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Pharmacokinetics and metabolism of intravenous midazolam in preterm infants
Author(s) -
Wildt S. N.,
Kearns G. L.,
Hop W. C. J.,
Murry D. J.,
AbdelRahman S. M.,
Anker J. N.
Publication year - 2001
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(01)15882-0
Subject(s) - midazolam , pharmacokinetics , volume of distribution , medicine , gestational age , chemistry , anesthesia , pharmacology , pregnancy , biology , sedation , genetics
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 (C max ), time to reach C max (T max ), and 1‐OH‐M/M area under the concentration‐time curve from time zero to the last sampling time point (AUC 0−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. Clinical Pharmacology & Therapeutics (2001) 70 , 525–531; doi: 10.1016/S0009‐9236(01)15882‐0