Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19
Authors: Balevic Stephen J. , Benjamin Daniel K. , Powderly William G. , Smith P. Brian , Gonzalez Daniel , McCarthy Matthew W. , Shaw Linda K. , Lindsell Christopher J. , Bozzette Sam , Williams Daphne , Linas Benjamin P. , Blamoun John , Javeri Heta , Hornik Christoph P. ,   ACTIV-1 IM Study Group, Patel Mahendra , Sanyal Arun , Green Jason , Wu Huimin , Linas Benjamin , Grant Philip , Iyer Vivek , Yang Otto , Balani Bindu , Parnia Sam , Dare Ryan , Morse Caryn G. , Harris Estelle S. , Wortmann Glenn , Hill Nicholas , Patel Shama , Garcia-Diaz Julia , Thapamager Suman , Devine Megan , Bojanowski Christine M. , Meisenberg Barry , Marshall Gailen , Dandachi Dima , Sabin Arick , Breemo Anthony , Sinha Suman , Goss Christopher , Reece Rebecca , Aouad Arlette , Glassman Seth , Morris Peter , Patel Bela , Bello Fatimah , Cardozo Fernandes Juliana , Carbajal Oscar , Ravera Lorena , Castro Mozar , Villegas-Chiroque Miguel , Oscar Riera Fernando , Camacho Adrian , Stadnik Claudio , Gave Jorge , Biondi Rodrigo , Gamarra Velarde Ronal , Cerbino Neto Jose , Ditondo Juan , Losso Marcelo H. , Dolz Mariano , O’Sullivan Alexandra , Gavin Brian , Beumont-Mauviel Maria , Ca Huyen , Beci Rose , Molina Daniel , Rao Sandhya , Stock Thomas , Erhardt William , Read Sarah , Springer Jessica , Presti Rachel , Thompson Ryley , Gray Kimberly , Henry Cathy , Haile Alem , Klebert Michael , Kessels Lisa , Vehe Kathryn , Bakos Kristopher , Spitz Teresa , Hubert Sara , Alyatim Raghd , Schneider Brittany , Ayres Chapelle , Spec Andrej , Blair Laura , Afghanzada Anita , Schodl Natalie , Wahid Lana , Engemann John J. , Pinero Gloria , McLendon-Arvik Beth , Whitt Lynn , Shroba Jenny , Salsgiver Elizabeth , Alleyne Candace , Gwak Anna , Pickell Nicholas , Spagnoletti Jack , Goh Samson , Robb Katharine , Cenname Michael , Small Catherine , Plate Markus , Burgos Rodrigo , Lindsey Brenna , Herald Fischer , Echeverria Stephanie , Lewis Dorendra , Patel Mahesh , Bengtson Charles D. , Schmid Andreas , Lovell Kimberly , Lovelett Carly , Soule Daniel , Jaremczuk Daniel , Flanagan Jennie , Murray Cameron , Sands Kylie , Flint Kyle , Mohaddes Sara , Harrington Caryn , Broughal Kylie , Sogoian David , Cox Karen , Javeri Heta , Ponce Philip O. , Dixon Danielle O. , Bowling Jason E. , Patterson Jan E. , Taylor Barbara S. , Serrano Ruth C. , Sallee Kaylin , Tragus Robin , Catano Gabriel , Scholler Irma , Barajas Rose Ann , Garcia Armando , Soileau Bridgette , Heard Patricia , Camilo Endo Carvajal Manuel , Ehwarieme Rukevwe , Chandramohan Divya , Cabo Alejandro , Nawwar Abdelhameed , Quill Caroline M. , Choudhury Nayeem , Arrington Ashley , Holyfield Isaiah , Smith Abby , Brown Glenda , Varner Kyle , Baxter Joni , Roundy Tracy , Co Mary , Wessolossky Mireya , Perez-Velazquez Juan , Holter-Chakrabarty Jennifer , Karfonta Brittany , Anjum Juvaria , Marathe Jai , Castagne Myriam , Mompoint Daniel , Schroeder Ryan , Rao Mallika , Nguyen Johnathan , Plewa Jake , Donlinger Sue , Breslin Marylynn , Dodson Susan , Jenkins Mitch , Williamson John , Middleton Elizabeth A. , Tavadze Mai , Sebhatu Romai , Pierobon Jessica , Miller Nate , Lee John , Doshi Pratik , Dentino Andrew , Martin Jessica , Hinojosa Erik , Torres Pablo , Sanchez Ricardo , Murga Gladys , de la Gala Silvana , Chaiña Jhon , Ramos Jorge , Malca Jenny , Castillo Kathia , Calderon Galvez Johana , Icochea Perez Maria Lyda , Becerra Nunez Claudia Carolina , Betteta Riondato Sandra , Delgado Málaga Sandra , Barreda Sánchez Cecilia , Sánchez Morales Sylvia , Yaringano Palacios Myriam , Galarza Cuba Dora , Hermenegildo Ivan , Falla Benites Mayra , Neyra Stefania , Hernández Josefina , García Victoria , Palacios Katherine , Matos Miluska , Zuloeta Fiorella , del Carpio Fiorella , Chacaltana Gloria , de la Cruz Carmen , Ceriolli Breda Felipe , Mello Roux Leite Mauricio , Milbradt Tobias , Rodeles Luz , Benzaquen Nadia , Pezzini Sebastian , Alberdi Lucila , Serravalle Priscila , Russo Giulia , Ferini Franco , Guala Maria Eugenia , Crespo Alejandro , Benitez Agostina , Cristaldi Maria Elena , Di Renzo Paula , Gramagalia Corina , Tessini Antonela , Alonso Joana Evelin , Pic Carmen , Ceraldi Georgina , Mondino Azucena , Higareda Almaraz Iliana , Madrigal Robles Víctor Hugo , Rosas Ismerio María Fernanda , Rodarte Rodriguez Maria Fernanda , Olmos Meza Norma Esther , de la Cruz Barba Norma Esther , Alba Ponce Ana Maria , Calderon Juan Manuel , Borsetta Eduardo , Sandoval Noemí , Vazquez Daniela , Mansilla Malena , Molina Marta , Jara Yamila , De Bona Laura , Eduarda Claus Maria , Pille Arthur , Lahitte Matías , Fenés Mariángeles , Bianchi Cecilia , Miserere María Emilia , Alzogaray Maria Fernanda , Christian Sanchez Carrillo Halbert , Mano Aldana , Zuain Myrna , Toibaro Javier J. , Pachioli Valeria , Chaio Sebastián , Malamud Natalia , Bharucha David B. , Dorr Patrick , Sadeh Jonathan , Kelly Sheila , Stevens Marita , Cao Huyen , DeZure Adam , Juneja Kavita , Abdelghany Mazin , Jasion Theresa , Olson Rachel , Roebuck Megan , Huvane Jacqueline , Lindsell Christopher J. , Leimberger Jeff , Yow Eric , Huang Zhen , Kim Hwasoon , Anderson Carla , Elliott Carrie , Swartz Merri , Garg Jyotsna , Nelson Neta , Kalaria Divya , Philogene Ketty , Schulz Tim , Kuek Averie , Bah Fatou , Mitchell Jarrard , Polo Elizabeth , Wong Michelle , Baldan Sharon , Mendez Sandra , Stevens Bradford , Toledo Marcela , Abba Talita , Herrejon Emma , Gomez Cristina , Mardari Georgeta , Putta Neeraja , Mason Robin , Hamilton Holli , Eisnor Derek , O’Rourke Anna , Patel Aditi , Brody Betty , Chiang Anna , Lind Brian , Portilla Lilli M. , Gadhia Ami D. , Vepa Sury , Carlson Marti Emily , Gardner Bobbi , Rutter Joni , Schmitt Clare , Kurilla Michael 
Published: April 2024

ImportanceThe pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown.ObjectiveTo characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments.Design, Setting, and ParticipantsThis 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.ExposureSingle intravenous infusion of abatacept (10 mg/kg with a maximum dose of 1000 mg).Main Outcomes and MeasuresMortality 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.ResultsOf 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 &amp;lt; .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 &amp;lt; .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 &amp;lt; .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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT04593940