Abstract
Introduction: Tacrolimus is the backbone immunosuppressant after solid organ transplantation. Tacrolimus has a narrow therapeutic window with large intra- and inter-patient pharmacokinetic variability leading to frequent over- and under-immunosuppression. While routine therapeutic drug monitoring (TDM) remains the standard of care, tacrolimus pharmacokinetic variability may be influenced by circadian rhythms. Our aim was to analyze tacrolimus pharmacokinetic/pharmacodynamic profiles on circadian rhythms comparing morning and night doses of a twice-daily tacrolimus formulation. Methods: This is a post-hoc analysis from a clinical trial to study the area under curve (AUC) and the area under effect (AUE) profiles of calcineurin inhibition after tacrolimus administration in twenty-five renal transplant patients. Over a period of 24 h, an intensive sampling (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 20, and 24 h) was carried out. Whole blood and intracellular tacrolimus concentrations and calcineurin activity were measured by UHPLC-MS/MS. Results: Whole blood and intracellular AUC12–24 h and Cmax achieved after tacrolimus night dose was significantly lower than after morning dose administration (AUC0–12 h) (p < 0.001 for both compartments). AUE0–12 h and AUE12–24 h were not statistically different after morning and night doses. Total tacrolimus daily exposure (AUC0–24 h), in whole blood and intracellular compartments, was over-estimated when assessed by doubling the morning AUC0–12 h data. Conclusion: The lower whole blood and intracellular tacrolimus concentrations after night dose might be influenced by a distinct circadian clock. This significantly lower tacrolimus exposure after night dose was not translated into a significant reduction of the pharmacodynamic effect. Our study may provide conceptual bases for better understanding the TDM of twice-daily tacrolimus formulation.
Highlights
Tacrolimus is the backbone immunosuppressant after solid organ transplantation
The area under concentration-time curve (AUC) is the most accurate assessment of overall Tac exposure it is difficult to implement in clinical daily practice (Wallemacq et al, 2009)
The AUC, Caverage and Ctrough values were higher after the morning dose than the night doses (Table 2)
Summary
Tacrolimus is the backbone immunosuppressant after solid organ transplantation. Tacrolimus has a narrow therapeutic window with large intra- and inter-patient pharmacokinetic variability leading to frequent over- and underimmunosuppression. While routine therapeutic drug monitoring (TDM) remains the standard of care, tacrolimus pharmacokinetic variability may be influenced by circadian rhythms. Our aim was to analyze tacrolimus pharmacokinetic/pharmacodynamic profiles on circadian rhythms comparing morning and night doses of a twice-daily tacrolimus formulation. Tacrolimus (Tac) is the most commonly used immunosuppressor after solid organ transplantation. Therapeutic Tac doses are adjusted by monitoring the morning whole blood trough concentrations (Ctrough), even though some controversies remain regarding the relationship between Ctrough and clinical outcomes. The area under concentration-time curve (AUC) is the most accurate assessment of overall Tac exposure it is difficult to implement in clinical daily practice (Wallemacq et al, 2009). Routine therapeutic drug monitoring (TDM) of morning trough concentrations remains as the standard of care. A poor correlation between Tac dosage and trough levels exists, further research of factors influencing Tac exposure is strongly recommended (Hesselink et al, 2005; Wallemacq et al, 2009)
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