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.