Gastrointestinal absorption of doxapram in neonates
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A Bairam1, L Akramoff-Gershan, K Beharry
1Department of Pediatrics, McGill University-Montreal Children's Hospital Research Institute, Canada.
Insights
Oral doxapram was studied in premature infants with apnea. Poor absorption and gastrointestinal side effects suggest caution against its routine use, despite potential for IV replacement.
Area of Science:
- Neonatal Pharmacology
- Pediatric Respiratory Medicine
Background:
- Apnea of prematurity is a common respiratory challenge in neonates.
- Intravenous doxapram is used, but oral administration offers potential advantages.
Purpose of the Study:
- To evaluate the pharmacokinetics and safety of oral doxapram in premature infants with refractory apnea.
- To determine appropriate dosing for achieving therapeutic plasma concentrations.
Main Methods:
- Six premature infants received escalating oral doses of doxapram (12-36 mg/kg/6 hr).
- Plasma doxapram and ketodoxapram concentrations were measured using high-performance liquid chromatography.
- Bioavailability was estimated, and drug metabolism was assessed.
Main Results:
- Plasma doxapram concentrations increased with dose but indicated poor oral absorption (ratio 0.10-0.12).
- Ketodoxapram, an active metabolite, showed stable plasma concentrations.
- Doses up to 24 mg/kg/6 hr may be needed for therapeutic levels, but gastrointestinal effects were noted.
Conclusions:
- Oral doxapram exhibits poor bioavailability in newborns, necessitating higher doses.
- Interpatient variability, poor absorption, and GI adverse effects limit its routine use.
- Further research is needed to optimize oral doxapram therapy in neonates.
Abstract:
Doxapram was administered orally to six premature babies (3 males, 3 females) with refractory apnea at a mean gestational age of 29 +/- 2.3 weeks, mean birthweight of 1142 +/- 359 gm and a mean postnatal age of 24 days. They received 12, 24, and 36 mg/kg/6 hr on day 1, 2, and 3, respectively, assuming a bioavailability of 50%. Serial plasma doxapram concentrations, determined by high-performance liquid chromatography, increased with incremental doses. The drug underwent oxidative metabolism, producing ketodoxapram, the plasma concentration of which remained stable during treatment. The ratio of plasma concentrations to oral doses ranged from 0.10 to 0.12, suggesting that doxapram is poorly absorbed in the newborn. Oral doxapram may replace the intravenous infusion but doses may have to be increased to, but not exceeding, 24 mg/kg/6 hr to achieve therapeutic plasma concentrations. Interpatient variability, poor absorption and gastrointestinal adverse effects caution against the routine use of oral doxapram.