A randomized cross-over comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily tacrolimus on renal function in healthy volunteers

Jeffrey S Zaltzman, Vesta Lai, Miklos Z Schulz, Kyung-Hee Moon, David Z Cherney, Jeffrey S Zaltzman, Vesta Lai, Miklos Z Schulz, Kyung-Hee Moon, David Z Cherney

Abstract

Calcineurin inhibitor nephrotoxicity remains an issue for transplant recipients. The pharmacokinetic profile (PK) of the once-daily tacrolimus extended release (Tac-ER) includes equivalent exposure [AUC(0-24 h) ] but lower Cmax versus twice-daily tacrolimus immediate release (Tac-IR). We hypothesized that the unique PK profiles would result in pharmacodynamic differences in renal function. Nineteen healthy male subjects were allocated to once-daily Tac-ER and twice-daily Tac-IR in a prospective, randomized, two period, cross-over study. Tacrolimus was titrated to achieve trough levels of 8-12 ng/ml. Twenty four hours ERPF and GFR estimated by para-aminohippurate and sinistrin clearance were performed at baseline and at the end of each 10-day dosing period. Mean Tac C0 was 11.0 ± 2.2 and 11.3 ± 1.8 ng/ml for Tac-ER and Tac-IR, respectively. The mean Effective 24 h renal plasma flow (ERPF) was significantly higher with Tac-ER compared with Tac-IR (658 ± 127 vs. 610 ± 93 ml/min/1.73 m(2) , P = 0.046). There was a trend to a greater mean GFR over 24 h for Tac-ER at 114.5 ± 13.6 ml/min/1.73 m(2) compared with 108.9 ± 9.7 ml/min/1.73 m(2) for Tac-IR, P = 0.116. Under controlled physiological conditions, ERPF was significantly improved with Tac-ER compared with Tac-IR, likely owing to the differing PKs of these tacrolimus preparations (ClinicalTrials.gov Identifier: NCT01681134).

Keywords: nephrotoxicity; renal physiology; tacrolimus.

© 2014 Steunstichting ESOT.

Figures

Figure 1
Figure 1
Box plots for tacrolimus AUC(0–24 h)(hr ng/ml) for Tac-ER and Tac-IR. n = 17. (P = 0.326).
Figure 2
Figure 2
Mean (SEM) 24 h tacrolimus blood concentration versus time profile in ng/ml on day 10 of study, Tac-ER (dashed line) and Tac-IR (solid line), n = 17.
Figure 3
Figure 3
Mean (SEM) effective renal plasma flow (ERPF; ml/min/1.73 m2) versus time at baseline (no treatment) (solid gray line), Tac-ER (dashed gray line), and Tac-IR (solid black line) (P = 0.046), n = 17.
Figure 4
Figure 4
Mean (SEM) time-matched change from baseline (no treatment) in effective renal plasma flow (ERPF; ml/min/1.73 m2) versus time for Tac-ER (dashed line) (P = 0.07) and Tac-IR (solid line) (P = 0.677), n = 17.
Figure 5
Figure 5
Mean (SEM) effective glomerular filtration rate (GFR; ml/min/1.73 m2) versus time at baseline (no treatment) (solid gray line), Tac-ER (dashed gray line), and Tac-IR (solid black line) (P = 0.116), n = 17.

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Source: PubMed

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