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Comparing ultrafiltration and equilibrium dialysis to measure unbound plasma dolutegravir concentrations based on a design of experiment approach.

ABSTRACT: Dolutegravir therapeutic drug monitoring (TDM) could be improved by measuring the unbound dolutegravir plasma concentration (Cu), particularly in patients experiencing virological failure or toxicity despite achieving appropriate DTG total plasma concentrations. Equilibrium dialysis (ED) is the gold standard to measure Cu, but ED is time consuming, precluding its use in clinical practice. In contrast, ultrafiltration is applicable to TDM, but is sensitive to numerous analytical conditions. In order to evaluate measurements of Cu by ultrafiltration, ultrafiltration conditions were validated by comparison with ED. DTG concentrations were measured by LC-MS/MS. Three ultrafiltration factors (temperature, duration and relative centrifugal force [RCF]) were evaluated and compared to ED (25/37 °C), using a design of experiment strategy. Temperature was found to influence Cu results by ED (p = 0.036) and UF (p = 0.002) when results were analysed with ANOVA. Relative centrifugal force (2000 g) and time (20 min) interacted to influence Cu (p = 0.006), while individually they did not influence Cu (p = 0.88 and p = 0.42 for RCF and time). Ultrafiltration conditions which yielded the most comparable results to ED were 37 °C, 1000 g for 20 min. Ultrafiltration results greatly depended on analytical conditions, confirming the need to validate the method by comparison with ED in order to correctly interpret DTG Cu.

SUBMITTER: Metsu D

PROVIDER: S-EPMC7378073 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Comparing ultrafiltration and equilibrium dialysis to measure unbound plasma dolutegravir concentrations based on a design of experiment approach.

Metsu David D Lanot Thomas T Fraissinet François F Concordet Didier D Gayrard Véronique V Averseng Manon M Ressault Alice A Martin-Blondel Guillaume G Levade Thierry T Février Frédéric F Chatelut Etienne E Delobel Pierre P Gandia Peggy P

Scientific reports 20200723 1

Dolutegravir therapeutic drug monitoring (TDM) could be improved by measuring the unbound dolutegravir plasma concentration (Cu), particularly in patients experiencing virological failure or toxicity despite achieving appropriate DTG total plasma concentrations. Equilibrium dialysis (ED) is the gold standard to measure Cu, but ED is time consuming, precluding its use in clinical practice. In contrast, ultrafiltration is applicable to TDM, but is sensitive to numerous analytical conditions. In or ...[more]

PMID: 32703975

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Project description:Background and objectivesRapid ultrafiltration rates are associated with adverse outcomes among patients on hemodialysis. The Centers for Medicare and Medicaid Services is considering an ultrafiltration rate quality measure for the ESRD Quality Incentive Program. Two measure developers proposed ultrafiltration rate measures with different selection criteria and specifications. We aimed to compare the proposed ultrafiltration rate measures and quantify dialysis facility operational burden if treatment times were extended to lower ultrafiltration rates.Design, setting, participants, & measurementsData were taken from the 2012 database of a large dialysis organization. Analyses of the Centers for Medicare and Medicaid Services measure considered 148,950 patients on hemodialysis, and analyses of the Kidney Care Quality Alliance measure considered 151,937 patients. We described monthly patient and facility ultrafiltration rates and examined differences in patient characteristics across ultrafiltration rate thresholds and differences in facilities across ultrafiltration rate measure scores. We computed the additional treatment time required to lower ultrafiltration rates <13 ml/h per kilogram.ResultsUltrafiltration rates peaked in winter and nadired in summer. Patients with higher ultrafiltration rates were younger; more likely to be women, nonblack, Hispanic, and lighter in weight; and more likely to have histories of heart failure compared with patients with lower ultrafiltration rates. Facilities had, on average, 20.8%±10.3% (July) to 22.8%±10.6% (February) of patients with ultrafiltration rates >13 ml/h per kilogram by the Centers for Medicare and Medicaid Services monthly measure. Facilities had, on average, 15.8%±8.2% of patients with ultrafiltration rates ≥13 ml/h per kilogram by the Kidney Care Quality Alliance annual measure. Larger facilities (>100 patients) would require, on average, 33 additional treatment hours per week to lower all facility ultrafiltration rates <13 ml/h per kilogram when total treatment time is capped at 4 hours.ConclusionsUltrafiltration rates vary seasonally and across clinical subgroups. Extension of treatment time as a strategy to lower ultrafiltration rates may pose facility operational challenges. Prospective studies of ultrafiltration rate threshold implementation are needed.

Dataset Information

Comparing ultrafiltration and equilibrium dialysis to measure unbound plasma dolutegravir concentrations based on a design of experiment approach.

Publications

Comparing ultrafiltration and equilibrium dialysis to measure unbound plasma dolutegravir concentrations based on a design of experiment approach.

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