Relationship Between Antithymocyte Globulin Concentrations and Lymphocyte Sub-Populations in Kidney Transplant Patients.

BACKGROUND

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.

METHODS

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.

RESULTS

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 CD3CD56 cell counts over time were described by a pharmacokinetic-pharmacodynamic model with transit compartments, integrating both CD3CD56-independent and CD3CD56-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 CD3CD56-mediated elimination was influenced by the V158F-FCGR3A polymorphism. Binary efficacy and tolerance endpoints were defined as a CD3 count < 20 mm for at least 7 days and a CD4 count > 200 mm 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.

CONCLUSIONS

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.