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1.
J Antimicrob Chemother ; 79(7): 1597-1605, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38758205

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).


Subject(s)
Anti-HIV Agents , Emtricitabine , HIV Infections , Heterocyclic Compounds, 3-Ring , Lamivudine , Oxazines , Piperazines , Point-of-Care Testing , Pyridones , Tenofovir , Humans , Pyridones/urine , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/urine , Heterocyclic Compounds, 3-Ring/blood , Heterocyclic Compounds, 3-Ring/therapeutic use , Male , Emtricitabine/urine , Emtricitabine/pharmacokinetics , Emtricitabine/therapeutic use , Emtricitabine/blood , Adult , Piperazines/urine , Piperazines/blood , Lamivudine/urine , Lamivudine/pharmacokinetics , Lamivudine/blood , Female , HIV Infections/drug therapy , Tenofovir/urine , Tenofovir/pharmacokinetics , Tenofovir/therapeutic use , Tenofovir/blood , Anti-HIV Agents/urine , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/blood , Anti-HIV Agents/therapeutic use , Middle Aged , Pre-Exposure Prophylaxis/methods , Young Adult , Plasma/chemistry , Medication Adherence
2.
Drugs R D ; 19(4): 339-350, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31602556

ABSTRACT

BACKGROUND AND OBJECTIVES: The elderly population receives the majority of prescription drugs but are usually excluded from Phase 1 clinical trials. Alternative approaches to estimate increases in toxicity risk or decreases in efficacy are therefore needed. This study predicted the pharmacokinetics (PK) of three renally excreted antiretroviral drugs in the elderly population and compared them with known exposures in renal impairment, to evaluate the need for dosing adjustments. METHODS: The performance of the physiologically based pharmacokinetic (PBPK) models for tenofovir, lamivudine and emtricitabine were verified using clinical data in young and older subjects. Models were then used to predict PK profiles in a virtual population aged 20 to 49 years (young) and a geriatric population aged 65 to 74 years (elderly). Predicted exposure in the elderly was then compared with exposure reported for different degrees of renal impairment, where doses have been defined. RESULTS: An increase in exposure (AUC) with advancing age was predicted for all drugs. The mean ratio of the increase in exposure were 1.40 for emtricitabine, 1.42 for lamivudine and 1.48 for tenofovir. The majority of virtual patients had exposures that did not require dosage adjustments. About 22% of patients on tenofovir showed exposures similar to that in moderate renal impairment, where dosage reduction may be required. CONCLUSION: Comparison of the exposure in the elderly with exposure observed in patients with different levels of renal impairment, indicated that a dosage adjustment may not be required in elderly patients on lamivudine, emtricitabine and the majority of the patients on tenofovir. Clinical trials to verify these predictions are essential.


Subject(s)
Aging/urine , Anti-HIV Agents , Kidney Diseases/urine , Models, Biological , Adult , Aged , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/urine , Area Under Curve , Dose-Response Relationship, Drug , Emtricitabine/administration & dosage , Emtricitabine/urine , Humans , Kidney Function Tests , Lamivudine/administration & dosage , Lamivudine/urine , Middle Aged , Predictive Value of Tests , Tenofovir/administration & dosage , Tenofovir/urine , Young Adult
3.
J Acquir Immune Defic Syndr ; 82(3): 252-256, 2019 11 01.
Article in English | MEDLINE | ID: mdl-31335590

ABSTRACT

BACKGROUND: Urine provides a minimally invasive specimen that may allow for development of rapid tests to detect antiretroviral drugs and provide opportunities to improve individual adherence. This study sought to determine whether urine could provide a biomarker of adherence for currently approved pre-exposure prophylaxis and HIV treatment regimens. METHODS: Urine and blood were collected from 34 HIV-negative men who have sex with men aged 18-49 years, enrolled in a clinical trial comparing 2 antiretroviral regimens. Specimens were collected 4 and 24 hours after a single oral dose of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (n = 10) or tenofovir alafenamide (TAF)/FTC/cobicistat (COBI)/elvitegravir (EVG) (n = 8), or after 4 and 10 days of daily oral TDF/FTC (n = 9) or TAF/FTC/COBI/EVG (n = 7). Tenofovir (TFV), FTC, and EVG were measured by high-performance liquid chromatography-mass spectrometry. RESULTS: Median urine FTC concentrations at 4 and 24 hours were similar between men receiving TDF/FTC (4 hours 147 µg/mL; 24 hours 10 µg/mL) and men receiving TAF/FTC/COBI/EVG (4 hours 333 µg/mL, P = 0.173; 24 hours 13 µg/mL, P = 0.681). Median urine TFV concentrations were lower among men receiving TAF/FTC/COBI/EVG (4 hours 1.2 µg/mL; 24 hours 0.8 µg/mL) compared with men receiving TDF/FTC (4 hours 17 µg/mL, P < 0.001; 24 hours 7 µg/mL, P = 0.001). Urine TFV concentrations remained reduced among men receiving TAF/FTC/COBI/EVG compared with men receiving TDF/FTC after daily dosing. EVG was not consistently measurable in urine. CONCLUSIONS: High urine FTC and TFV concentrations could provide an indication of adherence to daily oral dosing with TDF or TAF-based regimens used for treatment and prevention.


Subject(s)
Anti-Retroviral Agents/urine , Biomarkers/urine , Emtricitabine/urine , HIV Infections/drug therapy , Homosexuality, Male , Sexual and Gender Minorities , Tenofovir/urine , Adenine/analogs & derivatives , Administration, Oral , Adolescent , Adult , Alanine , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/urine , Anti-Retroviral Agents/administration & dosage , Anti-Retroviral Agents/therapeutic use , Cobicistat/therapeutic use , Emtricitabine/administration & dosage , Emtricitabine/therapeutic use , Humans , Male , Middle Aged , Quinolones , Tenofovir/administration & dosage , Tenofovir/therapeutic use , Time Factors , Young Adult
4.
Biomed Chromatogr ; 32(4)2018 Apr.
Article in English | MEDLINE | ID: mdl-29216682

ABSTRACT

A combination of antiretroviral agents is frequently used in effective treatment of the human immunodeficiency virus infection. In this study, two different separation methods are presented for the simultaneous determination of emtricitabine, rilpivirine and tenofovir from raw materials and urine samples. Developed liquid chromatography and capillary electrophoresis methods were thoroughly optimized for high analytical performances. Optimization of multiple variables at the same time by performing a minimum number of experiments was achieved by the Box-Behnken design, which is an experimental design in response surface methodology, in capillary electrophoresis. The results of the experimental design ensure minimum analysis time with well-separated analytes. Separation conditions, such as different stationary phases, pH level, organic modifiers and temperatures in liquid chromatography method, were also optimized. In particular, among stationary phases, the core-shell column especially enhanced the effectiveness of separation in liquid chromatography. Both methods were fully validated and applied to real samples. The main advantage of the developed methods is the separation of the drug combination in a short time with high efficiency and without any time-consuming steps.


Subject(s)
Anti-Retroviral Agents/urine , Chromatography, Liquid/methods , Electrophoresis, Capillary/methods , Emtricitabine/urine , Rilpivirine/urine , Tenofovir/urine , Anti-Retroviral Agents/chemistry , Anti-Retroviral Agents/isolation & purification , Emtricitabine/chemistry , Emtricitabine/isolation & purification , Humans , Limit of Detection , Linear Models , Models, Statistical , Reproducibility of Results , Rilpivirine/chemistry , Rilpivirine/isolation & purification , Tenofovir/chemistry , Tenofovir/isolation & purification
6.
Water Res ; 85: 57-65, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26302215

ABSTRACT

In eThekwini, South Africa, the production of agricultural fertilizers from human urine collected from urine-diverting dry toilets is being evaluated at a municipality scale as a way to help finance a decentralized, dry sanitation system. The present study aimed to assess a range of human and environmental health hazards in source-separated urine, which was presumed to be contaminated with feces, by evaluating the presence of human pathogens, pharmaceuticals, and an antibiotic resistance gene. Composite urine samples from households enrolled in a urine collection trial were obtained from urine storage tanks installed in three regions of eThekwini. Polymerase chain reaction (PCR) assays targeted 9 viral and 10 bacterial human pathogens transmitted by the fecal-oral route. The most frequently detected viral pathogens were JC polyomavirus, rotavirus, and human adenovirus in 100%, 34% and 31% of samples, respectively. Aeromonas spp. and Shigella spp. were frequently detected gram negative bacteria, in 94% and 61% of samples, respectively. The gram positive bacterium, Clostridium perfringens, which is known to survive for extended times in urine, was found in 72% of samples. A screening of 41 trace organic compounds in the urine facilitated selection of 12 priority pharmaceuticals for further evaluation. The antibiotics sulfamethoxazole and trimethoprim, which are frequently prescribed as prophylaxis for HIV-positive patients, were detected in 95% and 85% of samples, reaching maximum concentrations of 6800 µg/L and 1280 µg/L, respectively. The antiretroviral drug emtricitabine was also detected in 40% of urine samples. A sulfonamide antibiotic resistance gene (sul1) was detected in 100% of urine samples. By coupling analysis of pathogens and pharmaceuticals in geographically dispersed samples in eThekwini, this study reveals a range of human and environmental health hazards in urine intended for fertilizer production. Collection of urine offers the benefit of sequestering contaminants from environmental release and allows for targeted treatment of potential health hazards prior to agricultural application. The efficacy of pathogen and pharmaceutical inactivation, transformation or removal during urine nutrient recovery processes is thus briefly reviewed.


Subject(s)
Anti-Bacterial Agents/urine , Antiviral Agents/urine , Gram-Negative Bacteria/isolation & purification , Gram-Positive Bacteria/isolation & purification , Urine/microbiology , Urine/virology , Anti-Bacterial Agents/isolation & purification , Antiviral Agents/isolation & purification , Drug Resistance, Microbial/genetics , Emtricitabine/isolation & purification , Emtricitabine/urine , Health Impact Assessment , Humans , South Africa , Sulfamethoxazole/isolation & purification , Sulfamethoxazole/urine , Trimethoprim/isolation & purification , Trimethoprim/urine
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