Rabbit antithymocyte globulins (rATGs) are polyclonal antibodies used to prevent acute cellular rejection in kidney transplantation. Their dosing remains largely empirical and the question of an individualized dose is still unresolved.
Data from a prospective study in 17 kidney transplant patients were used to develop a model describing the dose–concentration–response relationship of rATG with T-lymphocyte subpopulation counts over time. The model was validated using an independent cohort of kidney transplant patients treated by rATG in the same center.
Pharmacokinetics of rATG was described using a two-compartment model integrating a third compartment and a target-mediated elimination for active rATG. The kinetics of CD3+, CD4+, CD8+, and CD3−CD56+ cell counts over time were described by a pharmacokinetic-pharmacodynamic model with transit compartments, integrating both CD3−CD56+-independent and CD3−CD56+-dependent rATG-mediated lymphocyte depletion, and a positive feedback. Elimination of rATG was influenced by age and body surface area, while its distribution was also influenced by body surface area. CD3+ proliferation rate decreased with age and CD3−CD56+-mediated elimination was influenced by the V158F-FCGR3A polymorphism. Binary efficacy and tolerance endpoints were defined as a CD3+ count < 20 mm–3 for at least 7 days and a CD4+ count > 200 mm–3 at 1 year, respectively. Simulations showed that increasing or decreasing the standard 6-mg/kg dose will impact both tolerance and efficacy, while a dose decrease may be beneficial in elderly patients.
Our results can be used to design prospective clinical trials testing dose individualization based on patients’ characteristics.
Clinical Trial Registration
Eudract No. 2009-012673-35.
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The authors thank Djamila Lemay and Crystal Sung from Genzyme for the rATG concentration measurements.
The study was sponsored by Tours University Hospital and benefited from a grant from Genzyme (Sanofi). This work was partly supported by the French Higher Education and Research Ministry under the program ‘Investissements d’avenir’ Grant Agreement: LabEx MAbImprove ANR-10-LABX-53-01.
Conflicts of Interest/Competing Interests
Nicolas Azzopardi, Hélène Longuet, Gilles Thibault, Valérie Gouilleux-Gruart, Yvon Lebranchu, Matthias Büchler, and Philippe Gatault have no conflicts of interest that are directly relevant to the content of this article. David Ternant has given lectures for Amgen, Sanofi, Novartis, and Boehringer-Inghelheim, outside of the submitted work. Gilles Paintaud reports research grants from Amgen, Chugai, Lilly, Merck, Novartis, Shire (Takeda,) and Roche Pharma, outside of the submitted work.
The protocol was approved by the local ethics committee.
Consent to participate
Written informed consent was obtained from all patients.
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The code is available on request to the corresponding author.
Availability of data and material
Data and material are available on request to the corresponding author.
NA analyzed the data, performed the research and wrote the manuscript. HL included patients and collected and analyzed the data. DT analyzed the data and reviewed the research. GT produced and interpreted data and reviewed the research. VGG produced and interpreted the data. YL designed the research and included patients. MB included patients and reviewed the research. PG analyzed the data, designed and reviewed the research, and wrote the manuscript. GP designed the research, analyzed the data, reviewed the research, and wrote the manuscript. All authors reviewed the final version of the manuscript.
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Azzopardi, N., Longuet, H., Ternant, D. et al. Relationship Between Antithymocyte Globulin Concentrations and Lymphocyte Sub-Populations in Kidney Transplant Patients. Clin Pharmacokinet (2021). https://doi.org/10.1007/s40262-021-01053-7