Rapidly maturing fentanyl clearance in preterm neonates

Abstract

BackgroundFentanyl is frequently used off-label in preterm newborns. Due to very limited pharmacokinetic and pharmacodynamic data, fentanyl dosing is mostly based on bodyweight. This study describes the maturation of the pharmacokinetics in preterm neonates born before 32 weeks of gestation.Methods442 plasma samples from 98 preterm neonates (median gestational age: 26.9 (range 23.9–31.9) weeks, postnatal age: 3 (range 0–68) days, bodyweight 1.00 (range 0.39–2.37) kg) were collected in an opportunistic trial and fentanyl plasma levels were determined. NONMEM V.7.3 was used to develop a population pharmacokinetic model and to perform simulations.ResultsFentanyl pharmacokinetics was best described by a two-compartment model. A pronounced non-linear influence of postnatal and gestational age on clearance was identified. Clearance (L/hour/kg) increased threefold, 1.3-fold and 1.01-fold in the first, second and third weeks of life, respectively. In addition, clearance (L/hour/kg) was 1.4-fold and 1.7-fold higher in case of a gestational age of 28 and 31 weeks, respectively, compared with 25 weeks. Volume of distribution changed linearly with bodyweight and was 8.7 L/kg. To achieve similar exposure across the entire population, a continuous infusion (µg/kg/hour) dose should be reduced by 50% and 25% in preterm neonates with a postnatal age of 0–4 days and 5–9 days in comparison to 10 days and older.ConclusionBecause of low clearance, bodyweight-based dosages may result in fentanyl accumulation in neonates with the lowest postnatal and gestational ages which may require dose reduction. Together with additional information on the pharmacodynamics, the results of this study can be used to guide dosing.

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 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).…”

Comment on: "Preterm Physiologically Based Pharmacokinetic Model, Part I and Part II”

“…Birth leads to complex physiological changes in multiple organ systems, independent from gestational age, including the cardiovascular, respiratory, hepatic and renal systems, all of which impact the maturation of the PK of drugs [4][5][6]. The effect of birth has been repeatedly shown in population PK models for both hepatically cleared [7][8][9] and renally cleared drugs [10,11]. In those studies, the combination of gestational age or birthweight with postnatal age, and not PMA, were the best predictors of PK in a large heterogeneous group of preterm neonates.…”

Phenobarbital Increases Midazolam Clearance in Neonates Treated with Hypothermia: Do We Really Need to Know?

“…Allegaert/Smits/van den Anker Neonatology 2 DOI: 10.1159/000499742 activity already early in life. Similar patterns can be anticipated for other drugs when co-administered with phenobarbital, such as sildenafil (co-occurrence pulmonary hypertension) or fentanyl (narcotic) [6,7]. For all these drugs, a fast postnatal age-driven maturational increase in clearance is described, and it is reasonable to anticipate that this pattern will be further enhanced when phenobarbital is co-administered [6,7].…”