title: Diurnal cyclosporine dosing optimizes exposure and reduces the risk of acute rejection after kidney transplantation.
abstract: Acute rejection (AR) following transplantation may be due to episodic subtherapeutic cyclosporine (CsA) levels related to diurnal variation of hepatic drug metabolism. We postulated that asymmetrical dosing of CsA based on individualized pharmacokinetic profiles would optimize drug exposure and decrease the risk of AR. We prospectively treated all patients undergoing kidney transplantation with a diurnally split dose of CsA microemulsion given q 12 hours (3.5 mg/kg q a.m., 3.0 mg/kg qPM). Morning doses were adjusted to reach a day-time area under the concentration curve (AUC) of 7,800 ng hour/ml (utilizing 2 hour and 6 hour levels) and evening doses were adjusted to a morning trough of 300 ng/ml. Patients received high-dose steroids tapered to 20 mg prednisone by day 6. CsA was started within 36 hours and mycophenolate mofetil (1000 mg q 12 hour) was added on day 3 in most patients and continued for 3 months. Only one patient received antibody induction. Thirty kidneys (67% cadaveric) were transplanted into 28 adult patients (50% African American, 57% men). Therapeutic targets were reached in all patients prior to discharge and maintained during the study period. At 3 months follow-up, there was not a single episode of documented AR and mean creatinine was 1.5 +/- 0.1 mg/ml. Twelve patients required biopsy for allograft dysfunction; however no histological evidence of AR or CsA-toxicity was identified and the creatinine normalized in each case without altering immunosuppression. Patients continued to require increased CsA doses in the AM compared to the PM (P<0.05) throughout the study to maintain target levels. Diurnal dosing of CsA based on individual pharmacokinetic profiles optimizes CsA exposure and reduces the risk of AR during the first 3 months after transplantation.
authors.affiliation: Department of Surgery, University of South Alabama, Mobile, USA. bbrowne@Jaguar1.usouthal.edu
authors.forename: B J
authors.initials: BJ
authors.lastname: Browne
authors.forename: C O
authors.initials: CO
authors.lastname: Holt
authors.forename: O E
authors.initials: OE
authors.lastname: Emovon
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine