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.