Drug Disposition in Neonates with Patent Ductus Arteriosus

OBJECTIVE: To review the literature on the physiologic changes created by neonatal patent ductus arteriosus (PDA) and the potential impact on drug disposition in these infants. DATA SOURCES: An Index Medicus and bibliographic search of the English-language literature pertaining to neonatal PDA and drug usage in newborns. DATA SYNTHESIS: PDA in premature infants is associated with a variety of physiologic changes that could alter drug disposition. Perfusion of drug-elimination organs (i.e., liver and kidney) may be diminished, resulting in decreased drug elimination. Further, the general fluid overload state associated with PDA may result in larger volumes of distribution (Vd), and dilutional effects for many drugs. Drug absorption, Vd, tissue penetration, and clearance may be affected by the physiologic changes incurred by a PDA. Although the pharmacokinetics of several categories of therapeutic agents may be affected by a PDA, disposition changes with the aminoglycosides and indomethacin have been the best documented. The most reliable pharmacokinetic change appears to be related to drug Vd. The interpretation of many of these studies is confounded by a potential drug interaction with the concurrent administration of indomethacin for PDA closure. CONCLUSIONS: Close therapeutic drug monitoring is indicated in newborns with PDAs as abrupt changes in drug disposition can occur with PDA closure. PDA-induced changes in specific pharmacokinetic parameters of agents such as the aminoglycosides, indomethacin, and perhaps vancomycin may prove to be a valuable diagnostic adjunct for the identification of babies with undiagnosed PDA. More research into this pharmacophysiologic aspect of pharmacokinetics is warranted.

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Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates

Archives of Disease in Childhood ◽

10.1136/archdischild-2020-321381 ◽

2021 ◽

pp. archdischild-2020-321381

Author(s):

Samira Samiee-Zafarghandy ◽

Tamara van Donge ◽

Gerhard Fusch ◽

Marc Pfister ◽

George Jacob ◽

...

Keyword(s):

Patent Ductus Arteriosus ◽

Gestational Age ◽

Ductus Arteriosus ◽

Plasma Concentrations ◽

Preterm Neonates ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Target Exposure ◽

Patent Ductus

ObjectiveExploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates.DesignProspective, single-centre, open-label, pharmacokinetics study in preterm neonates.SettingNeonatal intensive care unit at McMaster Children’s Hospital.PatientsNeonates with a gestational age ≤28+6 weeks treated with oral ibuprofen for closure of a PDA.MethodsPopulation pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation.Main outcome measureAssociation between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC0–72h >900 mg·hour/L).ResultsTwenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours’ postdose on the first day, a strong correlation between ibuprofen concentrations and AUC0–72h was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure.ConclusionWe designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC0–72h >900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA.

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