Larger Dose Reductions of Vancomycin Required in Neonates with Patent Ductus Arteriosus Receiving Indomethacin versus Ibuprofen

Abstract

Ibuprofen and indomethacin are commonly used to induce ductus arteriosus closure in preterm neonates. Our group previously reported that ibuprofen decreased vancomycin clearance by 16%. In this study, we quantified the impact of indomethacin coadministration on vancomycin clearance by extending our vancomycin population pharmacokinetic model with a data set containing vancomycin concentrations measured in preterm neonates comedicated with indomethacin. The modeling data set includes concentration-time data of vancomycin administered alone or in combination with either ibuprofen or indomethacin collected in the neonatal intensive care units of UZ Leuven (Leuven, Belgium) and São Francisco Xavier Hospital (Lisbon, Portugal). The derived vancomycin pharmacokinetic model was subsequently used to propose dose adjustments that yield effective vancomycin exposure (i.e., area under the concentration-time curve from 0 to 24 h [AUC 0 -24 ] between 300 to 550 mg·h/liter, with a probability of Ͻ0.1 of subtherapeutic exposure) in preterm neonates with patent ductus arteriosus. We found that indomethacin coadministration reduced vancomycin clearance by 55%. Model simulations showed that the most recent vancomycin dosing regimen, which was based on an externally validated model, requires 20% and 60% decreases of the loading and maintenance doses of vancomycin, respectively, when aiming for optimized exposure in the neonatal population. By analyzing vancomycin data from preterm neonates comedicated with indomethacin, we found a substantial decrease in vancomycin clearance of 55% versus a previously reported 16% for ibuprofen. This decrease in clearance impacts vancomycin dosing, and we anticipate that other drugs eliminated by glomerular filtration are likely to be affected to a similar extent as vancomycin.

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

“…If one decides to treat the PDA, ibuprofen is currently considered as the drug of choice. Ibuprofen showed lower risks for side‐effects and a potential decreased risk for necrotising enterocolitis compared to indomethacin, whereas the role of acetaminophen for PDA still remains to be determined 3–6 . In addition, the reduction in clearance of the renally excreted antibiotic vancomycin was lower when ibuprofen instead of indomethacin was administered, suggesting less nephrotoxicity 4 …”

A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates

“…This setting is not unique, since similar to e.g. patent ductus arteriosus, where both the (patho)physiology of the clinical syndrome (vascular steal phenomenon, with lung overflow, and systemic hypoperfusion) (Hundscheid et al, 2019) and its pharmacological management (ibuprofen, indomethacin or paracetamol) will affect the phenotype (Allegaert et al, 2013;Cristea et al, 2019).…”

Target Drug Exposure Attainment in Children: How to Get from Better to Best

“…Unfortunately, such integration in electronic health records is currently only in development [12]. Using integrated CDS will minimize data translation errors, and data of predictors for the PK or pharmacodynamics may be continuously translated to suggested pharmacotherapy adjustments (e.g., creatinine for aminoglycosides and vancomycin, postnatal age for maturational effect, interacting comedication such as nonsteroidal anti-inflammatory drugs on vancomycin clearance) [13]. This would require reliable registered data of clinical care, which may be achieved using scanning, automated checks, and bi-directional data transfer.…”