Background:  Apricitabine (ATC) is a single enantiomer deoxycytidine analogue NRTI in development for the treatment of HIV-1 infection in patients with prior treatment experience. ATC has broadly linear pharmacokinetics with plasma and triphosphate t_1/2 of ~3 hours and 7 hours. Treatment with ATC for 10 days in a placebo controlled study in 63 treatment-naïve patients gave mean reductions in viral load vs placebo of –1.18 log₁₀ (400 mg/day), –1.40 (800 mg/day), –1.65 (1200 mg/day), and –1.58 (1600 mg/day) (all p <0.01 vs placebo).

Methods:  We developed a mathematical HIV disease state model characterizing the viral dynamics of ATC therapy, linked to both plasma and intracellular pharmacokinetics using data collected in the prior treatment-naïve study. Drug concentrations were fit by a 2-compartment pharmacokinetic model, with first order conversion to the triphosphate. The model incorporated uninfected and infected CD4 cells and production and clearance of HIV. Antiviral activity was modeled as intracellular ATC-triphosphate-inhibiting active viral replication, through a Hill-type function, with the pharmacodynamic parameters including EC₅₀ (triphosphate at which drug action is half maximal). Once the optimum fit between the model and the data had been achieved the model was used to predict the dose-dependent response to ATC for viruses with as much as a 6-fold reduced drug susceptibility. In these clinical trial simulations the pharmacokinetics/ pharmacodynamic model results, for each individual subject from the original trial, were used to predict responses to a range of regimens and altered EC₅₀ values. In separate simulations, each subject received ATC 200, 400, 600, and 800 mg twice daily, at 1x, 2x, 3x, 4x, and 6x multiples of wild type virus EC₅₀.

Results:  The model fit the data excellently, with a median R² for plasma, triphosphate, and viral load of 0.99, 0.89, and 0.94, respectively. The median wild type EC₅₀ for triphosphate was 0.09 ng/mL/million cells; median trough triphosphate concentrations for twice-daily dosing were:  200 mg (0.48 ng/mL/million cells), 400 mg (0.95), 600 mg (1.3), and 800 mg (2.3). At day 10 and 14 the dose thresholds for a median predicted reduction in viral load ≥1 log₁₀ against viruses with 2x, 3x, and 4x wild type EC₅₀ were 400 mg twice daily, 600 mg twice daily, and 800 mg twice daily, respectively. Against virus with 6x wild type EC₅₀ 800 mg twice daily was predicted to achieve a median reduction in viral load of ~0.8 log₁₀ at day 14

Conclusions:  These clinical trial simulations indicate that viruses with as much as a 6-fold reduction in susceptibility will be amenable to treatment with ATC 800 mg twice daily. A clinical study is ongoing to confirm the validity of these predictions.