  - Zhang J
AD  - Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer 
      Research Center, Seattle, Washington.
FAU - Anderson, Peter L
AU  - Anderson PL
AD  - Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado 
      Anschutz Medical Campus, Aurora.
FAU - Wagner, Theresa
AU  - Wagner T
AD  - Bridge HIV, San Francisco Department of Public Health, California.
FAU - Pan, Zhenyu
AU  - Pan Z
AD  - Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer 
      Research Center, Seattle, Washington.
FAU - Peda, Melissa
AU  - Peda M
AD  - Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer 
      Research Center, Seattle, Washington.
FAU - Gomez, Kailazarid
AU  - Gomez K
AD  - FHI 360, Durham, North Carolina.
FAU - Beamer, May
AU  - Beamer M
AD  - Magee-Womens Research Institute, Pittsburgh, Pennsylvania.
FAU - Jacobson, Cindy
AU  - Jacobson C
AD  - Magee-Womens Research Institute, Pittsburgh, Pennsylvania.
FAU - Strizki, Julie
AU  - Strizki J
AD  - Merck & Co, Kenilworth, New Jersey.
FAU - Dezzutti, Charlene S
AU  - Dezzutti CS
AD  - Magee-Womens Research Institute, Pittsburgh, Pennsylvania.
AD  - School of Medicine, University of Pittsburgh, Pennsylvania.
FAU - Piper, Jeanna M
AU  - Piper JM
AD  - National Institutes of Health, Division of AIDS, Bethesda, Maryland.
CN  - MTN-028 Protocol Team for the Microbicide Trials Network
LA  - eng
SI  - ClinicalTrials.gov/NCT02419456
GR  - UM1 AI068615/AI/NIAID NIH HHS/United States
GR  - UM1 AI068633/AI/NIAID NIH HHS/United States
GR  - UM1 AI069496/AI/NIAID NIH HHS/United States
GR  - UM1 AI106707/AI/NIAID NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Clin Infect Dis
JT  - Clinical infectious diseases : an official publication of the Infectious Diseases 
      Society of America
JID - 9203213
RN  - 0 (Anti-Retroviral Agents)
RN  - 0 (Piperazines)
RN  - 0 (Pyrimidines)
RN  - TL515DW4QS (vicriviroc)
SB  - IM
CIN - doi: 10.1093/cid/ciy653
CIN - doi: 10.1093/cid/ciy654
MH  - Adolescent
MH  - Adult
MH  - Anti-Retroviral Agents/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Body Fluids/chemistry
MH  - *Contraceptive Devices, Female
MH  - Drug-Related Side Effects and Adverse Reactions/epidemiology
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Middle Aged
MH  - Piperazines/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Pyrimidines/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Single-Blind Method
MH  - Young Adult
PMC - PMC6424086
OTO - NOTNLM
OT  - MK-2048
OT  - microbicide
OT  - pharmacokinetic
OT  - vaginal rings
OT  - vicriviroc
EDAT- 2018/10/06 06:00
MHDA- 2020/05/07 06:00
PMCR- 2019/10/04
CRDT- 2018/10/06 06:00
PHST- 2018/03/16 00:00 [received]
PHST- 2018/09/18 00:00 [accepted]
PHST- 2018/10/06 06:00 [pubmed]
PHST- 2020/05/07 06:00 [medline]
PHST- 2018/10/06 06:00 [entrez]
PHST- 2019/10/04 00:00 [pmc-release]
AID - 5115666 [pii]
AID - ciy652 [pii]
AID - 10.1093/cid/ciy652 [doi]
PST - ppublish
SO  - Clin Infect Dis. 2019 Mar 19;68(7):1129-1135. doi: 10.1093/cid/ciy652.