Background: Anti-Thymocyte Globulin (ATG) is a polyclonal antibody used as an immunosuppressant to prevent graft-versus-host-disease in haematopoietic stem cell transplantation. While recent studies have worked toward understanding the pharmacokinetic-pharmacodynamic relationship via population pharmacokinetic modelling, dosing remains weight-based and largely empirical in clinical practice.
Aims: To evaluate current ATG dosing regimens and improve pharmacokinetic target attainment by utilising therapeutic drug monitoring.
Methods: Conventional and novel ATG regimens were examined using Monte Carlo simulation with an existing population pharmacokinetic model and an in-silico population of 10,000 representative patients. Individualised ATG dosing regimens were simulated with sparse sampling, empirical Bayesian estimation of pharmacokinetic parameters, and a dose optimisation function. Post-transplant AUC and probability of target attainment was determined for each regimen.
Results: No conventional ATG dosing regimen was able to dose >25% of individuals within the defined target range of 60-95AU.day/mL. Model-based dose optimisation was only able to improve target attainment by up to 9%. In all cases, pharmacokinetic parameter estimation was poor, with ETA shrinkage of >30% noted on three of the five variable pharmacokinetic parameters influencing ATG elimination.
Conclusions: Wide inter-individual variability of ATG leads to universally poor target attainment with current weight-based dosing regimens. Improving attainment by means of Bayesian estimation and dose optimisation leads to minor improvements only and is unlikely to be of clinical benefit in stem cell transplant recipients. Further research into factors influencing the pharmacokinetic parameters of ATG is required to allow for dose individualisation and optimisation.
Keywords: Anti-thymocyte Globulin, haematological malignancy, dose optimisation, population pharmacokinetics