(T-107) Use of Emtricitabine-Triphosphate Concentrations in Dried Blood Spots to Evaluate Pre-Exposure Prophylaxis (PrEP) Adherence

Alexandra Dunbar – Pharmaceutical Sciences – University of Colorado Anschutz Medical Campus; Kristina Brooks – Pharmaceutical Sciences – University of Colorado Anschutz Medical Campus; Peter Anderson – Pharmaceutical Sciences – University of Colorado Anschutz Medical Campus

Objectives: Intraerythrocytic tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) are used to assess cumulative and recent adherence to tenofovir disoproxil-based HIV PrEP, respectively. TFV-DP reflects average doses per week over the previous 6-8 weeks due to its long half-life (t1/2) in RBCs (~17-21 days), but FTC-TP has typically been used only as a qualitative check of dosing within the past few days due to its short t1/2 (~35 h). With the tenofovir prodrug form, tenofovir alafenamide (TAF), ~10-fold more blood is assayed from DBS, which means that FTC-TP is quantifiable for longer in the F/TAF combination. The goal of this analysis was to develop a model for FTC-TP in DBS to determine if FTC-TP concentration thresholds in DBS could inform PrEP adherence patterns for F/TAF.

Methods: A popPK model was developed using FTC-TP concentrations in DBS (2x7 mm punches) from the TAF-DBS study, a 36-week randomized, prospective, crossover study (NCT02962739). Healthy, HIV-negative volunteers (n=36) were randomized to 2 different 12-week F/TAF 200/25 mg dosing regimens (33%, 67%, or 100% of daily dosing) separated by a 12-week washout period. DBS were collected by convenience sampling weekly. FTC-TP was quantified using LC/MS-MS (lower limit of quantitation [LLOQ]: 0.1 pmol/punches). The model was developed using microconstant parameterization with QRPEM algorithm and the M3 method to handle concentrations below the LLOQ (BLQ) (Phoenix NLME v 8.5.2.4). Baseline age, BMI, eGFR, hematocrit, weight, race, and sex were screened (p-value add/remove: 0.01/0.001). The final model was used to evaluate adherence patterns by simulating 1-7 doses/week over the course of a month (n=1000). DBS collections were simulated to occur at the end of the month (720 h).

Results: A total of 1307 FTC-TP concentrations were used for model development (32% BLQ). FTC-TP in DBS was adequately described by a 1-compartment model with first-order absorption and elimination, V/F as a scalar, and an additive and proportional residual error structure. Random effects around ka were removed due to high shrinkage. Typical values for ka, V/F, and ke were 0.42 h-1 (95% CI 0.36, 0.48), 3.84x108 punch (3.54x108, 4.13x108), and 0.019 h-1 (0.017, 0.020), respectively. The model estimated t1/2 was 37.3 h (34.7, 39.8). No covariates were included in the final model. Interindividual variability (IIV) was 19.2% (%CV) and 17.4% for V/F and Ke, respectively. Simulated median (IQR) concentrations after 1-7 doses/week were 0.97 (0.79, 1.11), 1.19 (0.95, 1.41), 1.42 (1.10, 1.68), 3.59 (2.98, 4.08), 3.73 (3.06, 4.25), 3.89 (3.09, 4.52), and 4.11 (3.29, 4.79) pmol/punches at the end of the month, respectively.

Conclusions: With an F/TAF PrEP regimen, FTC-TP DBS concentrations were described by a 1-compartment model with half-life estimates being consistent with results from washout studies. From simulation, distinct FTC-TP concentration thresholds were not identified between each dosing pattern, illustrating the challenges establishing adherence gradients for short half-life drugs. Further investigation and simulations are ongoing to probe how best to use FTC-TP to help differentiate adherence patterns.

Citations: [1] Anderson, P. L., Liu, A. Y., Castillo-Mancilla, J. R., Gardner, E. M., Seifert, S. M., McHugh, C., Wagner, T., Campbell, K., Morrow, M., Ibrahim, M., Buchbinder, S., Bushman, L. R., Kiser, J. J., & MaWhinney, S. (2017). Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy. Antimicrobial agents and chemotherapy, 62(1), e01710-17. https://doi.org/10.1128/AAC.01710-17

[2] Castillo-Mancilla, J., Seifert, S., Campbell, K., Coleman, S., McAllister, K., Zheng, J. H., Gardner, E. M., Liu, A., Glidden, D. V., Grant, R., Hosek, S., Wilson, C. M., Bushman, L. R., MaWhinney, S., & Anderson, P. L. (2016). Emtricitabine-Triphosphate in Dried Blood Spots as a Marker of Recent Dosing. Antimicrobial agents and chemotherapy, 60(11), 6692–6697. https://doi.org/10.1128/AAC.01017-16

Keywords: popPK, PrEP, adherence