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.
Highlights
Tuberous sclerosis complex (TSC), is an autosomal dominant neurodermal syndrome, most of which are caused by abnormal organ development in the ectodermal tissue, involving multiple organs such as the brain, the skin, the peripheral nerves, and the kidney, and leading to the mammalian target of rapamycin pathway hyperactivation (Curatolo et al, 2008; van der Poest Clement et al, 2020)
Sirolimus is an mammalian target of rapamycin (mTOR) inhibitor and has been widely proved that it has good effects on treating many of the symptoms of TSC (Bissler et al, 2008; Davies et al, 2011; Nathan et al, 2015; Wataya-Kaneda et al, 2017). 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)
We found that the distribution of the final model was normal, and most of the observed sirolimus concentrations were within the 95% prediction intervals from the simulation data, showing the prediction-corrected sirolimus concentrations were well predicted by the final model
Summary
Tuberous sclerosis complex (TSC), is an autosomal dominant neurodermal syndrome, most of which are caused by abnormal organ development in the ectodermal tissue, involving multiple organs such as the brain, the skin, the peripheral nerves, and the kidney, and leading to the mammalian target of rapamycin (mTOR) pathway hyperactivation (Curatolo et al, 2008; van der Poest Clement et al, 2020). Sirolimus is an mTOR inhibitor and has been widely proved that it has good effects on treating many of the symptoms of TSC (Bissler et al, 2008; Davies et al, 2011; Nathan et al, 2015; Wataya-Kaneda et al, 2017). 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).
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