Purpose: Gadofosveset is a Gd-based contrast agent used for magnetic resonance imaging (MRI). Gadolinium kinetic\ndistribution models are implemented in T1-weighted dynamic contrast-enhanced perfusion MRI for characterization\nof lesion sites in the body. Physiology changes in a disease state potentially can influence the pharmacokinetics of\ndrugs and to this respect modify the distribution properties of contrast agents. This work focuses on the in silico\nmodelling of pharmacokinetic properties of gadofosveset in different population groups through the application of\nphysiologically-based pharmacokinetic models (PBPK) embedded in Simcyp�® population pharmacokinetics platform.\nMethods: Physicochemical and pharmacokinetic properties of gadofosveset were introduced into Simcyp�® simulator\nplatform and a min-PBPK model was applied. In silico clinical trials were generated simulating the administration of\nthe recommended dose for the contrast agent (i.v., 30 mg/kg) in population cohorts of healthy volunteers, obese,\nrenal and liver impairment, and in a generated virtual oncology population. Results were evaluated regarding basic\npharmacokinetic parameters of Cmax, AUC and systemic CL and differences were assessed through ANOVA and\nestimation of ratio of geometric mean between healthy volunteers and the other population groups.\nResults: Simcyp�® predicted a mean Cmax = 551.60 mg/l, a mean AUC = 4079.12 mg/L*h and a mean systemic\nCL = 0.56 L/h for the virtual population of healthy volunteers. Obese population showed a modulation in Cmax and\nCL, attributed to increased administered dose. In renal and liver impairment cohorts a significant modulation in\nCmax, AUC and CL of gadofosveset is predicted. Oncology population exhibited statistical significant differences\nregarding AUC when compared with healthy volunteers.\nConclusions: This work employed Simcyp�® population pharmacokinetics platform in order to compute gadofosvesetâ��s\npharmacokinetic profiles through PBPK models and in silico clinical trials and evaluate possible differences between\npopulation groups. The approach showed promising results that could provide new insights regarding administration of\ncontrast agents in special population cohorts. In silico pharmacokinetics could further be used for evaluating of possible\ntoxicity, interpretation of MRI PK image maps and development of novel contrast agents.
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