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Pharmacokinetics of vaginally applied integrase inhibitors in macaques.
- Source :
- Journal of Antimicrobial Chemotherapy (JAC); Nov2021, Vol. 76 Issue 11, p2894-2901, 8p
- Publication Year :
- 2021
-
Abstract
- <bold>Objectives: </bold>We conducted a detailed pharmacokinetic assessment in macaques treated with vaginal gels formulated with HIV integrase strand transfer inhibitors (INSTIs) to better understand drug distribution and identify INSTI concentrations associated with previously demonstrated in vivo protection against vaginal simian HIV challenge.<bold>Methods: </bold>Six macaques received vaginal gel containing 1% raltegravir (30 mg) once-weekly over 6 weeks. Following a washout period, five macaques received once-weekly gel containing 0.23% L-870,812 (7 mg). Drug concentrations were measured in plasma, mucosal fluids and vaginal tissues at baseline and 2, 5 and 24 h post-dosing.<bold>Results: </bold>The median maximum concentration (Cmax) for raltegravir and L-870,812 in plasma was below the limit of quantification and 41.1 ng/mL, respectively. The Cmax in vaginal fluids (1441 and 1250 μg/mL) and tissues (266.7 and 368.4 μg/g) was achieved 2-5 h after dosing, respectively. A similar half-life was observed for raltegravir and L-870,812 in vaginal fluids (8-10 h) and remained 3-4 orders of magnitude above the protein-adjusted IC95 (0.016 and 0.106 μg/mL, respectively) at 24 h. Drug concentrations in vaginal fluids correlated well with those in vaginal tissues (Pearson r ≥ 0.788). Both drugs were consistently detected in rectal fluids 2 h after vaginal dosing, albeit at much lower levels (31-92-fold) than those in vaginal fluids.<bold>Conclusions: </bold>To the best of our knowledge, this study provides the first data on INSTI levels in vaginal tissues associated with in vivo protection and demonstrates rectal drug distribution of INSTIs after vaginal dosing. These findings may inform dose selection for topical products with INSTIs for HIV prevention. [ABSTRACT FROM AUTHOR]
- Subjects :
- INTEGRASE inhibitors
MACAQUES
PHARMACOKINETICS
HIV prevention
SIMIAN immunodeficiency virus
RALTEGRAVIR
MAGNITUDE (Mathematics)
RNA virus infections
ANTI-HIV agents
RESEARCH
ANIMAL experimentation
RESEARCH methodology
MEDICAL cooperation
EVALUATION research
PRIMATES
COMPARATIVE studies
VAGINAL medication
RESEARCH funding
ENZYME inhibitors
THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 03057453
- Volume :
- 76
- Issue :
- 11
- Database :
- Complementary Index
- Journal :
- Journal of Antimicrobial Chemotherapy (JAC)
- Publication Type :
- Academic Journal
- Accession number :
- 153717315
- Full Text :
- https://doi.org/10.1093/jac/dkab293