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Development of rectal enema as microbicide (DREAM): Preclinical progressive selection of a tenofovir prodrug enema.
Hoang, Thuy; Date, Abhijit A; Ortiz, Jairo Ortiz; Young, Ting-Wei; Bensouda, Sabrine; Xiao, Peng; Marzinke, Mark; Rohan, Lisa; Fuchs, Edward J; Hendrix, Craig; Gumber, Sanjeev; Villinger, Francois; Cone, Richard A; Hanes, Justin; Ensign, Laura M.
Afiliação
  • Hoang T; The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA.
  • Date AA; The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA.
  • Ortiz JO; The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA.
  • Young TW; The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA.
  • Bensouda S; The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; Department of Medicine, Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Xiao P; New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, USA.
  • Marzinke M; Department of Medicine, Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Rohan L; Department of Pharmaceutical Sciences, University of Pittsburgh and Magee-Womens Research Institute, Pittsburgh, PA, USA.
  • Fuchs EJ; Department of Medicine, Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Hendrix C; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA; Department of Medicine, Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Gumber S; Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
  • Villinger F; New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, USA.
  • Cone RA; The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; Department of Biophysics, Johns Hopkins University, Baltimore, MD, USA.
  • Hanes J; The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA. Electronic address: hanes@jhmi.edu.
  • Ensign LM; The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA. Electronic address: lensign@jhmi.edu.
Eur J Pharm Biopharm ; 138: 23-29, 2019 May.
Article em En | MEDLINE | ID: mdl-29802984
ABSTRACT
HIV pre-exposure prophylaxis (PrEP) strategies have the potential to prevent millions of incident HIV infections each year. However, the efficacy of PrEP strategies has been plagued by issues of non-adherence, likely because of the difficulty in motivating otherwise healthy people to adhere to treatment regimens that require significant behavioral changes and daily discipline. An alternative approach to PrEP is to focus on strategies that fit in to normal, and even desirable, sexual behaviors, such as the use of cleansing enemas by men who have sex with men (MSM) prior to receptive anal intercourse (RAI). Here, we describe preclinical efforts toward optimizing a tenofovir (TFV)-based enema formulation for rectal PrEP. Using a murine model, we compared the plasma and tissue pharmacokinetics of TFV and various TFV prodrugs, including tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and hexadecyloxypropyl tenofovir (CMX157), after dosing as enema formulations with varying osmolality and ion content. We observed that the enema vehicle composition played a more important role than the TFV prodrug properties in achieving rapid and therapeutically relevant tenofovir diphosphate (TFV-DP) concentrations in mouse colorectal tissue. Our results support the next steps, which are further preclinical (non-human primate) and clinical development of a hypo-osmolar TFV enema product for rectal PrEP.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Reto / Pró-Fármacos / Tenofovir / Anti-Infecciosos Limite: Animals Idioma: En Revista: Eur J Pharm Biopharm Assunto da revista: FARMACIA / FARMACOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Reto / Pró-Fármacos / Tenofovir / Anti-Infecciosos Limite: Animals Idioma: En Revista: Eur J Pharm Biopharm Assunto da revista: FARMACIA / FARMACOLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos