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

Abstract

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 (AUC0-12) (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 (MRT0-12) and time to the peak concentration (tmax) 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 AUC0-12 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 (Cmax) or morning/night trough levels between patients with and without AR. In regard to the correlation between tacrolimus concentrations in each sampling time and AUC0-12, the morning trough concentrations were less predictable for daytime AUC0-12 (r2 = 0.125), but there was a weak correlation to nighttime AUC0-12 (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.

Untreated Rejection in 6-Month Protocol Biopsies Is Not Associated with Fibrosis in Serial Biopsies or with Loss of Graft Function

“…Trough levels of both CsA and tacrolimus are not closely correlated with drug exposure (17,18,(32)(33)(34), the risk for allograft rejection (35,36), or their adverse effects (37,38). The AUC 0-12h and derived parameters, such as absorption profiles, have been shown to correlate more closely with clinical outcome also in patients who received prophylaxis with basiliximab (39).…”

The Rate of Gastric Emptying Determines the Timing but Not the Extent of Oral Tacrolimus Absorption: Simultaneous Measurement of Drug Exposure and Gastric Emptying by Carbon-14-Octanoic Acid Breath Test in Stable Renal Allograft Recipients

“…Of course, very early after successful transplantation, gastric motility might be even more extensively disturbed than in chronic stable recipients, possibly resulting in more marked alterations of tacrolimus absorption. The effect of diurnal variation in tacrolimus exposure (Tada et al, 2003) and ethnicity (Mancinelli et al, 2001) could not have played a role in the current study since all measurements were performed in the morning, after an overnight fast, and all participants were of Caucasian origin. Also, concomitant drugs that could have influenced gastric emptying were excluded per protocol and double-checked on every visit.…”

Circadian Pharmacokinetics of Mycophenolic Acid and Implication of Genetic Polymorphisms for Early Clinical Events in Renal Transplant Recipients

“…Circadian variation in the pharmacokinetics of calcineurin inhibitors have been reported over recent years, which described differences in the calcineurin inhibitor absorption profile or area under the concentrationtime curve (AUC) between morning and night doses for heart and liver allograft recipients (6,7). In our previous study, although tacrolimus pharmacokinetics did not show circadian variations, the lower nighttime AUC of tacrolimus corresponded to the occurrence of acute rejection (AR) in renal transplant recipients (8).…”