icon-folder.gif   Conference Reports for NATAP  
  17th International Workshop
on Clinical Pharmacology of
HIV and Hepatitis Therapy
June 8-10, 2016, Washington DC
Back grey_arrow_rt.gif
Simulations See Protection From HIV With Long-Acting Injectable Tenofovir
17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC
Mark Mascolini
In silico modeling predicted that tenofovir injected intramuscularly every 1 or 3 months would yield concentrations high enough to protect 99% of treated people from HIV [1]. The findings may provide a start for development of long-acting injectable tenofovir PrEP, but the concentration cutoffs used to determine efficacy rest on clinical data for tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) [2] and will probably differ for tenofovir alone.
Oral TDF with or without FTC has proved effective as PrEP in high-risk populations, but trials clearly show that protection from HIV depends on good PrEP adherence. A long-acting injectable PrEP drug could greatly improve adherence, and a few such candidates are approaching late stages of development. University of Liverpool investigators used physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling "to provide a quantitative framework for development of NRTI-based long-acting PrEP."
The Liverpool team integrated in vitro and population PK data for TDF into PBPK models and simulated PKs for 500 individuals. They validated the models against clinical data for standard oral regimens then included the PD concentration cutoffs for oral TDF/FTC PrEP efficacy (50%, 90%, and 99% reduction in HIV [2]) in the models. Finally the investigators used validated models to predict PK and PD after intramuscular injection of theoretical long-acting tenofovir formulations.
Simulated PK parameters for oral tenofovir reflected parameters in published clinical data. Simulation of long-acting tenofovir predicted that a once-monthly injection would provide suitable tenofovir exposure at a dose of 750 mg and a release rate of 0.002/h. With an every-3-month injection, projected dose and release rate were 1000 mg and 0.001/h.
Predicted tenofovir minimum plasma concentrations (Cmin) averaged 34.7 +/- 18.08 ng/mL with the once-monthly injection and 10.5 +/- 4.08 ng/mL with the every-3-month injection. Respective projected 2-day intracellular Cmins for tenofovir-diphosphate (TFV-DP, the active form of the drug) were 45.9 +/- 16.00 fmol/10(6) cells and 40.7 +/- 14.48 fmol/10(6) cells. Thirty days after the monthly injection, projected intracellular TFV-DP would be 144.9 +/- 58.74 fmol/10(6) cells. Ninety days after the every-3-month injection, projected intracellular TFV-DP would be 68.5 (+/- 27.15) fmol/10(6) cells.
Simulated intracellular 30-day Cmins lay above levels linked to a 90% lower risk of HIV acquisition [2] in more than 99% of patients taking simulated monthly tenofovir injections. For people taking quarterly injections, simulated 90-day intracellular Cmins lay above concentrations linked to a 90% lower HIV risk in 98.8%.
These findings, the researchers proposed, indicate that long-acting tenofovir "may be a suitable candidate for monthly or quarterly intramuscular long-acting [use] if pharmaceutical challenges can be met." They noted that simulation of PrEP pharmacodynamics assumed tenofovir "distribution into key tissues and mucosa is comparable between the traditional oral formulations and intramuscular injections as would be expected for a solid drug nanoparticle formulation." And they stressed that concentration cutoffs used come from TDF/FTC data and those cutoffs "are likely to be different for [tenofovir] monotherapy."
1. Curley P, Moss DM, Rajoli RKR, et al. In silico pharmacokinetic/pharmacodynamic simulation of long acting tenofovir injectable formulation for pre exposure prophylaxis strategies. 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC. Abstract O14.
2. Anderson PL, Glidden DV, Liu A, Buchbinder S, et al. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med. 2012;4:151ra125. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721979/