K. Abduljalil, T.N. Johnson, M. Jamei1, D. Edwards, A. Rostami-Hodjegan
Simcyp limited, Sheffield, UK
Background: Physiologically Based Pharmacokinetic models, to the best of our knowledge, have not been applied in modelling of developmental changes in concentration-response relationship across the paediatric age range. One study has shown that the development of the immune system was an important determinant of variation in CsA therapy in the paediatric population1. The pharmacodynamics (PD) changes coupled with the age related changes in PK, due to developmental physiology and CYP3A4 ontogeny will result in both altered exposure and response in children.
Objectives: To simulate the developmental immunosuppressive effect of CsA in a virtual healthy paediatric population stratified for their ages using the Simcyp paediatric simulator.
Methods: Prior in vitro and in vivo information on the metabolism and kinetics of CsA and developmental knowledge on physiology of paediatric population were incorporated into the Simcyp Simulator. Simulations of cyclosporine PK and the decrease in Peripheral Blood Monocyte effects were performed in infant (0-1 y), pre-adolescent (4-12 y) and adult (>12 y) populations using Paediatric Simcyp. The proliferation of PBM in vitro was used as a PD marker of the immunosuppressive effect of CsA. The PKPD relationship was taken from Marshall et al., 19991 and the simulated PK/PD profiles were compared to original observations1&2.
Results: Simulated/observed ratios for C0h, C2hr, and AUC0-8hr, are 1.17, 0.75, and 1.06 – fold, respectively for the pre-adolescent group. Simulated AUC0-24,ss for blood concentrations showed no significant difference between this group and adults, but was about 2-fold lower than that of infants. By accounting for the difference in the sensitivity of PD in infant compared with older children and adult, the AUCR increased by about 26% in infant, but was only 6% lower in adults compared with pre-adolescent group.
Conclusions: Simulation results for reduction of PBM following CsA in neonates compared with the pre-adolescence and adult population showed consistency with clinical observations in terms of different effects of age and on drug exposure and effect. The higher sensitivity in neonates to CsA may necessitate reduction of the drug dose in this population. Clinical trial simulations similar to the one shown in this study can be used to investigate the design of POPPK-PD studies in different ages and their power.
References
[1] Marshall JD, Kearns GL. Clin Pharmacol Ther. 1999; 66: 66-75.
[2] Acott PD, Crocker JF, Transplant Proc. 2006; 38: 2835-41.
Reference: PAGE 21 (2012) Abstr 2329 [www.page-meeting.org/?abstract=2329]
Poster: Paediatrics