Establishment of intracellular tenofovir-diphosphate as the key determinant for in vitro-in vivo translation of antiviral efficacy

Bennett Ma; Aline Barth; Carolyn M McHale; Ming-Tain Lai

doi:10.1016/j.antiviral.2018.01.005

Establishment of intracellular tenofovir-diphosphate as the key determinant for in vitro-in vivo translation of antiviral efficacy

Antiviral Res. 2018 Mar:151:1-3. doi: 10.1016/j.antiviral.2018.01.005. Epub 2018 Jan 11.

Authors

Bennett Ma¹, Aline Barth², Carolyn M McHale³, Ming-Tain Lai³

Affiliations

¹ Pharmacokinetics, Pharmacodynamics and Drug Metabolism, MSD, West Point, PA, 19486, USA. Electronic address: [email protected].
² Pharmacokinetics, Pharmacodynamics and Drug Metabolism, MSD, West Point, PA, 19486, USA.
³ Antiviral Research, MSD, West Point, PA, 19486, USA.

PMID: 29337165
DOI: 10.1016/j.antiviral.2018.01.005

Abstract

In vitro evaluation of tenofovir disproxil fumarate (TDF) and tenofovir alafenamide (TAF) revealed comparable antiviral effects with respect to the tenofovir-diphosphate (TFV-DP) level in human peripheral blood mononuclear cells (PBMCs), despite the EC₅₀ values determined based on prodrug concentrations were nearly two orders of magnitude apart. In vivo EC₅₀ obtained from meta-analyses were in good agreement with the in vitro results, indicating intracellular TFV-DP can be employed for in vitro-in vivo translation of viral inhibition for tenofovir prodrugs. Current analysis indicated that the intracellular concentrations of TFV-DP achieving maximal antiviral effect in vitro can be directly translatable in the clinic to accomplish maximal viral load suppression attainable by tenofovir-prodrugs.

MeSH terms

Adenine / analogs & derivatives*
Adenine / pharmacokinetics
Adenine / pharmacology
Adenine / therapeutic use
Alanine
Anti-HIV Agents / pharmacokinetics
Anti-HIV Agents / pharmacology*
Anti-HIV Agents / therapeutic use
Cytoplasm / metabolism
Databases, Factual
Dose-Response Relationship, Drug
HIV Infections / drug therapy
HIV Infections / virology
HIV-1 / drug effects
Humans
Leukocytes, Mononuclear
Meta-Analysis as Topic
Organophosphates / pharmacokinetics
Organophosphates / pharmacology*
Organophosphates / therapeutic use
Prodrugs / pharmacokinetics
Prodrugs / pharmacology
Prodrugs / therapeutic use
Tenofovir / pharmacokinetics
Tenofovir / pharmacology
Tenofovir / therapeutic use
Viral Load / drug effects
Virus Replication / drug effects*

Substances

Anti-HIV Agents
Organophosphates
Prodrugs
tenofovir diphosphate
Tenofovir
tenofovir alafenamide
Adenine
Alanine