Population pharmacokinetic model as a tool for simulating cyclosporine exposure in children

Abstract

Therapeutic drug monitoring (TDM) of cyclosporine is indicated due to its variable pharmacokinetics. Demographic, clinical and TDM data are used to develop a population pharmacokinetic (popPK) model. These models identify factors causing variability in drug exposure parameters like maximum (Cmax), minimum concentration (Cmin) and area under the curve (AUC). Based on data from 58 patients from the University Children's Hospital, a popPK model was developed with body mass and haemoglobin as variability factors. The model was used to simulate Cmax, Cmin and AUC in the e-campsis® program (Calvagone, France) in a virtual population of patients in two different clinical scenarios: when patients have normal and reduced haemoglobin levels, and each of the two scenarios at two time points. The median values of Cmin, Cmax and AUC in the low-level haemoglobin group at the first and second time points were, respectively: 215 ng/mL, 1851 ng/mL and 6343 ng/mL, and 221 ng/mL, 1918 ng/mL and 6687 ng/mL; and in normallevel haemoglobin group 331 ng/mL, 2265 ng/mL and 7857 ngh/mL, and 318 ng/mL, 2035 ng/mL and 7210 ngh/mL. The most pronounced effect of haemoglobin is on Cmin, where the group with normal haemoglobin had 53.95% higher Cmin levels, i.e. 43.89% compared to the group with reduced levels. Application of simulations based on popPK models is a useful tool for predicting drug exposure. Thus, the balance between the efficacy and safety of the therapy is optimized, which enables precise and timely correction of the dosage in order to achieve the maximum therapeutic response.