OA06.01
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Pharmacokinetics, safety, and vaginal bleeding associated with continuous versus cyclic 90-day use of dapivirine and levonorgestrel vaginal rings for multipurpose prevention of HIV and pregnancy

Title
Pharmacokinetics, safety, and vaginal bleeding associated with continuous versus cyclic 90-day use of dapivirine and levonorgestrel vaginal rings for multipurpose prevention of HIV and pregnancy
Presenter
Sharon Achilles
Authors
S. Achilles * (1), C.W. Kelly (2), D.L. Blithe (3), J. Long (3), B.A. Richardson (2), B. Devlin (4), C.W. Hendrix (5), S.M. Poloyac (6), M.A. Marzinke (5), D. Singh (7), J.M. Piper (8), J. Steytler (4), B.A. Chen (9)
Institutions
(1) University of Pittsburgh, Department of Obstetrics, Gynecology and Reproductive Sciences/School of Medicine, Pittsburgh, United States, (2) Statistical Center for HIV/AIDS Research & Prevention/Fred Hutchinson Cancer Research Center, Seattle, United States, (3) NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Heath Research, Contraceptive Development Program, Bethesda, United States, (4) International Partnership for Microbicides, Silver Spring, United States, (5) Johns Hopkins University, Department of Medicine, Division of Clinical Pharmacology, Baltimore, United States, (6) University of Pittsburgh, Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, United States, (7) Magee-Womens Research Institute, Pittsburgh, United States, (8) NIH/National Institute of Allergy and Infectious Diseases, Division of AIDS, Bethesda, United States, (9) University of Pittsburgh, Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, Pittsburgh, United States

BACKGROUND: We compared pharmacokinetics, safety, and vaginal bleeding associated with continuous versus cyclic use of a 90-day multipurpose prevention technology (MPT) vaginal ring for sustained delivery of dapivirine (DPV) for HIV pre-exposure prophylaxis and levonorgestrel (LNG) for contraception.
METHODS: In this Phase-1 trial, healthy HIV-uninfected women were randomized (1:1) to continuous or cyclic (28-days in/2-days out) use pattern of an MPT ring containing 200mg DPV/320mg LNG over 90-days. We quantified plasma DPV and LNG via liquid chromatography-mass spectrometry. We assessed vaginal bleeding and adverse events (AE) by daily text messaging.
RESULTS: Twenty-five evaluable participants had median age 36.0 years (range 21-43) and BMI 27 (range 20-39), and 20 (80%) self-identified as white. There were 84 AEs: 59 Grade-1, 24 Grade-2, and one Grade-4 (anemia related to cyclic product use). The number of women with =Grade-2 genitourinary AEs did not differ by continuous (3/12, 25%) or cyclic (5/13, 38%) use. With continuous use, median Cmax for DPV and LNG were 750pg/mL (IQR 475-1401) and 1675pg/mL (IQR 645-2575), respectively (Figure 1). Two days after ring removal (cyclic group), plasma DPV remained =concentration associated with previously demonstrated efficacy. Number of days with no bleeding, spotting/light, moderate, and heavy bleeding did not differ by use pattern (Table 1).

mtn044 r4p abstract fig1.jpg

Table 1: Days of bleeding

Continuous (n=12)Cyclic (n=13)
Total days967 days on study1156 days on study
No bleeding557 (58%)671 (58%)
Spotting/light bleeding303 (31%)353 (31%)
Moderate bleeding101 (10%)112 (10%)
Heavy bleeding6 (1%)20 (2%)

CONCLUSIONS: Serum DPV and LNG concentrations previously associated with efficacy for HIV and pregnancy prevention respectively are achieved or exceeded with cyclic and continuous use of this MPT ring without toxicity. Vaginal bleeding profiles did not differ.