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Randomized Controlled Trial
. 2024 Apr 1;7(4):e247615.
doi: 10.1001/jamanetworkopen.2024.7615.

Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19: A Secondary Analysis of the ACTIV-1 IM Randomized Clinical Trial

Stephen J Balevic  1   2 , Daniel K Benjamin Jr  1   2 , William G Powderly  3 , P Brian Smith  1   2 , Daniel Gonzalez  1 , Matthew W McCarthy  4 , Linda K Shaw  1 , Christopher J Lindsell  1 , Sam Bozzette  5 , Daphne Williams  6 , Benjamin P Linas  7 , John Blamoun  8 , Heta Javeri  9 , Christoph P Hornik  1   2 ; ACTIV-1 IM Study Group
Collaborators, Affiliations
Randomized Controlled Trial

Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19: A Secondary Analysis of the ACTIV-1 IM Randomized Clinical Trial

Stephen J Balevic et al. JAMA Netw Open. .

Abstract

Importance: The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown.

Objective: To characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments.

Design, setting, and participants: This study is a secondary analysis of data from the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) randomized clinical trial conducted between October 16, 2020, and December 31, 2021. The trial included hospitalized adults who received abatacept in addition to standard of care for treatment of COVID-19 pneumonia. Data analysis was performed between September 2022 and February 2024.

Exposure: Single intravenous infusion of abatacept (10 mg/kg with a maximum dose of 1000 mg).

Main outcomes and measures: Mortality at day 28 was the primary outcome of interest, and time to recovery at day 28 was the secondary outcome. Drug exposure was assessed using the projected area under the serum concentration time curve over 28 days (AUC0-28). Logistic regression modeling was used to analyze the association between drug exposure and 28-day mortality, adjusted for age, sex, and disease severity. The association between time to recovery and abatacept exposure was examined using Fine-Gray modeling with death as a competing risk, and was adjusted for age, sex, and disease severity.

Results: Of the 509 patients who received abatacept, 395 patients with 848 serum samples were included in the population pharmacokinetic analysis. Their median age was 55 (range, 19-89) years and most (250 [63.3%]) were men. Abatacept clearance increased with body weight and more severe disease activity at baseline. Drug exposure was higher in patients who survived vs those who died, with a median AUC0-28 of 21 428 (range, 8462-43 378) mg × h/L vs 18 262 (range, 9628-27 507) mg × h/L (P < .001). Controlling for age, sex, and disease severity, an increase of 5000 units in AUC0-28 was associated with lower odds of mortality at day 28 (OR, 0.52 [95% CI, 0.35-0.79]; P = .002). For an AUC0-28 of 19 400 mg × h/L or less, there was a higher probability of recovery at day 28 (hazard ratio, 2.63 [95% CI, 1.70-4.08] for every 5000-unit increase; P < .001). Controlling for age, sex, and disease severity, every 5000-unit increase in AUC0-28 was also associated with lower odds of a composite safety event at 28 days (OR, 0.46 [95% CI, 0.33-0.63]; P < .001). Using the dosing regimen studied in the ACTIV-1 IM trial, 121 of the 395 patients (30.6%) would not achieve an abatacept exposure of at least 19 400 mg × h/L, particularly at the extremes of body weight. Using a modified, higher-dose regimen, only 12 patients (3.0%) would not achieve the hypothesized target abatacept exposure.

Conclusions and relevance: In this study, patients who were hospitalized with severe COVID-19 and achieved higher projected abatacept exposure had reduced mortality and a higher probability of recovery with fewer safety events. However, abatacept clearance was high in this population, and the current abatacept dosing (10 mg/kg intravenously with a maximum of 1000 mg) may not achieve optimal exposure in all patients.

Trial registration: ClinicalTrials.gov Identifier: NCT04593940.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Balevic reported receiving grants from the National Institutes of Health (NIH), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA), and the National Center for Advancing Translational Sciences (NCATS) paid to the Duke Clinical Research Institute during the conduct of the study. In addition, Dr Balevic reported receiving personal fees from UCB and Rutgers University outside the submitted work; receiving grants from the Childhood Arthritis and Rheumatology Research Alliance, Purdue Pharma, and the Patient-Centered Outcomes Research Institute outside the submitted work; and serving as a data and safety monitoring board member for NIAMS and as an interpersonnel agent for the US Food and Drug Administration Office of Pediatric Therapeutics outside the submitted work. Dr Benjamin reported receiving consulting fees from AbbVie Pharmaceuticals, PPD, and Syneos Health outside the submitted work. Dr Powderly reported receiving personal fees from Merck for HIV research advisory board service outside the submitted work. Dr Smith reported serving on an advisory committee for Syneos Health and receiving consulting fees from Biocryst, Provepharm, UCB, and Tellus outside the submitted work. Dr Lindsell reported receiving grants (paid to Duke Clinical Research Institute) from the NIH during the conduct of the study. In addition, Dr Lindsell reported receiving grants or support (paid to the institution) from the NIH, the US Department of Defense, the Centers for Disease Control and Prevention, Entegrion, Endpoint Health, AstraZeneca, Cytokinetics, Biomeme, Novartis, Emory University, Vanderbilt University, bioMerieux, and Rocket Pharmaceuticals for research services outside the submitted work. Dr Lindsell also reported holding a patent for risk prediction in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center and holding stock options in Bioscape Digital unrelated to the submitted work. Dr Linas reported receiving grants from NCATS during the conduct of the study. Dr Hornik reported receiving personal fees from Lightship, UCB, and SC Pharma outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Abatacept Exposure and Mortality at 28 Days
The solid line in each box plot represents the median; the diamond represents the mean. Open circles represent data beyond 1.5 times the IQR; P < .001. AUC0-28 indicates the area under the serum concentration time curve over 28 days. Not all outlier data points can be seen owing to overlapping symbols.
Figure 2.
Figure 2.. Abatacept Exposure and Safety
The solid line in each box plot represents the median; the diamond represents the mean. Open circles represent data beyond 1.5 times the IQR; P < .001. AUC0-28 indicates the area under the serum concentration time curve over 28 days. Not all outlier data points can be seen owing to overlapping symbols.
See this image and copyright information in PMC

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