Influence of cyclosporin dosing schedule on receptor occupancy in bone marrow transplantation: analysis with a PBPK-PD model
C. Gérard (1,2), N. Bleyzac (3,4), P. Girard (1,2), G. Freyer (1,2), Y. Bertrand (3), M. Tod (1,2,5).
(1) Université de Lyon, Lyon, F-69003, France; (2) Université Lyon 1, EA3738, CTO, Faculté de Médecine Lyon Sud, Oullins, F-69600, France; (3) Institut d’Hématologie et d’Oncologie Pédiatrique, Lyon, France; (4) Université Lyon 1, CNRS UMR5558, Faculté de Médecine, Lyon, F-69008, France; (5) Pharmacie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.
Objectives: In bone marrow transplantation, cyclosporin is administered to prevent graft-versus-host disease (aGvHD), which occurs mainly in three organs (skin, intestines and liver). This immunosuppressant drug acts on T lymphocytes and has some nephrotoxicity. Because its disposition depends on several sources of nonlinearity [1], organ exposure may be higher after intermittent infusions (II) than after continuous infusions (CI).
Methods: A physiologically-based pharmacokinetic model was developed in order to estimate cyclosporin exposure in interstitial fluid (space of T lymphocytes) of the target organs of aGvHD and in intracellular space of kidneys (nephrotoxicity). These simulations were used to compare exposures and receptor occupancies (RO) of pediatric patients that received cyclosporin either by II or CI. The relevant biological parameters and their interindividual variability were based on a clinical study in 2 groups of pediatric patients that received cyclosporin either by II (n = 31) or CI (n = 30) at an initial dose of 3 mg/kg/day.
Results: 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 (mean area under the curve (AUC) of 2.65 vs 2.39 h.mg/l). At steady state, there was no difference. By contrast, the exposure to cyclosporin in the intracellular space of kidney was greater at day 1 and at steady-state after CI than after II (mean AUC of 129 vs 112 h.mg/l). Regarding exposure of RO, AUCRO in interstitial fluid of aGvHD target organs and in kidney cells at day 1 and at steady state were greater after CI than after II (mean AUC AUCRO of 14.7 vs 12.9 h.mg/l). The therapeutic index, estimated as the ratio of AUCRO in blood to AUCRO in kidney cells, was 0.62 with CI versus 0.52 with II.
Conclusions: Regarding organ exposure, II may be more favorable than CI because of a greater exposure in target organs of GvHD and a lower exposure in kidney cells. However, concerning the receptor occupancies, the therapeutic index was slightly better after CI than after II. Further analyses are required to determine whether cyclosporin efficacy and toxicity depends on the average concentration or on the entire concentration profile in the interstitial or intracellular space of target organs. Ultimately, this information will contribute to determining the optimal mode of cyclosporin administration.
References:
[1] Tanaka C, Kawai R, Rowland M. J Pharmacokinet Biopharm 1999;27(6):597-623.
