Initial Dosage Recommendation for Sirolimus in Children With Tuberous Sclerosis Complex

Abstract

Sirolimus is already used in the treatment of tuberous sclerosis complex (TSC), however, with narrow therapeutic range and considerable inter-and intra-individual pharmacokinetic variability, making it hard to develop an appropriate sirolimus initial dosage regimen, especially in children with TSC. The aim of this study was to recommend the optimal sirolimus initial dosing regimen in pediatric patients with TSC. Underlying physiological and genetic factors were collected to explore the effects on clinical sirolimus concentrations by establishing a nonlinear mixed effect (NONMEM) model, and to further simulate the optimal sirolimus initial dosing regimen using Monte Carlo method in pediatric patients with TSC. The once-daily regimen and the twice-daily regimen were recommended, respectively. For once-daily regimen, the dosages of 0.10, 0.07, 0.05, 0.04, 0.03 mg/kg/day were recommended for children with weights of 5-10, 10-20, 20-30, 30-50, and 50-60 kg, respectively. For twice-daily regimen, the dosages of 0.04, 0.03, 0.02 mg/kg/day (the daily dose was divided evenly into two doses) were recommended for children with weights of 5-20, 20-40, 40-60 kg, respectively. The initial dosages of sirolimus in children with TSC were recommended for the first time.

Population Pharmacokinetics and Initial Dose Optimization of Sirolimus Improving Drug Blood Level for Seizure Control in Pediatric Patients With Tuberous Sclerosis Complex

“…Of course, to some extent, CYP3A4 and CYP3A5 may influence sirolimus metabolism in adults (Tamashiro et al, 2017;Zhang et al, 2017). However, it was interesting in our previous study that the initial dosage recommendation for sirolimus in children with TSC, CYP3A4, and CYP3A5 polymorphism did not significantly affect sirolimus clearance rates (Wang et al, 2020). The main reason was that included children had a wide age span (Wang et al, 2020).…”

“…However, it was interesting in our previous study that the initial dosage recommendation for sirolimus in children with TSC, CYP3A4, and CYP3A5 polymorphism did not significantly affect sirolimus clearance rates (Wang et al, 2020). The main reason was that included children had a wide age span (Wang et al, 2020). And it was reported that gene expression in different age development processes had development-dependent characteristics; meanwhile, CYP3A expression isoforms levels were highly variable after birth (Lacroix et al, 1997).…”

“…Blood concentrations were collected prior to the subsequent administration, and the sirolimus concentrations used in the current research were trough concentrations. Sirolimus concentrations were detected using the Emit 2000 Sirolimus Assay (Siemens Healthcare Diagnostics Inc.) with a range of linear response, 3.5-30 ng/ml, whose values of inter-assay variability [coefficient of variation (CV%)] < 4.0%, and values of intra-assay CV (%) < 6.2% (Wang et al, 2020).…”

“…A one-compartment model with first-order elimination was used to describe the model because all the concentrations in this research were trough concentrations. The pharmacokinetic parameters, apparent oral clearance (CL/F), volume of distribution (V/F), and absorption rate constant [Ka, fixed at 0.485/h (Wang et al, 2020)], were included.…”

“…Moreover, He et al reported that sirolimus has a significant effect on seizures associated with TSC, and it could be used as the first-line medication for pediatric patients with TSC-associated epilepsy (He et al, 2020). However, sirolimus has a narrow therapeutic window with considerable inter-and intra-individual pharmacokinetic variabilities (Wang et al, 2020), making it difficult to design a sirolimus initial dosage regimen, especially for sirolimus improving drug blood level for seizure control in pediatric patients with TSC. Therefore, the purposes of this study were to explore the population pharmacokinetics and initial dose optimization of sirolimus improving drug blood level for seizure control in pediatric patients with TSC.…”