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Randomized Controlled Trial
. 2024 Jul 1;79(7):1597-1605.
doi: 10.1093/jac/dkae147.

Tenofovir, emtricitabine, lamivudine and dolutegravir concentrations in plasma and urine following drug intake cessation in a randomized controlled directly observed pharmacokinetic trial to aid point-of-care testing

Laura J Else  1 , Laura Dickinson  1 , Stacey Edick  2 , Ashley Zyhowski  3 , Ken Ho  2 , Leslie Meyn  2 , Sujan Dilly-Penchala  1 , Beth Thompson  1 , Victoria Shaw  1 , Saye Khoo  1 , Rhonda M Brand  2   3
Affiliations
Randomized Controlled Trial

Tenofovir, emtricitabine, lamivudine and dolutegravir concentrations in plasma and urine following drug intake cessation in a randomized controlled directly observed pharmacokinetic trial to aid point-of-care testing

Laura J Else et al. J Antimicrob Chemother. .

Abstract

Background: Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence interventions.

Objectives: We report the pharmacokinetics of tenofovir [dosed as tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF)], emtricitabine (FTC), lamivudine (3TC) and dolutegravir (DTG) in plasma and urine following drug cessation to evaluate adherence targets in urine for POCT.

Methods: Subjects were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15 days. Plasma and spot urine were collected on Day 15 (0-336 h post final dose). Drug concentrations were quantified using LC-MS, and non-linear mixed-effects models applied to determine drug disposition between matrices and relationship with relevant plasma [dolutegravir protein-adjusted 90% inhibitory concentration (PA-IC90 = 64 ng/mL) and minimum effective concentration (MEC = 324 ng/mL)] and urinary thresholds [tenofovir disoproxil fumarate 1500 ng/mL].

Results: Of 30 individuals enrolled, 29 were included (72% female at birth, 90% Caucasian). Median (range) predicted time to plasma dolutegravir PA-IC90 and MEC were 83.5 (41.0-152) and 49.0 h (23.7-78.9), corresponding to geometric mean (90%) urine concentrations of 5.42 (4.37-6.46) and 27.4 ng/mL (22.1-32.7). Tenofovir in urine reached 1500 ng/mL by 101 h (58.6-205) with an equivalent plasma concentration of 6.20 ng/mL (4.21-8.18).

Conclusions: These data support use of a urinary tenofovir threshold of <1500 ng/mL (tenofovir disoproxil fumarate-based regimens) as a marker of three or more missed doses for a POCT platform. However, due to low dolutegravir concentrations in urine, POCT would be limited to a readout of recent dolutegravir intake (one missed dose).

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Figures

Figure 1.
Figure 1.
Geometric mean (95% CI—dashed lines) concentrations in plasma and urine for (a) tenofovir (tenofovir alafenamide; TFVTAF), (b) emtricitabine (FTC), (c) tenofovir (tenofovir disoproxil; TFVTDF), (d) lamivudine (3TC) and (e) dolutegravir (DTG) (Arm 1) and (f) DTG (Arm 2), during the 14 day drug intake cessation period. Plasma values are indicated with grey lines (circles) and urine values with black lines (triangles). Detectable concentrations below the assay LLQ are expressed as half-LLQ values.
Figure 2.
Figure 2.
Proportion of plasma and urine samples with NRTI [tenofovir alafenamide (TFVTAF), tenofovir disoproxil fumarate (TFVTDF), emtricitabine (FTC), lamivudine (3TC)] and dolutegravir (DTG) levels above the LC-MS assay LLQ. Plasma values are indicated with a solid line (circles) and urine values with a dotted line (triangles). TFVTAF = pink; TFVTDF = green; FTC = yellow; 3TC = orange; DTG = grey. The LLQs were 1 ng/mL (TFV), 5 ng/mL (FTC/3TC) and 10 ng/mL (DTG) in plasma, and 12.5 ng/mL (NRTI) and 10 ng/mL (DTG) in urine. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Figure 3.
Figure 3.
Proportion of urine samples with tenofovir (TFV) concentrations >1500 ng/mL [tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) dosing] or >150 ng/mL (TAF dosing). The blue dashed line shows the 1500 ng/mL threshold and the red dashed line shows the 150 ng/mL threshold. TFVTAF = pink triangles; TFVTDF = green triangles. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
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