Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19
Stephen J. Balevic, Daniel K. Benjamin, William G. Powderly, P. Brian Smith, Daniel Gonzalez, Matthew W. McCarthy, Linda K. Shaw, Christopher J. Lindsell, Sam Bozzette, Daphne Williams, Benjamin P. Linas, John Blamoun, Heta Javeri, Christoph P. Hornik, Mahendra Patel, Arun Sanyal, Jason Green, Huimin Wu, Benjamin Linas, Philip Grant, Vivek Iyer, Otto Yang, Bindu Balani, Sam Parnia, Ryan Dare, Caryn G. Morse, Estelle S. Harris, Glenn Wortmann, Nicholas Hill, Shama Patel, Julia Garcia-Diaz, Suman Thapamager, Megan Devine, Christine M. Bojanowski, Barry Meisenberg, Gailen Marshall, Dima Dandachi, Arick Sabin, Anthony Breemo, Suman Sinha, Christopher Goss, Rebecca Reece, Arlette Aouad, Seth Glassman, Peter Morris, Bela Patel, Fatimah Bello, Juliana Cardozo Fernandes, Oscar Carbajal, Lorena Ravera, Mozar Castro, Miguel Villegas-Chiroque, Fernando Oscar Riera, Adrian Camacho, Claudio Stadnik, Jorge Gave, Rodrigo Biondi, Ronal Gamarra Velarde, Jose Cerbino Neto, Juan Ditondo, Marcelo H. Losso, Mariano Dolz, Alexandra O’Sullivan, Brian Gavin, Maria Beumont-Mauviel, Huyen Ca, Rose Beci, Daniel Molina, Sandhya Rao, Thomas Stock, William Erhardt, Sarah Read, Jessica Springer, Rachel Presti, Ryley Thompson, Kimberly Gray, Cathy Henry, Alem Haile, Michael Klebert, Lisa Kessels, Kathryn Vehe, Kristopher Bakos, Teresa Spitz, Sara Hubert, Raghd Alyatim, Brittany Schneider, Chapelle Ayres, Andrej Spec, Laura Blair, Anita Afghanzada, Natalie Schodl, Lana Wahid, John J. Engemann, Gloria Pinero, Beth McLendon-Arvik, Lynn Whitt, Jenny Shroba, Elizabeth Salsgiver, Candace Alleyne, Anna Gwak, Nicholas Pickell, Jack Spagnoletti, Samson Goh, Katharine Robb, Michael Cenname, Catherine Small, Markus Plate, Rodrigo Burgos, Brenna Lindsey, Fischer Herald, Stephanie Echeverria, Dorendra Lewis, Mahesh Patel, Charles D. Bengtson, Andreas Schmid, Kimberly Lovell, Carly Lovelett, Daniel Soule, Daniel Jaremczuk, Jennie Flanagan, Cameron Murray, Kylie Sands, Kyle Flint, Sara Mohaddes, Caryn Harrington, Kylie Broughal, David Sogoian, Karen Cox, Heta Javeri, Philip O. Ponce, Danielle O. Dixon, Jason E. Bowling, Jan E. Patterson, Barbara S. Taylor, Ruth C. Serrano, Kaylin Sallee, Robin Tragus, Gabriel Catano, Irma Scholler, Rose Ann Barajas, Armando Garcia, Bridgette Soileau, Patricia Heard, Manuel Camilo Endo Carvajal, Rukevwe Ehwarieme, Divya Chandramohan, Alejandro Cabo, Abdelhameed Nawwar, Caroline M. Quill, Nayeem Choudhury, Ashley Arrington, Isaiah Holyfield, Abby Smith, Glenda Brown, Kyle Varner, Joni Baxter, Tracy Roundy, Mary Co, Mireya Wessolossky, Juan Perez-Velazquez, Jennifer Holter-Chakrabarty, Brittany Karfonta, Juvaria Anjum, Jai Marathe, Myriam Castagne, Daniel Mompoint, Ryan Schroeder, Mallika Rao, Johnathan Nguyen, Jake Plewa, Sue Donlinger, Marylynn Breslin, Susan Dodson, Mitch Jenkins, John Williamson, Elizabeth A. Middleton, Mai Tavadze, Romai Sebhatu, Jessica Pierobon, Nate Miller, John Lee, Pratik Doshi, Andrew Dentino, Jessica Martin, Erik Hinojosa, Pablo Torres, Ricardo Sanchez, Gladys Murga, Silvana de la Gala, Jhon Chaiña, Jorge Ramos, Jenny Malca, Kathia Castillo, Johana Calderon Galvez, Maria Lyda Icochea Perez, Claudia Carolina Becerra Nunez, Sandra Betteta Riondato, Sandra Delgado Málaga, Cecilia Barreda Sánchez, Sylvia Sánchez Morales, Myriam Yaringano Palacios, Dora Galarza Cuba, Ivan Hermenegildo, Mayra Falla Benites, Stefania Neyra, Josefina Hernández, Victoria García, Katherine Palacios, Miluska Matos, Fiorella Zuloeta, Fiorella del Carpio, Gloria Chacaltana, Carmen de la Cruz, Felipe Ceriolli Breda, Mauricio Mello Roux Leite, Tobias Milbradt, Luz Rodeles, Nadia Benzaquen, Sebastian Pezzini, Lucila Alberdi, Priscila Serravalle, Giulia Russo, Franco Ferini, Maria Eugenia Guala, Alejandro Crespo, Agostina Benitez, Maria Elena Cristaldi, Paula Di Renzo, Corina Gramagalia, Antonela Tessini, Joana Evelin Alonso, Carmen Pic, Georgina Ceraldi, Azucena Mondino, Iliana Higareda Almaraz, Víctor Hugo Madrigal Robles, María Fernanda Rosas Ismerio, Maria Fernanda Rodarte Rodriguez, Norma Esther Olmos Meza, Norma Esther de la Cruz Barba, Ana Maria Alba Ponce, Juan Manuel Calderon, Eduardo Borsetta, Noemí Sandoval, Daniela Vazquez, Malena Mansilla, Marta Molina, Yamila Jara, Laura De Bona, Maria Eduarda Claus, Arthur Pille, Matías Lahitte, Mariángeles Fenés, Cecilia Bianchi, María Emilia Miserere, Maria Fernanda Alzogaray, Halbert Christian Sanchez Carrillo, Aldana Mano, Myrna Zuain, Javier J. Toibaro, Valeria Pachioli, Sebastián Chaio, Natalia Malamud, David B. Bharucha, Patrick Dorr, Jonathan Sadeh, Sheila Kelly, Marita Stevens, Huyen Cao, Adam DeZure, Kavita Juneja, Mazin Abdelghany, Theresa Jasion, Rachel Olson, Megan Roebuck, Jacqueline Huvane, Christopher J. Lindsell, Jeff Leimberger, Eric Yow, Zhen Huang, Hwasoon Kim, Carla Anderson, Carrie Elliott, Merri Swartz, Jyotsna Garg, Neta Nelson, Divya Kalaria, Ketty Philogene, Tim Schulz, Averie Kuek, Fatou Bah, Jarrard Mitchell, Elizabeth Polo, Michelle Wong, Sharon Baldan, Sandra Mendez, Bradford Stevens, Marcela Toledo, Talita Abba, Emma Herrejon, Cristina Gomez, Georgeta Mardari, Neeraja Putta, Robin Mason, Holli Hamilton, Derek Eisnor, Anna O’Rourke, Aditi Patel, Betty Brody, Anna Chiang, Brian Lind, Lilli M. Portilla, Ami D. Gadhia, Sury Vepa, Emily Carlson Marti, Bobbi Gardner, Joni Rutter, Clare Schmitt, Michael Kurilla,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: