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Prediction of Intracellular (IC) Tenofovir Diphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Concentrations Following Drug Intake Cessation
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Reported by Jules Levin
16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 26-28, 2015, Washington, DC
L. Dickinson1, H.M. Yapa2, A. Jackson2, G. Moyle2, L. Else1, A. Amara1, S. Khoo1, D. Back1, Z. Karolia2, C. Higgs2, M. Boffito2
1University of Liverpool, Department of Molecular & Clinical Pharmacology, Liverpool, United Kingdom; 2St. Stephen's Centre, Chelsea & Westminster Foundation Trust, London, United Kingdom
"Twenty-four, 36, 48 and 72h after stopping drug, 6%, 0%, 1% and 4% of predicted TFV-DP and 56%, 78%, 83% and 83% of FTC-TP were <16fmol/106 cells and 3.7pmol/106 cells, respectively (iPrEx HIV prevention targets)."
Background: Pharmacokinetic (PK) data describing prolonged time-courses of antiretrovirals in plasma and peripheral blood mononuclear cells (PBMCs) are important for understanding and management of late or missed doses and to assess appropriateness for preexposure prophylaxis (PrEP). PK of coformulated tenofovir disoproxil fumarate (DF)/emtricitabine/rilpivirine in plasma were evaluated in healthy volunteers up to 9 days following drug cessation. Use of non-linear mixed effects modeling was also explored to predict IC anabolites, TFV-DP and FTC-TP.
Materials & Methods: Individuals received daily tenofovir DF/emtricitabine/rilpivirine (245/200/25 mg) for 14 days. Drug intake was stopped and serial sampling occurred prior to the final dose and up to 216h (9 days) post-stopping drug. Concentrations were determined by LC-MS/MS. Separate population PK models were developed for tenofovir and emtricitabine (NONMEM v. 7.2) and all plasma and IC data were modeled simultaneously. Plasma tenofovir, emtricitabine and time-matched TFV-DP and FTC-TP concentrations from a previous healthy volunteer study (n=16) investigating tenofovir/emtricitabine/efavirenz PK after drug cessation (EFV study) were used to describe the relationship between plasma and IC anabolite concentrations. Plasma PK parameters for the present study were fixed to their individual Bayesian estimates and population parameters obtained for the relationship between plasma concentrations and IC anabolites used as prior information to predict IC TFV-DP and FTC-TP concentration-time profiles for the present study (0-168h; 7 days).
Results: Eighteen volunteers (11 female) completed the study. Two-compartment oral models described plasma tenofovir and emtricitabine [CL/F (RSE%): 67L/h (7%) and 20L/h (6%), respectively]. Inclusion of weight and creatinine clearance significantly improved the tenofovir model and tenofovir relative bioavailability was 33% higher for the present study than the EFV study due to food intake. Creatinine clearance was associated with emtricitabine CL/F. Plasma and PBMC compartments were linked by first-order rate constant, k24 [TFV-DP: 3.20h-1 (18%); FTC-TP: 0.15h-1 (22%)] and elimination of TFV-DP and FTC-TP described by k40 [0.0059h-1 (18%) and 0.019h-1 (6%), respectively]. Geometric mean (90% CI) TFV-DP and FTC-TP AUC0-24, AUC0-168, Cmax and C24 were 1456fmol.h/106 cells (1302-2193) and 87.8pmol.h/106 cells (79.2-150), 7495fmol.h/106 cells (6792-11486) and 273pmol.h/106 cells (252-440), 92.2fmol/106 cells (83.8-135) and 6.2pmol/106 cells (5.7-10.5), 54.0fmol/106 cells (48.2-87.9) and 3.1pmol/106 cells (2.9-5.6), respectively. Model-derived IC half-lives (0-168) were 116h (TFV-DP) and 37h (FTC-TP). Twenty-four, 36, 48 and 72h after stopping drug, 6%, 0%, 1% and 4% of predicted TFV-DP and 56%, 78%, 83% and 83% of FTC-TP were <16fmol/106 cells and 3.7pmol/106 cells, respectively (iPrEx HIV prevention targets).
Plasma tenofovir and emtricitabine terminal elimination plasma half-life within 216h was longer than 0-24 [tenofovir: 31h (27-40) vs. 13.3h (12.5-15.1); emtricitabine: 41h (36-54) vs. 6.4h (5.9-7.6)]. Plasma rilpivirine at 216h was 4.5ng/mL (4.2-6.2) and half-lives 0-216 and 0-24 were 47h (41-59) and 35h (28-46), respectively.
Conclusions: Inclusion of plasma and IC data from a previous study as prior information allowed prediction of IC TFV-DP and FTC-TP from plasma
concentrations. Although adherence to antiretrovirals should be promoted, these data contribute to our understanding of drug behavior following treatment interruption.
Most of the predicted TFV-DP concentrations were above the 16fmol/106 cells target up to 3 days
after the final dose but >50% of individuals had FTC-TP concentrations below 3.7 pmol/106 cells
between 24-72h after stopping drug
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