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

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 [Cmax] and area under the serum concentration‐time curve from time zero extrapolated to infinity [AUC0‐INF] were 20% and 25%, respectively). Mean half‐life (T1/2) occurred 7.2 days postinfusion. Belatacept total body clearance was 0.48 mL/h/kg, and volume of distribution at steady‐state (Vss) 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.

Early outcomes comparing induction with antithymocyte globulin vs alemtuzumab in two steroid‐avoidance protocols in pediatric renal transplantation

“…Similarly, only one child underwent conversion to steroid‐inclusive immunosuppression due to assumed inadequate chronic immunosuppression as manifested by a rejection episode in the face of good medication adherence. In the other two converted patients, one had calcineurin inhibitor toxicity and was transitioned to a regimen using belatacept and steroids and the other was the adolescent with severe non‐adherence, AMR, and DSA development.…”

CMV high-risk status and posttransplant outcomes in kidney transplant recipients treated with belatacept

“…Although longer‐term follow‐up and additional studies from other centers are needed, we should consider options for this population as more data emerge. This question is timely as the use of belatacept is increasing, including in pediatric recipients who are more likely to be CMV seronegative 15 . Potential approaches range from (1) avoiding belatacept in CMV high‐risk recipients altogether, (2) initiation of belatacept‐based treatment with conversion to CNI‐based treatment for the estimated 50% who develop CMV viremia either immediately or after failure of first‐line treatment, or (3) initiation of belatacept‐based treatment with a pause in belatacept when viremia develops until viremia is fully controlled.…”

Prediction of Clearance of Monoclonal and Polyclonal Antibodies and Non-Antibody Proteins in Children: Application of Allometric Scaling

“…The values for observed clearance of monoclonal and polyclonal antibodies and non-antibody proteins were obtained from the literature [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ] and the predicted clearance values were compared with the observed values for each drug. In this study, there were 13 monoclonal antibodies, seven polyclonal antibodies, and nine therapeutic proteins (non-antibodies).…”