Supplementary Material for: Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia

Background: Diazoxide is the first-line treatment for
pediatric hyperinsulinemic hypoglycemia (HI). This study aimed to
elucidate the pharmacokinetics of diazoxide in children with HI. Methods:
We obtained 81 blood samples from 22 children with HI. Measured serum
diazoxide concentrations were used for population pharmacokinetic
analysis. Patient factors influencing pharmacokinetics were estimated
using nonlinear mixed-effects model analysis. Relationships between drug
exposure and adverse drug reactions were also investigated. Results:
Diazoxide disposition in the body was described by a 1-compartment
model. Oral clearance (CL/F) and the volume of distribution were
proportional to body weight (WT), as expressed by CL/F in males
(liters/h) = 0.0358 + 0.00374 × WT (kg). CL/F in females was 39% greater
than that in males. Steady-state concentrations of diazoxide were
similar following twice- and 3 times-daily dosing when the total daily
doses were comparable. A patient whose serum diazoxide concentration
exceeded 100 μg/mL over a 4-month period developed hyperglycemia. No
significant correlation was observed between severity of hirsutism and
diazoxide concentration. Conclusion: We have proposed for
the first time a population pharmacokinetic model for diazoxide in
children with HI. The potential risk of diabetes mellitus and/or
hyperglycemia increases when serum concentrations of diazoxide exceed
100 μg/mL.