The disposition of intravenous doxapram in man

Abstract

The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg . kg-1) and by intravenous infusion (6.5 mg . kg-1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances 5.9 and 5.6 ml . min-1 . kg-1) following i.v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 microgram . ml-1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 microgram . ml-1 from 15--25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.

Doxapram Only Slightly Reduces the Shivering Threshold in Healthy Volunteers

“…We are unable to determine in the present study whether the differences between target and actual plasma levels resulted from differences in drug disposition, clearance, or nonlinear pharmacokinetic effects due to dosage scaling. Assuming a steady state plasma concentration was achieved before shivering occurred, the total plasma clearance calculated from our data was 12.9 ± 5 mL·kg -1 ·min -1 [range 5.8-21.5 mL·kg -1 ·min -1 ], a value larger than that reported by Clements et al (11). However, Jamali et al (24) found that 4 of 17 neonates had much greater clearance rates of doxapram (19.0-29.2 mL·kg -1 ·min -1 ) than the others.…”

“…Doxapram was infused using a modification of the simplified infusion regimen of Clements et al (11), which was stated to produce a constant plasma concentration of 2 μg/mL. In this case with an objective of 4 μg/mL, the infusion rates were doubled under the assumption of linear pharmacokinetics.…”

Pharmacokinetics of Doxapram in Idiopathic Apnea of Prematurity

“…[21] have recently reported a mean elimination half-life of 9.9 ± 2.9 h for doxapram in apneic prematures. In the infants we studied the half-life of 6.6 ± 5.7 h was double that found in adult vol unteers [15]; however, the clearance of 420 ± 100 ml/kg/h was larger than in adults [15]. The large Vd of 4.1 ± 2.7 litre/kg in the babies studied, compared to adults [ 15], may explain this.…”

“…Because the prolonged half-life may significantly de lay reaching therapeutic levels, we also use a loading dose of 3 mg/kg given over 15 min as Clements et al [15] reported excessive re sponse with a rapid bolus in adults. This reg iment gave doxapram levels of 1.2-2.8 mg/1 within 2 h in 3 patients not included in this report.…”

“…In the last 10 years the use of aminophylline and caffeine respiratory depression associated with the administration of narcotics to mothers [7], recent publications [8][9][10][11][12][13] have reported its successful use to control neonatal apnea un responsive to standard therapy. Although pharmacokinetic studies have been con ducted in adults [14][15][16], information on the pharmacokinetics of doxapram in newborn infants was scarce [8,17]. This report de scribes the pharmacokinetics of doxapram as determined from plasma levels obtained during continuous intravenous infusion of doxapram hydrochloride in 13 premature in fants with apnea unresponsive to aminophylline or caffeine.…”