Influence of Dosing Schedule on Organ Exposure to Cyclosporin in Pediatric Hematopoietic Stem Cell Transplantation: Analysis with a PBPK Model

Abstract

Cyclosporin is administered by intermittent infusions (II) or continuous infusions (CI) to prevent acute graft-versus-host disease (aGVHD). Because cyclosporin disposition is nonlinear, organ exposure may be higher after II than after CI, but saturation of receptors must be accounted for. The aim of the study was to compare both types of administration using a mechanistic model. A physiologically based pharmacokinetic model was developed to estimate cyclosporin exposure and receptor occupancies (RO) in aGVHD target organs and kidneys and to compare these estimations in pediatric patients that received cyclosporin either by II or CI. The relevant biological parameters were based on a clinical study in 2 groups of pediatric patients that received cyclosporin either by II (n = 31) or CI (n = 30). Simulations showed that the exposure to cyclosporin in the interstitial fluid of aGVHD target organs was greater at day 1 after II than after CI. In kidneys, the opposite order was observed. AUC(RO) in all organs was greater after CI than after II. The therapeutic index (the ratio of AUC(RO) in blood to AUC(RO) in kidneys) was greater with CI than with II. CI may be slightly more favorable than II for aGVHD prevention.