Pharmacokinetics and metabolism of intravenous midazolam in preterm infants

S. N. De Wildt, G. L. Kearns, W. C.J. Hop, D. J. Murry, S. M. Abdel-Rahman, J. N. Van Den Anker

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Background: Midazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants. Methods: The pharmacokinetics of midazolam and its hydroxylated metabolite (1-OH-midazolam) after a single 0.1 mg/kg intravenous dose of midazolam were determined in 24 preterm infants (gestational age, 26 to 34 weeks; postnatal age, 3 to 11 days). Blood samples were obtained before drug administration and at 0.5, 1, 2, 4, 6, 12, and 24 hours after the start of the infusion. Midazolam and 1-OH-midazolam concentrations were determined by use of gas chromatography-mass spectrometry. Results: Total body clearance, apparent volume of distribution, and plasma half-life of midazolam were (median [range]): 1.8 (0.7-6.7) ml/kg per min, 1.1 (0.4-4.2) L/kg, and 6.3 (2.6-17.7) h, respectively. In 19 of 24 preterm infants, 1-OH-midazolam concentrations could be detected: 1-OH-midazolam (1-OH-M) maximal concentration of drug in plasma (Cmax), time to reach Cmax (Tmax), and 1-OH-M/M area under the concentration-time curve from time zero to the last sampling time point (AUC0-t) ratio were [median (range)]: 8.2 (<0.5-68.2) ng/ml, 6 (1-12) h, and 0.09 (<0.001-1), respectively. Midazolam plasma clearance was increased in those infants who had indomethacin (INN, indometacin) exposure. Discussion: Consequent to immature hepatic cytochrome P450 3A4 (CYP3A4) activity, midazolam clearance and 1-OH-midazolam concentrations are reduced markedly in preterm infants as compared to concentrations in previous reports from studies in older children and adults. Indomethacin exposure and its apparent impact on midazolam clearance support alteration of drug disposition produced by a patent ductus arteriosus or by the direct effects of indomethacin on hemodynamic or renal function.

Original languageEnglish (US)
Pages (from-to)525-531
Number of pages7
JournalClinical Pharmacology and Therapeutics
Volume70
Issue number6
DOIs
StatePublished - Dec 1 2001

Fingerprint

Midazolam
Premature Infants
Pharmacokinetics
Indomethacin
Pharmaceutical Preparations
Cytochrome P-450 CYP3A
Patent Ductus Arteriosus
Plasma Volume
Neonatal Intensive Care Units
Benzodiazepines
Gas Chromatography-Mass Spectrometry
Gestational Age
Half-Life
hydroxide ion

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

De Wildt, S. N., Kearns, G. L., Hop, W. C. J., Murry, D. J., Abdel-Rahman, S. M., & Van Den Anker, J. N. (2001). Pharmacokinetics and metabolism of intravenous midazolam in preterm infants. Clinical Pharmacology and Therapeutics, 70(6), 525-531. https://doi.org/10.1067/mcp.2001.120683

Pharmacokinetics and metabolism of intravenous midazolam in preterm infants. / De Wildt, S. N.; Kearns, G. L.; Hop, W. C.J.; Murry, D. J.; Abdel-Rahman, S. M.; Van Den Anker, J. N.

In: Clinical Pharmacology and Therapeutics, Vol. 70, No. 6, 01.12.2001, p. 525-531.

Research output: Contribution to journalArticle

De Wildt, SN, Kearns, GL, Hop, WCJ, Murry, DJ, Abdel-Rahman, SM & Van Den Anker, JN 2001, 'Pharmacokinetics and metabolism of intravenous midazolam in preterm infants', Clinical Pharmacology and Therapeutics, vol. 70, no. 6, pp. 525-531. https://doi.org/10.1067/mcp.2001.120683
De Wildt, S. N. ; Kearns, G. L. ; Hop, W. C.J. ; Murry, D. J. ; Abdel-Rahman, S. M. ; Van Den Anker, J. N. / Pharmacokinetics and metabolism of intravenous midazolam in preterm infants. In: Clinical Pharmacology and Therapeutics. 2001 ; Vol. 70, No. 6. pp. 525-531.
@article{5a7f20cf36b3495d85f383574ab9e2bb,
title = "Pharmacokinetics and metabolism of intravenous midazolam in preterm infants",
abstract = "Background: Midazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants. Methods: The pharmacokinetics of midazolam and its hydroxylated metabolite (1-OH-midazolam) after a single 0.1 mg/kg intravenous dose of midazolam were determined in 24 preterm infants (gestational age, 26 to 34 weeks; postnatal age, 3 to 11 days). Blood samples were obtained before drug administration and at 0.5, 1, 2, 4, 6, 12, and 24 hours after the start of the infusion. Midazolam and 1-OH-midazolam concentrations were determined by use of gas chromatography-mass spectrometry. Results: Total body clearance, apparent volume of distribution, and plasma half-life of midazolam were (median [range]): 1.8 (0.7-6.7) ml/kg per min, 1.1 (0.4-4.2) L/kg, and 6.3 (2.6-17.7) h, respectively. In 19 of 24 preterm infants, 1-OH-midazolam concentrations could be detected: 1-OH-midazolam (1-OH-M) maximal concentration of drug in plasma (Cmax), time to reach Cmax (Tmax), and 1-OH-M/M area under the concentration-time curve from time zero to the last sampling time point (AUC0-t) ratio were [median (range)]: 8.2 (<0.5-68.2) ng/ml, 6 (1-12) h, and 0.09 (<0.001-1), respectively. Midazolam plasma clearance was increased in those infants who had indomethacin (INN, indometacin) exposure. Discussion: Consequent to immature hepatic cytochrome P450 3A4 (CYP3A4) activity, midazolam clearance and 1-OH-midazolam concentrations are reduced markedly in preterm infants as compared to concentrations in previous reports from studies in older children and adults. Indomethacin exposure and its apparent impact on midazolam clearance support alteration of drug disposition produced by a patent ductus arteriosus or by the direct effects of indomethacin on hemodynamic or renal function.",
author = "{De Wildt}, {S. N.} and Kearns, {G. L.} and Hop, {W. C.J.} and Murry, {D. J.} and Abdel-Rahman, {S. M.} and {Van Den Anker}, {J. N.}",
year = "2001",
month = "12",
day = "1",
doi = "10.1067/mcp.2001.120683",
language = "English (US)",
volume = "70",
pages = "525--531",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Pharmacokinetics and metabolism of intravenous midazolam in preterm infants

AU - De Wildt, S. N.

AU - Kearns, G. L.

AU - Hop, W. C.J.

AU - Murry, D. J.

AU - Abdel-Rahman, S. M.

AU - Van Den Anker, J. N.

PY - 2001/12/1

Y1 - 2001/12/1

N2 - Background: Midazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants. Methods: The pharmacokinetics of midazolam and its hydroxylated metabolite (1-OH-midazolam) after a single 0.1 mg/kg intravenous dose of midazolam were determined in 24 preterm infants (gestational age, 26 to 34 weeks; postnatal age, 3 to 11 days). Blood samples were obtained before drug administration and at 0.5, 1, 2, 4, 6, 12, and 24 hours after the start of the infusion. Midazolam and 1-OH-midazolam concentrations were determined by use of gas chromatography-mass spectrometry. Results: Total body clearance, apparent volume of distribution, and plasma half-life of midazolam were (median [range]): 1.8 (0.7-6.7) ml/kg per min, 1.1 (0.4-4.2) L/kg, and 6.3 (2.6-17.7) h, respectively. In 19 of 24 preterm infants, 1-OH-midazolam concentrations could be detected: 1-OH-midazolam (1-OH-M) maximal concentration of drug in plasma (Cmax), time to reach Cmax (Tmax), and 1-OH-M/M area under the concentration-time curve from time zero to the last sampling time point (AUC0-t) ratio were [median (range)]: 8.2 (<0.5-68.2) ng/ml, 6 (1-12) h, and 0.09 (<0.001-1), respectively. Midazolam plasma clearance was increased in those infants who had indomethacin (INN, indometacin) exposure. Discussion: Consequent to immature hepatic cytochrome P450 3A4 (CYP3A4) activity, midazolam clearance and 1-OH-midazolam concentrations are reduced markedly in preterm infants as compared to concentrations in previous reports from studies in older children and adults. Indomethacin exposure and its apparent impact on midazolam clearance support alteration of drug disposition produced by a patent ductus arteriosus or by the direct effects of indomethacin on hemodynamic or renal function.

AB - Background: Midazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants. Methods: The pharmacokinetics of midazolam and its hydroxylated metabolite (1-OH-midazolam) after a single 0.1 mg/kg intravenous dose of midazolam were determined in 24 preterm infants (gestational age, 26 to 34 weeks; postnatal age, 3 to 11 days). Blood samples were obtained before drug administration and at 0.5, 1, 2, 4, 6, 12, and 24 hours after the start of the infusion. Midazolam and 1-OH-midazolam concentrations were determined by use of gas chromatography-mass spectrometry. Results: Total body clearance, apparent volume of distribution, and plasma half-life of midazolam were (median [range]): 1.8 (0.7-6.7) ml/kg per min, 1.1 (0.4-4.2) L/kg, and 6.3 (2.6-17.7) h, respectively. In 19 of 24 preterm infants, 1-OH-midazolam concentrations could be detected: 1-OH-midazolam (1-OH-M) maximal concentration of drug in plasma (Cmax), time to reach Cmax (Tmax), and 1-OH-M/M area under the concentration-time curve from time zero to the last sampling time point (AUC0-t) ratio were [median (range)]: 8.2 (<0.5-68.2) ng/ml, 6 (1-12) h, and 0.09 (<0.001-1), respectively. Midazolam plasma clearance was increased in those infants who had indomethacin (INN, indometacin) exposure. Discussion: Consequent to immature hepatic cytochrome P450 3A4 (CYP3A4) activity, midazolam clearance and 1-OH-midazolam concentrations are reduced markedly in preterm infants as compared to concentrations in previous reports from studies in older children and adults. Indomethacin exposure and its apparent impact on midazolam clearance support alteration of drug disposition produced by a patent ductus arteriosus or by the direct effects of indomethacin on hemodynamic or renal function.

UR - http://www.scopus.com/inward/record.url?scp=0035652107&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035652107&partnerID=8YFLogxK

U2 - 10.1067/mcp.2001.120683

DO - 10.1067/mcp.2001.120683

M3 - Article

C2 - 11753268

AN - SCOPUS:0035652107

VL - 70

SP - 525

EP - 531

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 6

ER -