2/11/14. Introduction: Challenges in pediatric HCT. Introduction: ATG (Thymoglobulin )

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1 /11/1 Population pharmacokinetics of antithymocyte globulin (ATG) in children receiving allogeneic-hematopoietic cell transplantation: towards individualized dosing to improve survival Rick Admiraal, MD PhD-student University Medical Center Utrecht Leiden University Medical Center Leiden Academic Center for Drug Research The Netherlands Introduction: Challenges in pediatric HCT Reducing the toxicity of HCT: Short term toxicity Long term toxicity Improving efficacy Better disease control Balancing optimal disease control and reduced toxicity Introduction: ATG (Thymoglobulin ) In vivo lymphodepletion Thymoglobulin (anti-thymocyte globulin, ATG) Different brands ATG; horse or rabbit derived Polyclonal rabbit derived IgG antibody Very broad range of targets T-lymphocytes Other lymphocytes Epithelium etc. ~9% of ATG directed against human targets (active ATG) 1

2 /11/1 Introduction: ATG (Thymoglobulin ) Critical therapeutic window: Underdosing GvHD Rejection Overdosing Delayed immune reconstitution, infection More relapse (ê Graft vs Leukemia) Pediatric UCB transplants No ATG Early ATG (day -9 to -) Late ATG (day - to ) Introduction: outcome Comparable EFS/OS a a a a. Lindemans et al Blood 1 b. Jol et al BMT 9 b Introduction: PK/PD DOSE Drug Concentration Efficacy Safety Pharmaco kinetics Pharmaco aco dynamics Dose is o'en a poor descriptor of response

3 /11/1 Project aim Describing the pharmacokinetics of active Thymoglobulin in pediatric HCT Explore the influence of weight and other factors on PK First step in development of individualized dosing regimen Evaluate current dosing regimen of Thymoglobulin Learning Objective Describe the effect of weight on the pharmacokinetics of active Thymoglobulin Methods Patients treated from to 1 at two pediatric SCT-units in the Netherlands Serum active Thymoglobulin concentrations quantified by flow cytometry Population pharmacokinetic (PK) modelling (NONMEM) Population mean Between patient variability Covariates influencing variability Model validation with advanced methods (bootstrap, NPDE) Simulations 3

4 /11/1 Results: patient characteristics Leiden Utrecht Total Number3of3patients3(n) Number3of3HCTs3(n) Male3sex3(%) Age3(years) 6.3(.7L1).93(1.7L13.9) 6.3(.3L1.6) Weight3(kg) 13(13L38) 3(1L6) 13(13L) Number3of3samples3[n3(mean3per3patient)] 33(1) 7613(6) 31133(11) Starting3day3ATG3(days3before3transplantation) 3(L6) 3(L7) 3(L6) Diagnosis((%) Malignancy 6 Immune-deficiency Bone-marrow-failure 1 6 Metabolic-disease 1 9 Benign-hematology Auto9immune-disease 1 Stem(cell(source((%) Bone-marrow Peripheral-blood-stem-cells 3 1 Cordblood Cordblood-plus-haplo-or-nd-cordblood 6 Leucocyte3count3before3conditioning3(x31^9) 3.73(.3L.7).3(.7L7.1) 3(.3L6.) Lymfocyte3count3before3conditioning3(x31^9).883(.9L.1).873(.6L.71).873(.8L.) Shown3as3median3(interquartile3range)3unless3otherwise3specified Results: PK-model 1 Dose MAX Central volume of distribution Body weight Peripheral volume of distribution MAX Body weight Baseline lymphocytes Results: PK-model Ln Concentration active Thymoglobulin (AU/ml) 1 1 Tm (Intercompartmental distribution) Km (Clearance) 1 1

5 /11/1 Results: Model performance 1 Body weight = 9kg Concentrations/predictions Body weight = 1kg Body weight = 36kg Results: Model performance years old >1. years old <. years old. 6. years old Current dosing regimen Cumulative 1 mg/kg Thymoglobulin over days Simulations Higher exposure with higher weight! kg Concentration active Thymoglobulin (AU/ml) kg kg

6 1,,8,6,,, /11/1 Audience Response Question A cumulative dose of 1mg/kg Thymoglobulin over days, the current dosing regimen, leads to a constant exposure in all age groups A) True B) False Conclusions A model was developed and validated, describing active Thymoglobulin pharmacokinetics, yielding accurate predictions Weight and baseline lymphocytes important factors influencing the PK Current dosing regimen results in increasing exposure with higher weight First step in developing an individualized dosing regimen Perspectives Pharmacokinetic-pharmacodynamic (concentrationeffect) relationship needs to be explored Development of a dosing regimen to reach optimal exposure Cumulative Overall Survival OS according to active Thymoglobulin exposure post-hct Low post- transplant exposure 79% (±7%) 61% (±%) High post- transplant exposure Multivariate predictors for worse overall survival: Post-HCT AUC >, p=. Mismatched donor, p=.1 Malignancy, p=.7 Log- rank p=.6 Survival (days) 6

7 /11/1 Acknowledgements University Medical Center Utrecht Jaap Jan Boelens Marc Bierings Toine Egberts Leiden University Medical Center Robbert Bredius Maarten van Tol Els Jol Arjan Lankester Anja Janssen Leiden Academic Center for Drug Research Catherijne Knibbe Charlotte van Kesteren Mijndert Danhof ZonMW scholarship 7