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Chronopharmacokinetics of Tacrolimus in Kidney Transplant Recipients: Occurrence of Acute Rejection

From the Department of Pharmaceutical Science, Akita University Hospital, Akita, Japan (Dr. Tada, Dr. Suzuki); the Department of Urology, Akita University School of Medicine, Akita, Japan (Dr. Satoh, Dr. Iinuma, Dr. Shimoda, Dr. Kato); and the Department of Pharmaceutical Administration, Hokkaido College of Pharmacy, Hokkaido, Japan (Dr. Murakami, Dr. Hayase).

The circadian variation of clinical pharmacokinetics of tacrolimus was studied using 16 adult renal transplant recipients 1 month after the operation. The recipients were administered tacrolimus twice a day (9 a.m. and 9 p.m.), and whole-blood samples were obtained just prior to and 1, 2, 3, 6, 9, and 12 hours after oral administration. Histological specimens of transplant kidney were collected by an allograft core biopsy on day 28 after the transplantation. There were no circadian changes in the area under the concentration-time curve (AUC_0-12) (214 ng•h/mL during daytime vs. 223 ng•h/mL during nighttime) resulting from morning and night doses. A slight delay in mean residence time (MRT_0-12) and time to the peak concentration (t_max) was found after night doses, but there was no statistical significance. Three patients (18.8%) had a clinical acute rejection (AR) episode 4 to 6 weeks after transplantation, and AUC_0-12 at nighttime was significantly lower (18.4% on average) in patients with AR in comparison to those without AR. There was no statistical significance in maximum concentration (C_max) or morning/night trough levels between patients with and without AR. In regard to the correlation between tacrolimus concentrations in each sampling time and AUC_0-12, the morning trough concentrations were less predictable for daytime AUC_0-12 (r² = 0.125), but there was a weak correlation to nighttime AUC_0-12 (r² = 0.424). Tacrolimus concentrations at 2, 3, and 6 hours after the morning dose (C₂, C₃, and C₆) had a good correlation against daytime AUC. The results of this study indicate that the variance on the clinical pharmacokinetics of tacrolimus between daytime and nighttime in renal transplant patients is not significant, while the lower nighttime AUC corresponded to the occurrence of AR.

Key Words: Tacrolimus • circadian variation • bioavailability • kidney transplant patient • rejection

Address for reprints: Toshio Suzuki, Department of Pharmaceutical Science, Akita University Hospital, Hondo 1-1-1, Akita 010-8543, Japan.

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