Documentation concerning the pharmacokinetics and dosage recommendations of diazoxide in neonates a

Fråga: Documentation concerning the pharmacokinetics and dosage recommendations of diazoxide in neonates and newborns in treatment of hypoglycemia.

Sammanfattning: There is sparse documentation concerning the pharmacokinetics of diazoxide in neonates and infants. Concerning dosage recommendations, an initial dose of 10 mg per kg daily in three divided doses has been suggested, usual maintenance doses have ranged from 8 to 15 mg per kg daily in two or three divided doses.

Svar: Diazoxide is a non-diuretic benzothiadizine derivate chemically related to the thiazide diuretics. Parenterally it is used as an antihypertensive agent. It is used orally in neonates and infants for management of hypoglycemia associated with leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell adenoma and adenomatosis (1). For treatment of hypoglycemia the oral preparation is available on licence in Sweden.

Diazoxide produces an increase in blood glucose by a direct action on the insulin secretion. There seems to be an extrapancreatic action involved as well, but the mechanism is unclear (1).

The increase in blood glucose is apparent within one hour of administration and high glucose levels are maintained during 4-6 hours (1). Finally, it also acts as a peripheral vasodilator (1).

A literature search, including Medline, Drugline and pharmacological handbooks, has been performed as well as personal communication with the manufacturer (2). Data concerning the pharmacokinetics in neonates and newborns is sparse. In adults diazoxide is readily absorbed (85-95 per cent) (1). There is no evidence of presystemic metabolism (1). The half-life is 20-60 hours in adults (3). Approximately 90 per cent of diazoxide is bound to plasma albumin. Similar results were obtained in adults(91.9 per cent) and newborns(87.7 per cent)(1).

In a study of disposition of diazoxide in four children at the age of four months to six years, the elimination half-life of diazoxide was in the range of 9.5-24 hours (4). The child with the shortest half-life had concomitant treatment with phenobarbitone, phenytoin and primidone. The elimination of diazoxide from blood was linear except in one patient, who had received extremely high doses of diazoxide and showed a dose-dependent elimination (4).

Diazoxide is eliminated through glomerular filtration (1). In patients with impaired renal function the serum half-life of diazoxide is increased (1). Hepatic biotransformation of diazoxide is quantitatively less important than urinary excretion of the unchanged drug (1). During the neonatal period and early infancy the elimination of many drugs that are excreted in the urine in unchanged form is restricted by the immaturity of glomerular filtration and renal tubular secretion (5). Thus, these patients probably have a decreased clearance of diazoxide and therefore a prolonged half-life and time to steady-state compared to infants.

In a pharmacological handbook (3,6) the following dose suggestions in neonates and infants for treatment of hypoglycemia are found: an initial dose of 10 mg per kg daily in three divided doses, usual maintenance doses have ranged from 8 to 15 mg/kg daily in two or three divided doses. Up to 20 mg/kg daily has been suggested in children with leucine-sensitive hypoglycemia. 1 Dollery, Therapeutic drugs. 1991; 1st ed:

2 Birgitta Åkerström, manufacturer representative, Shering-Plough
3 Goodman and Gilman, The pharmacological basis of therapeutics, 1996; 9th ed:
4 Pruitt AW, Dayton PG, Patterson JH: Disposition of diazoxide in children. Clin Pharmacol Ther 1972; 14: 73-82
5 Rane A, Wilson JT: Clinical pharmacokinetics in infants and children. Clin Pharmacokinet 1976; 1: 2-24

6 Martindale, The extra pharmacopoeia, 1996; 31st ed: