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Clinical Drug Investigation
Published in: Clinical Drug Investigation 2/2014

Open Access 01-02-2014 | Original Research Article

Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Belatacept in Adult Kidney Transplant Recipients

Authors: Jinshan Shen, Robert Townsend, Xiaoli You, Yun Shen, Ping Zhan, Zexun Zhou, Dong Geng, Dianna Wu, Nadia McGirr, Kathleen Soucek, Elizabeth Proszynski, Janice Pursley, Eric Masson

Published in: Clinical Drug Investigation | Issue 2/2014

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Abstract

Background and Objectives

Belatacept is a first-in-class, selective co-stimulation blocker recently approved for the prophylaxis of organ rejection in adult kidney transplant recipients. The objective of this study was to report the pharmacokinetics, pharmacodynamics, and immunogenicity of belatacept.

Methods

The pharmacokinetics, pharmacodynamics (CD86 receptor occupancy), and immunogenicity of belatacept were studied in de novo adult kidney transplant recipients in phase II and III clinical studies.

Results

Following multiple doses of 5 or 10 mg/kg, the geometric mean (percentage coefficient of variation) maximum serum concentration and area under the serum concentration–time curve over one dosing interval of belatacept were 136 (20 %) and 238 (27 %) μg/mL, and 13,587 (27 %) and 21,241 (35 %) μg·h/mL, respectively. The median belatacept elimination half-life was 8–9 days. Belatacept exhibited concentration-dependent binding to CD86 receptors. The pre-dose CD86 receptor occupancy by belatacept decreased from 94 to 65 % between day 5 and 1 year post-transplant, with corresponding pre-dose trough serum concentrations of belatacept decreasing from ~35 to 4 μg/mL during this period. The cumulative incidence of developing anti-belatacept antibodies was 5.3 % up to 3 years post-transplant and had no impact on belatacept exposure.

Conclusions

Belatacept in adult kidney transplant demonstrated linear pharmacokinetics with low variability, concentration-dependent pharmacodynamics, and a low incidence of anti-drug antibodies.
Literature
1.
Meier-Kriesche HU, Schold JD, Srinivas TR, et al. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004;4(3):378–83.PubMedCrossRef
2.
Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351(26):2715–29.PubMedCrossRef
3.
Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin J Am Soc Nephrol. 2007;2(2):374–84.PubMedCrossRef
4.
Nujolix® (belatacept) [package insert]. Princeton: Bristol-Myers Squibb Co.; 2013.
5.
Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant. 2005;5(3):443–53.PubMedCrossRef
6.
Latek R, Fleener C, Lamian V, et al. Assessment of belatacept-mediated costimulation blockade through evaluation of CD80/86-receptor saturation. Transplantation. 2009;87(6):926–33.PubMedCrossRef
7.
Paweletz C, Andersen JN, Pollock R, et al. Identification of direct target engagement biomarkers for kinase-targeted therapeutics. PLoS One. 2011;6(10):e26459.PubMedCentralPubMedCrossRef
8.
Valencia X. An open-label pharmacokinetic study in de novo renal transplant subjects receiving a belatacept-based immunosuppressant regimen. Princeton: Bristol-Myers Squibb; 2009. (Data on file).
9.
Ferguson R, Grinyo J, Vincenti F, et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant. 2011;11(1):66–76.PubMedCrossRef
10.
Johnson A. Open-label, randomized, controlled, multiple-dose study of efficacy and safety of BMS-224818 as part of a quadruple drug regimen in renal transplant recipients (pharmacokinetic sub-study). Princeton: Bristol-Myers Squibb; 2008. (Data on file).
11.
Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010;10(3):535–46.PubMedCrossRef
12.
Larsen C, Grinyo J, Medina-Pestana J, et al. Belatacept-based regimens vs a cyclosporine-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation. 2010;90(12):1528–35.PubMedCrossRef
13.
Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant. 2010;10(3):547–57.PubMedCrossRef
14.
Vincenti F, Blancho G, Durrbach A, et al. Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol. 2010;21(9):1587–96.PubMedCrossRef
15.
Neoral® Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED; Neoral® Oral Solution (cyclosporine oral solution, USP) MODIFIED [package insert]. Basel: Novartis International AG; 2012.
16.
Myler H, Phillips KR, Dong H, et al. Validation and life-cycle management of a quantitative ligand-binding assay for the measurement of Nulojix®, a CTLA-4-Fc fusion protein, in renal and liver transplant patients. Bioanalysis. 2012;4(10):1215–26.PubMedCrossRef
17.
Zhou Z, Shen J, Hong Y, et al. Time-varying belatacept exposure and its relationship to efficacy/safety responses in kidney-transplant recipients. Clin Pharmacol Ther. 2012;92(2):251–7.PubMedCrossRef
18.
Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005;353(8):770–81.PubMedCrossRef
19.
Shen J, Townsend R, Kaul S. An integrated approach to develop belatacept dosing regimens for phase 3 studies in renal transplant subjects [abstract no. OII-A-4]. Clin Pharmacol Ther. 2011;89(Suppl 1):S37.
20.
Grinyo J, Charpentier B, Pestana JM, et al. An integrated safety profile analysis of belatacept in kidney transplant recipients. Transplantation. 2010;90(12):1521–7.PubMedCrossRef
21.
Wadhwa M, Thorpe R. Unwanted immunogenicity: lessons learned and future challenges. Bioanalysis. 2010;2(6):1073–84.PubMedCrossRef
22.
Kuypers DR. Immunotherapy in elderly transplant recipients: a guide to clinically significant drug interactions. Drugs Aging. 2009;26(9):715–37.PubMedCrossRef
23.
Seitz K, Zhou H. Pharmacokinetic drug–drug interaction potentials for therapeutic monoclonal antibodies: reality check. J Clin Pharmacol. 2007;47:1104–18.PubMedCrossRef
24.
Lee J-I, et al. CYP-mediated therapeutic protein–drug interactions. Clin Pharmacokinet. 2010;49(5):295–310.PubMedCrossRef
Metadata
Title
Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Belatacept in Adult Kidney Transplant Recipients
Authors
Jinshan Shen
Robert Townsend
Xiaoli You
Yun Shen
Ping Zhan
Zexun Zhou
Dong Geng
Dianna Wu
Nadia McGirr
Kathleen Soucek
Elizabeth Proszynski
Janice Pursley
Eric Masson
Publication date
01-02-2014
Publisher
Springer International Publishing
Published in
Clinical Drug Investigation / Issue 2/2014
Print ISSN: 1173-2563
Electronic ISSN: 1179-1918
DOI
https://doi.org/10.1007/s40261-013-0153-2

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