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Detection of erythropoiesis stimulating agent Luspatercept after administration to healthy volunteers for antidoping purposes.

ABSTRACT: Luspatercept (Reblozyl®) is a newly approved anti-anemic drug prohibited by the World Anti-Doping Agency. It promotes erythropoiesis by limiting apoptosis of immature erythroblasts and the risk of misuse by athletes for doping is high. Proposed detection methods have been published recently but only evaluated in vitro. The objective of this study was to perform the first administration of luspatercept in healthy volunteers for antidoping purpose and to evaluate the detectability in serum, dried capillary blood spots (DBS, collected using TASSO M20 device), and urine. Indirect detection was also evaluated by analyzing hematological parameters for the Athlete Biological Passport. Four volunteers (two males, two females) received one subtherapeutic dose of luspatercept (0.25 mg/kg) followed 3 weeks after by a second dose. Samples were collected from before administration until 7 weeks after the second dose. After immunopurification, electrophoretic separation SDS-/SAR-/IEF- polyacrylamide gel electrophoresis (PAGE), and immunodetection, luspatercept was detected at high levels in serum until the end of the collection, sign of a very slow elimination and similarly detected unchanged at lower levels in urine from 2 days after the first administration until 7 weeks postadministration. DBS showed also the same long window of detection. Luspatercept effects were however of limited amplitude on hematological markers, and only two subjects presented atypical points outside the physiological limits during the study. The direct detection method was very efficient, and change of electrophoretic method and detection antibody can be used for confirmation of suspicious samples.

SUBMITTER: Marchand A

PROVIDER: S-EPMC10084338 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Detection of erythropoiesis stimulating agent Luspatercept after administration to healthy volunteers for antidoping purposes.

Marchand Alexandre A Miller Geoff G Martin Laurent L Gobbo Coralie C Crouch Andre K AK Eichner Daniel D Ericsson Magnus M

Drug testing and analysis 20220707 11-12

Luspatercept (Reblozyl®) is a newly approved anti-anemic drug prohibited by the World Anti-Doping Agency. It promotes erythropoiesis by limiting apoptosis of immature erythroblasts and the risk of misuse by athletes for doping is high. Proposed detection methods have been published recently but only evaluated in vitro. The objective of this study was to perform the first administration of luspatercept in healthy volunteers for antidoping purpose and to evaluate the detectability in serum, dried ...[more]

PMID: 35789123

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Project description:Rationale & objectiveSince the change in erythropoiesis-stimulating agent (ESA) labeling and bundling of dialysis services in the United States, few studies have addressed the clinical importance of ESA hyporesponsiveness and none have considered health care resource use in this population. We aimed to further explore ESA hyporesponsiveness and its consequences.Study designRetrospective observational cohort study.Setting & participantsUS Renal Data System Medicare participants receiving dialysis with a minimum 6 months of continuous ESA use from 2012 to 2014.PredictorsErythropoietin resistance index (≥2.0 U/kg/wk/g/L) and ESA dose were used to identify ESA hyporesponders and hyporesponsive subgroups: isolated, intermittent, and chronic.OutcomesAssociations between ESA responsiveness and mortality, cardiovascular hospitalization rates, and health care resource use were evaluated and compared across subgroups.Analytical approachBaseline characteristics were compared using Wilcoxon rank sum tests for continuous variables and χ2 tests for categorical variables. Incidence rates of health care resource use were modeled using an unadjusted and adjusted generalized linear model.ResultsOf 834,115 dialysis patients in the CROWNWeb database, 38,891 ESA hyporesponders and 59,412 normoresponders met all inclusion criteria. Compared with normoresponders, hyporesponders were younger women, weighed less, and had longer durations of dialysis (all P < 0.001). Hyporesponders received 3.8-fold higher ESA doses (mean, 94,831 U/mo) and erythropoietin resistance index was almost 5 times higher than in normoresponders. Hyporesponders had lower hemoglobin levels and parathyroid hormone levels > 800 pg/mL, and iron deficiency was present in 26.5% versus 10.9% in normoresponders. One-year mortality was higher among hypo- compared with normoresponders (25.3% vs 22.6%). Hyporesponders also had significantly higher rates of hospitalization for cardiovascular events, emergency department visits, inpatient stays, home health agency visits, skilled nursing facility, and hospice days.LimitationsOnly US Medicare patients were included and different hyporesponder definitions may have influenced the results.ConclusionsThis study explored ESA hyporesponsiveness using new definitions and incorporated clinical and economic outcomes. It established that ESA-hyporesponsive dialysis patients had higher mortality, cardiovascular hospitalization rates, and health care costs as compared with ESA-normoresponsive patients.

Dataset Information

Detection of erythropoiesis stimulating agent Luspatercept after administration to healthy volunteers for antidoping purposes.

Publications

Detection of erythropoiesis stimulating agent Luspatercept after administration to healthy volunteers for antidoping purposes.

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