title: Cyclosporine exposure and calcineurin phosphatase activity in living-donor liver transplant patients: twice daily vs. once daily dosing.
abstract: We have compared the pharmacokinetics and pharmacodynamics of cyclosporine between once- and twice-daily dosing regimens in de novo patients of living-donor liver transplantation (LDLT). A total of 14 patients were enrolled in this study, who had received cyclosporine microemulsion (Neoral) twice a day (BID, n = 5) or once daily in the morning (QD, n = 9) after transplantation. On postoperative day (POD) 6, the QD regimen significantly increased cyclosporine exposure; the blood concentration at 2 hours postdose (C2) and area under the concentration-time curve (AUC) for 4 hours (AUC(0-4)), compared with the BID regimen. Moreover, the area under the calcineurin (CaN) activity in peripheral blood mononuclear cells time-curve (AUA) for 12 hours (AUA(0-12)) and 24 hours (AUA(0-24)) were decreased by approximately 42 and 25% with the QD regimen relative to the BID regimen, respectively. The C2 level was significantly correlated with the AUC(0-4) (r2 = 0.95), which was negatively related to the AUA(0-12) with a large interindividual variability (r(2) = 0.59). However, a significant correlation was found between the AUA(0-12) or AUA(0-24) and CaN activity at trough time points. According to a maximum inhibitory effect attributable to the drug (E(max)) model, the mean estimates of E(max) and the C(b) value that gives a half-maximal effect (EC50) for CaN inhibition were not significantly different between the 2 groups, respectively. These findings suggest that a once daily morning administration of cyclosporine may improve oral absorption and help to provide an effective CaN inhibition early after LDLT. Furthermore, CaN activity at trough time points would be a single surrogate predictor for the overall CaN activity throughout dosing intervals following cyclosporine administration.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Fukudo
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Toshiya
authors.initials: T
authors.lastname: Katsura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ogura
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Oike
authors.forename: Yasutsugu
authors.initials: Y
authors.lastname: Takada
authors.forename: Koichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017093:Liver Failure / Q000175:diagnosis / Q000601:surgery; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000009:adverse effects / Q000379:methods*; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010865:Pilot Projects; D011446:Prospective Studies; D014181:Transplantation Immunology / Q000187:drug effects*; D023001:Transplantation Tolerance / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; C120817:calcineurin phosphatase; D010744:Phosphoric Monoester Hydrolases