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

Abstract

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 tuberous sclerosis complex (TSC). Eighty pediatric patients diagnosed with TSC-related epilepsy were included for analysis. Sirolimus concentrations, physiological and biochemical indexes, and drug combination were collected to build a nonlinear mixed effect (NONMEM) model. Initial dose optimization was simulated by the Monte Carlo method. The weight and concomitant medication of oxcarbazepine affected sirolimus clearance. Without oxcarbazepine, for once-daily sirolimus regimen, the doses of 0.07, 0.06, 0.05, 0.04, and 0.03 mg/kg/day were recommended for weights of 5–7.5, 7.5–11.5, 11.5–19, 19–40, and 40–70 kg, respectively; for twice-daily sirolimus regimen, the doses of 0.05, 0.04, and 0.03 were recommended for weights of 5–8, 8–20, and 20–70 kg, respectively. With oxcarbazepine, for once-daily sirolimus regimen, the doses of 0.09, 0.08, 0.07, 0.06, 0.05, and 0.04 mg/kg/day were recommended for weights of 5–7.5, 7.5–10, 10–13.5, 13.5–20, 20–35, and 35–70 kg, respectively; for twice-daily sirolimus regimen, the doses of 0.06, 0.05, 0.04, and 0.03 were recommended for weights of 5–7, 7–14.5, 14.5–38, and 38–70 kg, respectively. The present study was the first to establish a population pharmacokinetic model of sirolimus improving drug blood level for seizure control in pediatric patients with TSC and recommend the initial dosage regimen.

Population Pharmacokinetic Analysis and Dosing Optimization of Sirolimus in Children With Tuberous Sclerosis Complex

“…But this value tended to be lower than that reported in children with kaposiform hemangioendothelioma (0.46 L/h/kg) 12 and children withd neurofibromatosis type 1 (0.33 L/h/kg) 11,21 . Moreover, the CL/F was estimated to be 0.42 L/h/kg in another PopPK study conducted in pediatric patients with TSC 13 . Inconsistencies in these results may be attributed to different sample size or discrepancies in age and body size at different stages of biological maturation.…”

“…11,21 Moreover, the CL/F was estimated to be 0.42 L/h/kg in another PopPK study conducted in pediatric patients with TSC. 13 Inconsistencies in these results may be attributed to different sample size or discrepancies in age and body size at different stages of biological maturation.…”

“…Although several studies have described the population pharmacokinetic (PopPK) characteristics of sirolimus in pediatric patients, [9][10][11][12] pharmacokinetic data for children with TSC are still limited. 13,14 In addition, the therapeutic range for oral sirolimus is narrow, and the apparent clearance and apparent volume of distribution (V d ) are highly variable in pediatric patients, 9 which might lead to treatment failure or increased drugrelated toxicity. Thus, the main objectives of this study were to explore the effects of various covariates on the sirolimus pharmacokinetics in pediatric patients with TSC and to optimize dosage regimens using a modeling and simulating approach.…”

“…Although several studies have described the population pharmacokinetic (PopPK) characteristics of sirolimus in pediatric patients, 9–12 pharmacokinetic data for children with TSC are still limited 13,14 . In addition, the therapeutic range for oral sirolimus is narrow, and the apparent clearance and apparent volume of distribution (V d ) are highly variable in pediatric patients, 9 which might lead to treatment failure or increased drug‐related toxicity.…”

Initial sirolimus dosage recommendations for pediatric patients with PIK3CD mutation-related immunodeficiency disease

“…PIK3CD mutation-related immunodeficiency disease, which is also known as activated phosphoinositide 3-kinase δ syndrome (APDS)-1, and which is mainly due to an overactivated PI3K/Akt/mTOR signaling pathway, can be treated from the cause using sirolimus, an mTOR inhibitor (Luo et al, 2018;Kang et al, 2020;Singh et al, 2020;Redenbaugh and Coulter, 2021;Rivalta et al, 2021). However, the significant inter-individual variability and a narrow therapeutic index of sirolimus make it difficult to set the dosages for administration (Chen et al, 2021b;Zhang et al, 2022). In the final PPK model of sirolimus from pediatric patients with PIK3CD mutation-related immunodeficiency disease, body weight and concomitant use of posaconazole were included, where, under the same weight; the clearances of sirolimus were 1 : 0.238 between children without posaconazole and children with posaconazole.…”