Population Pharmacokinetics and Initial Dosage Recommendation of Tacrolimus in Children with Juvenile Dermatomyositis

BACKGROUND: There is a gap in the pharmacokinetic data on tacrolimus in children with juvenile dermatomyositis (JDM). This study aimed to develop a population pharmacokinetics (PopPK) model for tacrolimus in patients with JDM and formulate model-based recommended dosing regimens. METHODS: The PopPK model for tacrolimus was retrospectively developed in 31 children with JDM using nonlinear mixed-effects modeling. The trough concentrations of tacrolimus at different doses were simulated using the Monte Carlo method in children with different body weights. RESULTS: The one-compartment model with first-order absorption and elimination best described the pharmacokinetic data of tacrolimus. In the final model, body weight and concomitant use of voriconazole (VRC) significantly affected the apparent clearance (CL/F) of tacrolimus. The calculation of interindividual clearance was performed as follows: 12.635 × (WT/33.5)0.296 × (1-0.426 × VRC). The tacrolimus CL/F ratio in children with JDM was 1:0.574 between those without VRC coadministration and those with VRC coadministration at equivalent body weights. For patients with JDM and body weights of 10-20, 20-30, 30-40, and 40-60 kg, the recommended initial doses of tacrolimus without the combined use of VRC were 0.12, 0.08, 0.06, and 0.05 mg·kg-1·d-1 (q12h), respectively; the recommended initial doses of tacrolimus with the combined use of VRC were 0.07, 0.05, 0.04, and 0.03 mg·kg-1·d-1 (q12h), respectively. CONCLUSIONS: This is the first study to establish a PopPK model for tacrolimus. Drug dosage regimens devised on the basis of this model provide evidence-based recommendations for patients with JDM.