Once‐ Versus Twice‐Daily Tacrolimus Therapy: Does Improved Adherence Lead to Better Efficacy?—A Pharmacokinetic Perspective

Abstract Tacrolimus, a critical immunosuppressant in organ transplantation, is available in immediate‐release (IR‐T) and extended‐release (ER‐T) formulations. While ER‐T improves patient adherence, clinical studies have not demonstrated superior outcomes compared to IR‐T. However, the underlying reasons for this discrepancy remain unclear. This study aimed to evaluate tacrolimus exposure under non‐adherent dosing behaviors with IR‐T and ER‐T and to provide insights for selecting the optimal tacrolimus formulation. Monte Carlo simulations were conducted to assess the proportion of target attainment (%PTA) and deviation time (DT) from the therapeutic range in scenarios involving delayed or missed doses, based on published population pharmacokinetic models. The influence of renal function, the post‐transplantation period, and hematocrit levels on %PTA and DT were also analyzed. Our findings revealed that patients on ER‐T exhibited lower %PTA and longer DT than those on IR‐T when doses were delayed or missed, reflecting poorer “forgiveness.” This observation elucidates the lack of clinical superiority observed for ER‐T in previous studies. Furthermore, fast metabolizers experienced worse forgiveness with ER‐T, exacerbating the challenge of maintaining therapeutic levels. Additionally, a web‐based dashboard was developed to calculate the %PTA and DT for individual patients and to provide formulation recommendations tailored to their dosing behaviors and clinical characteristics. In conclusion, adherence and forgiveness play a crucial role in the success of pharmacotherapy. This study highlights the significance of pharmacokinetic modeling and simulation in providing evidence‐based recommendations for selecting the optimal tacrolimus formulation.