Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women

Andrea Ries Thurman, Jill L. Schwartz, Vivian Brache, Meredith R. Clark, Timothy McCormick, Neelima Chandra, Mark A Marzinke, Frank Z. Stanczyk, Charlene S. Dezzutti, Sharon L. Hillier, Betsy C. Herold, Raina Fichorova, Susana N. Asin, Christiane Rollenhagen, Debra Weiner, Patrick Kiser, Gustavo F. Doncel

Research output: Contribution to journalArticle

Abstract

To prevent the global health burdens of human immunodeficiency virus [HIV] and unintended/mistimed pregnancies, we developed an intravaginal ring [IVR] that delivers tenofovir [TFV] at ~10mg/day alone or with levonorgestrel [LNG] at ~20μg/day for 90 days. We present safety, pharmacokinetics, pharmacodynamics, acceptability and drug release data in healthy women. CONRAD A13-128 was a randomized, placebo controlled phase I study. We screened 86 women; 51 were randomized to TFV, TFV/LNG or placebo IVR [2:2:1] and 50 completed all visits, using the IVR for approximately 15 days. We assessed safety by adverse events, colposcopy, vaginal microbiota, epithelial integrity, mucosal histology and immune cell numbers and phenotype, cervicovaginal [CV] cytokines and antimicrobial proteins and changes in systemic laboratory measurements, and LNG and TFV pharmacokinetics in multiple compartments. TFV pharmacodynamic activity was measured by evaluating CV fluid [CVF] and tissue for antiviral activity using in vitro models. LNG pharmacodynamic assessments were timed based on peak urinary luteinizing hormone levels. All IVRs were safe with no significant colposcopic, mucosal, immune and microbiota changes and were acceptable. Among TFV containing IVR users, median and mean CV aspirate TFV concentrations remained above 100,000 ng/mL 4 hours post IVR insertion and mean TFV-diphosphate [DP] concentrations in vaginal tissue remained above 1,000 fmol/mg even 3 days post IVR removal. CVF of women using TFV-containing IVRs completely inhibited [94–100%] HIV infection in vitro. TFV/LNG IVR users had mean serum LNG concentrations exceeding 300 pg/mL within 1 hour, remaining high throughout IVR use. All LNG IVR users had a cervical mucus Insler score <10 and the majority [95%] were anovulatory or had abnormal cervical mucus sperm penetration. Estimated in vivo TFV and LNG release rates were within expected ranges. All IVRs were safe with the active ones delivering sustained high concentrations of TFV locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. The TFV and TFV/LNG rings are ready for expanded 90 day clinical testing.

Original languageEnglish (US)
Article numbere0199778
JournalPLoS One
Volume13
Issue number6
DOIs
StatePublished - Jun 1 2018

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Tenofovir
Female Contraceptive Devices
Pharmacodynamics
cervical mucus
Levonorgestrel
Pharmacokinetics
pharmacology
pharmacokinetics
placebos
Placebos
Safety
colposcopy
spermatozoa
antimicrobial proteins
microorganisms
contraceptives
Human immunodeficiency virus
HIV infections
luteinizing hormone
Cervix Mucus

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women. / Thurman, Andrea Ries; Schwartz, Jill L.; Brache, Vivian; Clark, Meredith R.; McCormick, Timothy; Chandra, Neelima; Marzinke, Mark A; Stanczyk, Frank Z.; Dezzutti, Charlene S.; Hillier, Sharon L.; Herold, Betsy C.; Fichorova, Raina; Asin, Susana N.; Rollenhagen, Christiane; Weiner, Debra; Kiser, Patrick; Doncel, Gustavo F.

In: PLoS One, Vol. 13, No. 6, e0199778, 01.06.2018.

Research output: Contribution to journalArticle

Thurman, AR, Schwartz, JL, Brache, V, Clark, MR, McCormick, T, Chandra, N, Marzinke, MA, Stanczyk, FZ, Dezzutti, CS, Hillier, SL, Herold, BC, Fichorova, R, Asin, SN, Rollenhagen, C, Weiner, D, Kiser, P & Doncel, GF 2018, 'Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women', PLoS One, vol. 13, no. 6, e0199778. https://doi.org/10.1371/journal.pone.0199778
Thurman, Andrea Ries ; Schwartz, Jill L. ; Brache, Vivian ; Clark, Meredith R. ; McCormick, Timothy ; Chandra, Neelima ; Marzinke, Mark A ; Stanczyk, Frank Z. ; Dezzutti, Charlene S. ; Hillier, Sharon L. ; Herold, Betsy C. ; Fichorova, Raina ; Asin, Susana N. ; Rollenhagen, Christiane ; Weiner, Debra ; Kiser, Patrick ; Doncel, Gustavo F. / Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women. In: PLoS One. 2018 ; Vol. 13, No. 6.
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AU - Clark, Meredith R.

AU - McCormick, Timothy

AU - Chandra, Neelima

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AU - Stanczyk, Frank Z.

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AU - Fichorova, Raina

AU - Asin, Susana N.

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N2 - To prevent the global health burdens of human immunodeficiency virus [HIV] and unintended/mistimed pregnancies, we developed an intravaginal ring [IVR] that delivers tenofovir [TFV] at ~10mg/day alone or with levonorgestrel [LNG] at ~20μg/day for 90 days. We present safety, pharmacokinetics, pharmacodynamics, acceptability and drug release data in healthy women. CONRAD A13-128 was a randomized, placebo controlled phase I study. We screened 86 women; 51 were randomized to TFV, TFV/LNG or placebo IVR [2:2:1] and 50 completed all visits, using the IVR for approximately 15 days. We assessed safety by adverse events, colposcopy, vaginal microbiota, epithelial integrity, mucosal histology and immune cell numbers and phenotype, cervicovaginal [CV] cytokines and antimicrobial proteins and changes in systemic laboratory measurements, and LNG and TFV pharmacokinetics in multiple compartments. TFV pharmacodynamic activity was measured by evaluating CV fluid [CVF] and tissue for antiviral activity using in vitro models. LNG pharmacodynamic assessments were timed based on peak urinary luteinizing hormone levels. All IVRs were safe with no significant colposcopic, mucosal, immune and microbiota changes and were acceptable. Among TFV containing IVR users, median and mean CV aspirate TFV concentrations remained above 100,000 ng/mL 4 hours post IVR insertion and mean TFV-diphosphate [DP] concentrations in vaginal tissue remained above 1,000 fmol/mg even 3 days post IVR removal. CVF of women using TFV-containing IVRs completely inhibited [94–100%] HIV infection in vitro. TFV/LNG IVR users had mean serum LNG concentrations exceeding 300 pg/mL within 1 hour, remaining high throughout IVR use. All LNG IVR users had a cervical mucus Insler score <10 and the majority [95%] were anovulatory or had abnormal cervical mucus sperm penetration. Estimated in vivo TFV and LNG release rates were within expected ranges. All IVRs were safe with the active ones delivering sustained high concentrations of TFV locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. The TFV and TFV/LNG rings are ready for expanded 90 day clinical testing.

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