AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 2
March 1991
GASTROINTESTINAL ABSORPTION OF DOXAPRAM IN NEONATES Aida Bairam, M.D.,* Lynne Akramoff-Gershan, M.D., Kae Beharry, Nicole Laudignon, M.D., Apostolos Papageorgiou, M.D., and Jacob V. Aranda, M.D., Ph.D.
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 birthweightof 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.
Doxapram is a respiratory stimulant used for idiopathic apnea of prematurity, refractory to the methylxanthines.1'2 The efficacy of this drug partly depends on the plasma concentrations achieved, with a tentative mean therapeutic plasma concentration of 2.9 ± 1.3 mg/ml.3 Currently, doxapram is given as a continuous intravenous infusion with a dose of 0.5 mg/kg/hr to 2.5 or 3 mg/kg/hr, titrated to the individual response. A major limiting factor is the necessity for an intravenous line that has to be maintained for several days even when babies are completely orally fed. In order to avoid the intravenous treatment, we designed this study to assess the gastrointestinal absorption of doxapram in the premature newborn infant and to determine whether therapeutic plasma concentrations can be achieved through the oral route. In addition, we also determined the metabolites of doxapram after oral dosing.
SUBJECTS AND METHODS
Six premature babies (3 males, 3 females) with a mean gestational age of 29 ± 2.3 weeks, and mean birthweight of 1142 ± 359 gm were studied. Their mean postnatal age at the beginning of treatment was 24 ± 22 days (range, 5 to 55). All infants had apnea previously treated with caffeine and were given doxapram at three different doses on 3 successive days (concomitantly with caffeine). Doxapram dose was increased incrementally from 12 mg/kg/6 hr on the first day, to 24 mg/kg/6 hr on the second day and to 36 mg/kg/6 hr on the third day. These doses of 12, 24, 36 mg/kg/6 hr were derived from intravenous doses of 1, 2, 3 mg/kg/hr and assuming a bioavailability of 50%. The intravenous solution of doxapram used in this treatment (doxapram, A.H. Robins, Montreal,
Departments of Pediatrics and of Pharmacology and Therapeutics, McGill University-Montreal Children's Hospital Research Institute and the Jewish General Hospital, Montreal, Canada This study was supported in part by MRC grant #MA-10219 *Dr. Bairam was a Fellow of the Pollack Foundation, Sir Mortimer B. Davis-Jewish General Hospital, Montreal Reprint requests: Dr. Aranda, Montreal Children's Hospital, 2300 Tupper Street, Montreal, Quebec, Canada H3H 1P3
110
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
ABSTRACT
ABSORPTION OF DOXAPRAM IN NEONATES/Bairam, et al
pressed as mean ± SEM, and the changes in heart rate (HR), respiratory rate (RR), TcPO2, and blood pressure were analyzed by using ANOVA for repeated measurements, and a p value of
March 1991
GASTROINTESTINAL ABSORPTION OF DOXAPRAM IN NEONATES Aida Bairam, M.D.,* Lynne Akramoff-Gershan, M.D., Kae Beharry, Nicole Laudignon, M.D., Apostolos Papageorgiou, M.D., and Jacob V. Aranda, M.D., Ph.D.
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 birthweightof 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.
Doxapram is a respiratory stimulant used for idiopathic apnea of prematurity, refractory to the methylxanthines.1'2 The efficacy of this drug partly depends on the plasma concentrations achieved, with a tentative mean therapeutic plasma concentration of 2.9 ± 1.3 mg/ml.3 Currently, doxapram is given as a continuous intravenous infusion with a dose of 0.5 mg/kg/hr to 2.5 or 3 mg/kg/hr, titrated to the individual response. A major limiting factor is the necessity for an intravenous line that has to be maintained for several days even when babies are completely orally fed. In order to avoid the intravenous treatment, we designed this study to assess the gastrointestinal absorption of doxapram in the premature newborn infant and to determine whether therapeutic plasma concentrations can be achieved through the oral route. In addition, we also determined the metabolites of doxapram after oral dosing.
SUBJECTS AND METHODS
Six premature babies (3 males, 3 females) with a mean gestational age of 29 ± 2.3 weeks, and mean birthweight of 1142 ± 359 gm were studied. Their mean postnatal age at the beginning of treatment was 24 ± 22 days (range, 5 to 55). All infants had apnea previously treated with caffeine and were given doxapram at three different doses on 3 successive days (concomitantly with caffeine). Doxapram dose was increased incrementally from 12 mg/kg/6 hr on the first day, to 24 mg/kg/6 hr on the second day and to 36 mg/kg/6 hr on the third day. These doses of 12, 24, 36 mg/kg/6 hr were derived from intravenous doses of 1, 2, 3 mg/kg/hr and assuming a bioavailability of 50%. The intravenous solution of doxapram used in this treatment (doxapram, A.H. Robins, Montreal,
Departments of Pediatrics and of Pharmacology and Therapeutics, McGill University-Montreal Children's Hospital Research Institute and the Jewish General Hospital, Montreal, Canada This study was supported in part by MRC grant #MA-10219 *Dr. Bairam was a Fellow of the Pollack Foundation, Sir Mortimer B. Davis-Jewish General Hospital, Montreal Reprint requests: Dr. Aranda, Montreal Children's Hospital, 2300 Tupper Street, Montreal, Quebec, Canada H3H 1P3
110
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
ABSTRACT
ABSORPTION OF DOXAPRAM IN NEONATES/Bairam, et al
pressed as mean ± SEM, and the changes in heart rate (HR), respiratory rate (RR), TcPO2, and blood pressure were analyzed by using ANOVA for repeated measurements, and a p value of
