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. Clinical Pharmacology & Therapeutics (2001) 70, 525–531; doi:

Inter-individual variation in midazolam clearance in children

“…Fourteen studies stated the compartment model used for the PK analysis. Seven used a two compartment model,11 12 14 15 17 18 21 one used a three compartment model,31 one used both one and two compartment model17 and five used a non-compartment model 1316 24 25 28 Ethnicity was described in only four studies 15…”

“…Seven used a two compartment model, 11 12 14 15 17 18 21 one used a three compartment model, 31 one used both one and two compartment model 17 and five used a non-compartment model. 13 16 24 25 28 Ethnicity was described in only four studies. 15 16 24 30 All studies except two were population PK studies.…”

“…11-13 16 Three studies in preterm neonates suggested a 4.5-, 5-and 10-fold variation in clearance in 15, 10 and 24 neonates, respectively. [11][12][13] One study involving five term neonates reported a twofold variation in clearance. 16 The mean clearance in preterm neonates ranged from 0.78 to 2.1 mL/kg/min and in term neonates ranged from 1.17 to 2.5 mL/kg/min.…”

Blood concentrations of midazolam in status epilepticus using an appropriate condition of HPLC

“…Generally, when used as a sedative or an anesthetic, the effect of MDZ occurred quickly and did not cause any circulation changes 8–10 . The pharmacological activity of 1‐OHMDZ and its metabolite, however, remains controversial 8,11–14 . It is definite that the amount of 1‐OHMDZ observed in the blood circulation was significant enough to cause a change in the MDZ and that the effect and safety of MDZ was clear.…”

Analgosedation in neonates: do we still need additional tools after 30 years of clinical research?

“…Midazolam is a short-acting benzodiazepine for sedation through γ-aminobutyric acid receptor interaction in the central nervous system. Midazolam undergoes extensive metabolism by cytochrome P450 3A to a hydroxylated metabolite (1-OH-midazolam) that also displays sedative effects 26. In neonates, hepatic cytochrome P450 3A activity is decreased, resulting in reduced midazolam clearance.…”