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.

Effect of cyclosporin pharmacokinetics on renal allograft outcome in African‐Americans

“…We acknowledge that sample size and lack of a control group limits conclusion that can be drawn from this study, but are encouraged by the improvement in the outcome of the A‐As in this cohort. Because of our initial experience with this strategy (11), it was ethically impossible to design a randomized trial. Moreover, the literature is replete with several similar reports showing significantly higher acute rejection rates at 1 yr than what we have observed (35–40% vs. <10%).…”

Large Within-Day Variation in Cyclosporine Absorption

“…Finally, across-study inconsistencies in the magnitude of any observed morning versus evening difference may be explained by the extent of a fasting versus fed difference. Although "diurnal" and "circadian" effects have been used (19) in connection to the mechanism underpinning this morningevening difference, our "reverse fasting" results clearly suggest that the morning versus evening differences that we saw under the study protocol are largely if not wholly attributed to a food effect and not to a "circadian" or "diurnal" effect per se. Applying Occam's razor, there seems to be no reason to hypothesize any mechanism beyond that associated with food effects to explain a.m.-p.m. differences in exposure to CsA.…”

A Review of the Pharmacokinetics of Cyclosporin

“… CsA clearance is indicated to follow a diurnal variation, and Browne et al have developed a diurnal dosing which improved therapy [99].…”