Recently Registered Midazolam Doses for Preterm Neonates Do Not Lead to Equal Exposure: A Population Pharmacokinetic Model

Abstract

Although midazolam is a frequently used sedative in neonatal intensive care units, its use in preterm neonates has been off‐label. Recently, a new dosing advice for midazolam for sedation on intensive care units has been included in the label (0.03 mg/[kg·h] for preterm neonates <32 weeks and 0.06 mg/[kg·h] for neonates >32 weeks). Concentration‐time data of a prospective multicenter study (29 patients, median gestational age 26.7 [range 24.0‐31.1 weeks]) were combined with previously published data (26 patients, median gestational age 28.1 [range 26.3‐33.6 weeks]), and a population pharmacokinetic model describing the maturation of midazolam pharmacokinetics was developed in NONMEM 7.3. Clearance was 73.7 mL/h for a neonate weighing 1.1 kg and changed nonlinearly with body weight (exponent 1.69). Volume of distribution increased linearly with body weight and was 1.03 L for a neonate weighing 1.1 kg. Simulations of the newly registered dosing show considerable differences in steady‐state concentrations in preterm neonates. To reach similar steady‐state concentrations of 400 µg/mL (±100 µg/mL), a dose of 0.03 mg/(kg·h) is adequate for neonates ≥1 kg and ≤2 kg but would have to be reduced to 0.02 mg/(kg·h) (−33%) in neonates <1 kg and increased to 0.04 mg/(kg·h) (+33%) in neonates weighing >2 kg and ≤2.5 kg. The impact of the observed differences in exposure is difficult to assess because no target concentrations have yet been defined for midazolam, but the current analysis shows that one should be cautious in giving dosage advice based on historical data with a lack of reliable pharmacokinetic and effect data.

Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus

“…The opportunistic sampling approach used in this study allowed us to study multiple drugs in parallel in a very fragile population, but might not have resulted in the optimal data to study the PK of Ribuprofen. [31][32][33] Despite this limited data we were able to confirm a higher CL R compared to CL S , as also observed in other preterm neonates and older populations (Figure 2). 10,11,[34][35][36] The limited data available can also explain the lack of identification of chiral inversion of R-to S-ibuprofen, as identified in piglets and well described in adults.…”

“…The opportunistic sampling approach used in this study allowed us to study multiple drugs in parallel in a very fragile population, but might not have resulted in the optimal data to study the PK of R‐ibuprofen 31–33 . Despite this limited data we were able to confirm a higher CL R compared to CL S , as also observed in other preterm neonates and older populations (Figure 2).…”

Cerebral Oxygenation and Activity During Surgical Repair of Neonates With Congenital Diaphragmatic Hernia: A Center Comparison Analysis

“…Patients in the midazolam group received midazolam preoperatively for multiple days and had a median midazolam dosage of 0.1 mg kg −1 h −1 intraoperatively. This is substantially higher than the dosing advice of 0.06 mg kg −1 h −1 for sedation with midazolam in neonates with a gestational age above 32 weeks (31), although this dosing advice was already questioned by our research group (32). The elimination half-life of midazolam is ∼6 h in the 1st week of life in full-term neonates (33), although severity of disease and inflammation may also affect the elimination of midazolam in critically ill neonates (34).…”

The bioavailability and maturing clearance of doxapram in preterm infants

“…32,33 This has also been reported for other drugs in preterm born infants who are substrates for CYP3A4, such as midazolam. 34,35 The high estimated oral bioavailability of 74% (RSE 10%) is somewhat higher than the reported 60% in healthy adults by Robson et al 36 in 1979. A higher proportion reaching the systemic circulation may be explained by an age-related lower first-pass effect due to low CYP3A activity in the liver and in the gut wall of newborns.…”