Impact of Drug Crystallinity on Pharmacokinetics in Tacrolimus Formulations

Abstract

Tacrolimus, an immunosuppressive drug with a narrow therapeutic index, exhibits significant pharmacokinetic variability influenced by its crystallinity. This study investigates the impact of drug crystallinity on key pharmacokinetic parameters, including maximum concentration (Cmax) and area under the curve (AUC), through a randomized, single-dose, four-treatment, four-period, four-way crossover study. Findings demonstrate that increased crystallinity leads to higher Cmax and lower AUC, presenting challenges in achieving bioequivalence with reference listed drugs (RLD). The study further explores the mechanistic underpinnings, indicating that solubility and dissolution rate modifications mediate these pharmacokinetic changes. Clinical implications suggest that crystallinity variability necessitates tailored formulation strategies to ensure therapeutic efficacy and consistent drug exposure. The results emphasize the need for stringent crystallinity control in tacrolimus formulations to optimize pharmacokinetic performance and improve clinical outcomes.