Phase I study of single-dose pharmacokinetics and pharmacodynamics of belatacept in adolescent kidney transplant recipients

• Type of Material: Article
• Authors: Asha Moudgil, Children's National Medical Center; Vikas R. Dharnidharka, Washington University; Daniel I. Feig, University of Alabama; Barry Warshaw, Emory University; Vidya Perera, Bristol-Myers Squibb; Bindu Murthy, Bristol-Myers Squibb; Mustimbo Roberts, Bristol-Myers Squibb; Martin S. Polinsky, Bristol-Myers Squibb; Robert B. Ettenger, University of California Los Angeles
• Language: English
• Date: 2019-04-01
• Publisher: Wiley: 12 months
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/ajt.15236
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 19
• Issue: 4
• Start Page: 1218
• End Page: 1223
• Grant/Funding Information: Robert B. Ettenger has received grant support from Bristol‐Myers Squibb, Veloxis, and Novartis, and a travel grant from Novartis.; Support for third‐party writing assistance for this manuscript was provided by Tiffany DeSimone, PhD, of CodonMedical, an Ashfield Company, part of UDG Healthcare plc, and was funded by Bristol‐Myers Squibb.; Daniel I. Feig has received research funding from Bristol‐Myers Squibb and Relypsa.; Asha Moudgil has received research funding from Bristol‐Myers Squibb.; This study was funded by Bristol‐Myers Squibb.; Vikas R. Dharnidharka has received consulting fees from Bristol‐Myers Squibb and Atara Biotherapeutics and grant support from Bristol‐Myers Squibb.; Barry L. Warshaw has received research funding from Bristol‐Myers Squibb.
• Keywords: Life Sciences & Biomedicine; nephrology; simulation; kidney transplantation; pharmacokinetics; SAFETY; CALCINEURIN INHIBITOR; OUTCOMES; SURVIVAL; living donor; pharmacodynamics; Transplantation; immunosuppressant - fusion proteins and monoclonal antibodies; CHILDREN; clinical research; belatacept; REGIMEN; Surgery; Science & Technology; CYCLOSPORINE; AGE; practice
• Research Categories: Health Sciences, General; Health Sciences, Medicine and Surgery

Abstract

Belatacept is an intravenously infused selective T cell costimulation blocker approved for preventing organ rejection in renal transplant recipients aged ≥18 years. This phase I trial examined the pharmacokinetics and pharmacodynamics (percentage CD86 receptor occupancy [%CD86RO]) of a single dose of belatacept (7.5 mg/kg) administered to kidney transplant recipients aged 12-17 years receiving a stable calcineurin inhibitor–based immunosuppressive regimen. Nine adolescents (mean age 15.1 years) who were seropositive for Epstein-Barr virus were enrolled; all completed the 6-month study. Pharmacokinetics suggested relatively low variability of exposure (coefficients of variation for maximum observed serum concentration [C max ] and area under the serum concentration-time curve from time zero extrapolated to infinity [AUC 0-INF ] were 20% and 25%, respectively). Mean half-life (T 1/2 ) occurred 7.2 days postinfusion. Belatacept total body clearance was 0.48 mL/h/kg, and volume of distribution at steady-state (V ss ) was low at 0.09 L/kg. Compared with historical data from healthy adult volunteers administered a single dose of belatacept 10 mg/kg and adult kidney transplant recipients administered multiple doses of belatacept 5 mg/kg, pharmacokinetic values for adolescents were similar, indicating consistency across adolescent and adult populations. Mean %CD86RO increased with increasing belatacept concentration, indicating a direct relationship between pharmacokinetics and pharmacodynamics. Four patients reported 7 serious adverse events; none was considered related to belatacept. These data will inform belatacept dose selection in future studies of adolescent kidney transplant recipients.