title: Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure.
abstract: Tenofovir (TFV) disoproxil fumarate (TDF)±emtricitabine (FTC) are widely used for HIV treatment and chemoprophylaxis, but variable adherence may lead to suboptimal responses. Methods that quantify adherence would allow for interventions to improve treatment and prevention outcomes. Our objective was to characterize the pharmacokinetics of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs); to extend the RBC analysis to dried blood spots (DBSs); and to model how RBC/DBS monitoring could inform recent and cumulative drug exposure/adherence. Blood samples were collected from 17 HIV-negative adults at 5 visits over a 30-day pharmacokinetics study of daily oral TDF/FTC. Dosing was discontinued on day 30 and blood was collected on days 35, 45, and 60 during the washout period. Plasma/RBCs/PBMCs/DBSs were all quantified by liquid chromatography/tandem mass spectrometry. DBSs were paired with RBCs and plasma for comparisons. The median (interquartile range) RBC TFV-DP half-life was 17.1 (15.7-20.2) versus 4.2 (3.7-5.2) days in PBMCs. At steady state, TFV-DP was 130 fmol/10(6) RBCs versus 98 fmol/10(6) PBMCs. FTC-TP was not quantifiable in most RBC samples. TFV-DP in RBCs versus DBSs yielded an r(2)=0.83. TFV-DP in DBSs was stable at -20°C. Simulations of TFV-DP in RBCs/DBSs, when dosed from one to seven times per week, demonstrated that each dose per week resulted in an average change of approximately 19 fmol/10(6) RBCs and 230 fmol/punch. TFV and FTC in plasma versus DBSs was defined by y=1.4x; r(2)=0.96 and y=0.8x; r(2)=0.99, respectively. We conclude that DBSs offer a convenient measure of recent (TFV/FTC) and cumulative (TFV-DP in RBCs) drug exposure with potential application to adherence monitoring.
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of Colorado-Anschutz Medical Campus , Aurora, Colorado 80045, USA.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Castillo-Mancilla
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Zheng
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rower
authors.forename: Amie
authors.initials: A
authors.lastname: Meditz
authors.forename: Edward M
authors.initials: EM
authors.lastname: Gardner
authors.forename: Julie
authors.initials: J
authors.lastname: Predhomme
authors.forename: Caitlin
authors.initials: C
authors.lastname: Fernandez
authors.forename: Jacob
authors.initials: J
authors.lastname: Langness
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Kiser
authors.forename: Lane R
authors.initials: LR
authors.lastname: Bushman
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000032:analysis* / Q000493:pharmacokinetics; D001774:Blood Chemical Analysis / Q000379:methods*; D002853:Chromatography, Liquid; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D003890:Desiccation; D000068679:Emtricitabine; D004912:Erythrocytes / Q000737:chemistry; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control; D006207:Half-Life; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000032:analysis* / Q000493:pharmacokinetics; D010949:Plasma / Q000737:chemistry; D013048:Specimen Handling / Q000379:methods*; D053719:Tandem Mass Spectrometry; D000068698:Tenofovir; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine