Introduction
Tacrolimus (TAC) was a macrolide immunosuppressant, had proven to be of immense utility in immunosuppression following organ transplant surgery [1, 2]. Its use had revolutionized the future of immunosuppressive regimens in solid organ transplantation and had been associated with better graft survival, a lower incidence of rejection, and improved drug tolerance with fewer side effects [3]. However, its monitoring remained complicated and underexposure increaseed the risk of rejection, whereas overexposure increased the risk of adverse effects, primarily hepatotoxicity and infections [4]. The pharmacokinetic variability of TAC complicated its daily dose assessment, potentially due to its narrow therapeutic window, propensity for clinically drug–drug interactions (DDI), patient age, hepatic dysfunction, concomitant medications as well as interindividual variability in its pharmacokinetic profile or disposition [5]. Among the potential causes for large variability, the high inter-patient pharmacokinetic variability of TAC, especially between adult and pediatric patients, justified dose adjustment based on age grouping [6].
Patients with immune compromise after solid organ transplantation were at risk for serious fungal infections. First-line treatment commonly consisted of the antifungal drug voriconazole (VRCZ) [7]. VRCZ was a potent antifungal agent used for the treatment of invasive fungal infections [8]. It had been reported that VRCZ inhibited the metabolism of TAC and the blood concentration/dose ratio of TAC was significantly correlated with the blood concentration of VRCZ when TAC was intravenously administered [9, 10]. Administration of VRCZ to TAC-treated adult patients resulted in a major DDI characterized by increased exposure to TAC [9-11]. Therefore, therapeutic drug monitoring (TDM) of TAC was essential when combined with VRCZ.
Despite the fact that clinical trials of TAC drug monitoring in organ transplant recipients were reflected in many studies, detailed and practical information on the interaction between TAC and VRCZ in pediatric cases was still scarce. The evidence of association in pediatric patients was not as extensive as adults [12]. Therefore, the aim of the present study was to construct a physiologically based pharmacokinetic (PBPK) model to quantify the DDI between TAC and different formulations of VRCZ in adults and pediatrics with different age groups. To overcome the large pharmacokinetic variability of TAC, optimize efficacy and reduce toxicity, we provide strong insights into the interaction between TAC exposure and VRCZ in pediatric patients and compare it to adults. It could assist the clinical implementation of precision medicine approaches to determine the factors that influence appropriate dosing.