Correspondence Antithymocyte globulin: Importance of good clinical pharmacological practice To the Editor: Antithymocyte globulin (ATG) is a polyclonal antibody widely used in hematopoietic cell transplantations (HCTs). Despite the fact that it has been used for more than 30 years, knowledge on its clinical pharmacology is still limited. The potentially lifethreatening risks of a suboptimal dose of ATG (too high or too low) are increasingly recognized. ATG has a crucial role in timely immune reconstitution, which predicts survival chances.1-5 Thorough studies are therefore of utmost importance to improve survival chances after HCT. In a recent report, Bouazza et al1 not only describe rabbit-ATG pharmacokinetics (PK) but also attempted to integrate the PK with pharmacodynamics (PD) in terms of lymphocyte counts over time. We appreciate the suggested integrated PK-PD model, but we have serious concerns regarding the methods and the conclusions drawn from this article. Several aspects of the study design and limited details on data, methods, and results raise various questions. The data set is too small in number (patients and samples) as well as in variety to derive the firmly drawn conclusions, especially regarding the suggested therapeutic target and a proposal for a dosing regimen for future pediatric patients undergoing HCT. The small cohort may induce model misspecification and fail to identify interpatient variability and potential covariates. Furthermore, the developed models are not validated, which is essential before deriving a new recommended dose. Moreover, technical issues need to be addressed. The parameterization of the PK model is unclear. Volume of distribution does not seem to be estimated, and thus no covariate relationships with volume were investigated. In almost all pediatric PK models, body weight is recognized as a predictor for volume. The authors should have addressed this in modeling their cohort with a weight range of 6.3 to 50 kg.3 Based on the mode of action of ATG, it is expected that absolute lymphocyte count before administration of ATG affects the clearance of ATG as recently described.3 Bouazza et al1 include this phenomenon in the PD part of their model, but the values for the relative standard error (0%) associated with these parameters (KTCbound and KTCfree) suggest identifiability problems for this part of the model. To define the therapeutic target, the authors solely used complete lymphocyte depletion as the PD end point. ATG is,
however, also used in the prevention of graft-versus-host disease and this should therefore be an end point as well. The same holds for immune reconstitution: too high exposure to ATG after HCT is negatively associated with survival and should be taken into account when suggesting a new dosing regimen. Not including those aspects is a crucial omission. Finally, previous studies have demonstrated that ATG exposure before and after HCT needs to be taken into account,4 which is a physiologically understandable finding given the mode of action of ATG. The report fails to provide any detail on this matter as well. Taken together, integrated PK-PD modeling on ATG is urgently needed to increase survival chances for patients undergoing HCT. Proper dosing advice, however, should be given only after thorough validation of population-PK-PD models to be good clinical pharmacological practice. Rick Admiraal, MDa,b Charlotte van Kesteren, PharmD, PhDa,b Stefan Nierkens, PhDb,c Jaap Jan Boelens, MD, PhDa,b From athe Blood and Marrow Transplantation Program, bU-DANCE, Lab Translational Immunology, and cU-DAIR, Lab Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. E-mail:
[email protected]. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Bouazza N, Urien S, Neven B, Moshous D, Nisoy J, Gabrion A, et al. Evaluation of antithymocyte globulin pharmacokinetics and pharmacodynamics in children. J Allergy Clin Immunol 2016;137:306-9.e4. 2. Lindemans CA, Chiesa R, Amrolia PJ, Rao K, Nikolajeva O, de Wildt A, et al. Impact of thymoglobulin prior to pediatric unrelated umbilical cord blood transplantation on immune reconstitution and clinical outcome. Blood 2014;123: 126-32. 3. Admiraal R, van Kesteren C, Jol-van der Zijde CCM, van Tol MM, Bartelink II, Bredius RR, et al. Population pharmacokinetic modeling of Thymoglobulin! in children receiving allogeneic-hematopoietic cell transplantation (HCT): towards improved survival through individualized dosing. Clin Pharmacokinet 2014;54: 435-46. 4. Admiraal R, van Kesteren C, Jol-van Der Zijde CM, Lankester AC, Bierings MB, Egberts TC, et al. Association between anti-thymocyte globulin exposure and CD41 immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol 2015;3026:8-11. 5. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia 2007;21:1387-94. http://dx.doi.org/10.1016/j.jaci.2016.02.036
1
