Disposition of diazoxide in children

Abstract

Pharmacokinetic studies in 4 children with hypo glycemia who required diazoxide therapy revealed a half‐life of the drug in blood of 9.5 to 24 hmlrs. The blood level of diazoxide in these children while receiving maintenance therapy was 15 to 50 p.g per milliliter. Hyperglycemia and acidosis developed in one of these patients in the presence of a persistent blood level above 100 ug per milliliter. Twenty‐four hour urinary excretion of unchanged drug in 2 patients was 20 and 33 per cent of the initial dose, and 80 per cent in one patient on maintenance. In order to investigate the fate of the drug better, 3H‐diazoxide was purified for use in adult volunteers and animals. The half‐life of the drug in plasma of 2 adults was 24 and 36 hours. In these subiects as much as 94 per cent of the radioactive dose was recovered in the urine. About half the radioactivity in urine was present as unchanged drug. The plasma half‐life of 3H‐diazoxide in rats and dogs was much shorter than in man.

Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia

“…The obtained half-life of diazoxide varied from 5.9 to 27.7 h, which is consistent with previous reports citing 9.5–24 h [14]. Our simulations indicated no significant difference in the C ss,av between the twice- and 3 times-daily dosing groups.…”

“…Typically, antiepileptic drugs are metabolized by CYP450 in the liver, while diazoxide is excreted by the kidneys. Pruitt et al [14] reported that the half-life of diazoxide was shorter in 2 children receiving phenobarbital and diphenylhydantoin, and attributed this to concomitant use of an antiepileptic agent. However, we suspect that confounding factor(s), such as WT, affected the outcome of this study.…”

“…The pharmacokinetics of diazoxide were assumed to adhere to a 1-compartment model with first-order elimination from the central compartment [14]. The structural parameters were total body clearance (CL/F, in which F represents oral bioavailability) and volume of distribution in the central compartment (V/F).…”

“…Up to now, the pharmacokinetics of diazoxide have been reported from only 4 adults [13, 14] and 4 children [14], yielding insufficient information considering this agent is used as a first-line treatment for HI in children. PPK analysis is recommended by the FDA in the US and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan as a useful method for assessing special populations such as pediatric and geriatric patients, and patients with complicated organ diseases [15, 16], as it can analyze pharmacokinetic features using sparsely sampled data which is more feasible in clinical settings [12].…”

Paradoxical Hypoglycaemia Associated with Diazoxide Therapy for Hyperinsulinaemic Hypoglycaemia

“…Subsequently, diazoxide was stopped, which stabilised the blood glucose concentration. The half-life of diazoxide in children is believed to be about 9.5-20 h with no data on neonates [13]. Following oral administration of diazoxide suspension, the hyperglycaemic effect begins within 1 h and lasts for approximately 8 h. The plasma concentration of diazoxide required for the hyperglycaemic effects in neonates is not known, although in adults, a peak blood level of 16 μg/ml has caused hyperglycaemia within 4 h of oral administration of a single dose of 10 mg/kg per day [14].…”