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

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.

Oral acetaminophen administration for patent ductus arteriosus (PDA) closure in preterm neonates

2021 ◽  
Vol 43 (3) ◽  
pp. 254-259
Author(s):  
Mahmood Samadi ◽  
Zahra Nabaee ◽  
Manizheh Mostafagharebaghi ◽  
Majid Mahalei ◽  
Elham Sheykhsaran ◽  
...  
Keyword(s):  
Patent Ductus Arteriosus ◽  
Gestational Age ◽  
Statistical Significance ◽  
Ductus Arteriosus ◽  
Preterm Neonates ◽  
Term Infants ◽  
Treatment Data ◽  
Kolmogorov Smirnov ◽  
Study Population ◽  
Patent Ductus

Background: Patent Ductus Arteriosus (PDA) is considered one of the most prevalent types of congenital heart disease. The closure of the ductus arteriosus physiologically occurs at the first 48-72 hours after the birth in healthy term infants. Different causes can result in the pathological opening of ductus arteriosus. This study aims to investigate the effect of oral acetaminophen on the closure of PDA in preterm neonates. Methods: The present study is a trial without control. Forty-five preterm neonates with a gestational age of <32 weeks were studied. Acetaminophen was orally administered with a dose of 10mg/kg every 6 hours for three days. Closure of ductus arteriosus was considered as the success of treatment. Data were analyzed using SPSS 15. Data were reported as )frequency-percent) and mean ± SD. To evaluate the normal distribution of data, we used a Kolmogorov-Smirnov test. Statistical significance was defined as P<0.05. Results: The study population consisted of 20 male and 25 female infants with the mean gestational age of 28.95 ± 1.66 weeks. Cesarean-born infants and vaginal-born infants consisted 17.8% and 82.2% of the study population, respectively. The proportion of PDA closure after administration of oralacetaminophen was 82.3%. Conclusion: The current study indicates that oral acetaminophen is highly effective in closing PDA. Considering its trivial side effects, it has the potency to be a convenient option for treating this condition.

Drug Disposition in Neonates with Patent Ductus Arteriosus

1993 ◽  
Vol 27 (11) ◽  
pp. 1383-1388 ◽  
Author(s):  
Peter Gal ◽  
Jamie T. Gilman
Keyword(s):  
Patent Ductus Arteriosus ◽  
English Language ◽  
Drug Disposition ◽  
Ductus Arteriosus ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Drug Elimination ◽  
Concurrent Administration ◽  
Liver And Kidney ◽  
Patent Ductus

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.

scholarly journals CYP2C9*2 is associated with indomethacin treatment failure for patent ductus arteriosus

2019 ◽  
Vol 20 (13) ◽  
pp. 939-946
Author(s):  
Sydney R Rooney ◽  
Elaine L Shelton ◽  
Ida Aka ◽  
Christian M Shaffer ◽  
Ronald I Clyman ◽  
...  
Keyword(s):  
Patent Ductus Arteriosus ◽  
Treatment Failure ◽  
Preterm Infants ◽  
Gestational Age ◽  
Genetic Factors ◽  
Ductus Arteriosus ◽  
Preterm Neonates ◽  
Multicenter Cohort Study ◽  
Patent Ductus ◽  
Indomethacin Treatment

Aims: To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA). Patients & Methods: This is a multicenter cohort study of 144 preterm infants (22–32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention. Results: In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60–0.96), surfactant use (AOR 9.77, 95% CI 1.15–83.26), and CYP2C9*2 (AOR 3.74; 95% CI 1.34–10.44) were each associated with indomethacin failure. Conclusion: Age, surfactant use, and CYP2C9*2 influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.

scholarly journals Association of patent ductus arteriosus (PDA) with prematurity and low birth weight neonates

2019 ◽  
Vol 6 (2) ◽  
pp. 781
Author(s):  
Gh Rasool Wani ◽  
Nazir Ahmad Parray ◽  
Mohd Rafiq Lone ◽  
Nisar Ahmad Ganie ◽  
Anwar Hussain ◽  
...  
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Patent Ductus Arteriosus ◽  
Gestational Age ◽  
Ductus Arteriosus ◽  
Preterm Neonates ◽  
Study Cohort ◽  
Care Hospital ◽  
Number Of Patients ◽  
Patent Ductus

Background: Patent ductus arteriosus (PDA) is a major morbidity encountered in preterm neonates, especially in babies less than 28 weeks gestation or 1000g. It may close spontaneously in preterm neonates; however, failure to close spontaneously in preterm neonates results in significant mortality and morbidity in them.Methods: This prospective study was conducted in a tertiary care hospital in north India over a period of one year. The study cohort consisted of preterm, newborn babies admitted in the hospital with gestational age less than 37weeks and birth weight <2500g.Results: In this study total number of patients admitted during the study were 2930. Out of these preterm low birth weight neonates were 432. Among preterm low birth weight neonates admitted, 132 neonates were excluded as per exclusion criteria. Patent ductus arteriosus was detected in 56 among the 300 neonates giving an overall incidence of patent ductus arteriosus 18.6%, the incidence of patent ductus arteriosus was 56.2% for neonates weighing less than 1000gm, 24.7% for neonates weighing between 1000-1499g, 11.6% for neonates weighing between 1500-1999g and 5.6% for the neonates weighing between 2000-2499g.Conclusions: Thus, incidence of patent ductus arteriosus was inversely proportional to gestational age and birth. Data also suggest that immaturity is the major determinant of the persistent patency of ductus arteriosus.

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

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
S. Cristea ◽  
K. Allegaert ◽  
A. C. Falcao ◽  
F. Falcao ◽  
R. Silva ◽  
...  
Keyword(s):  
Patent Ductus Arteriosus ◽  
Pharmacokinetic Model ◽  
Ductus Arteriosus ◽  
Preterm Neonates ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Data Set ◽  
Concentration Time ◽  
The Impact ◽  
Patent Ductus

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 [AUC0–24] between 300 to 550 mg·h/liter, with a probability of <0.1 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.

Wide Pulse Pressure Is Not Associated with Patent Ductus Arteriosus in the First Week of Life

2019 ◽  
Vol 36 (13) ◽  
pp. 1401-1404
Author(s):  
Alona Bin-Nun ◽  
Yair Kasirer ◽  
Francis Mimouni ◽  
Irina Schorrs ◽  
Daniel Fink ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Patent Ductus Arteriosus ◽  
Preterm Infants ◽  
Study Design ◽  
Gestational Age ◽  
Pulse Pressure ◽  
Ductus Arteriosus ◽  
Preterm Neonates ◽  
Patent Ductus

Objectives Widened pulse pressure is generally associated with patent ductus arteriosus (PDA). Surprisingly, this is often not true for preterm infants during the first week of life when systolic and diastolic pressures are both reduced and pulse pressure may remain unchanged. Study Design This is a retrospective, observational review of individual blood pressure (BP) parameters preterm neonates <30 weeks' gestational age during the first week of life as correlated with ductal patency and severity. Results Sixteen preterm neonates had a closed ductus on initial echocardiogram during the first week of life; 30 had a PDA that was open but hemodynamically insignificant; and 16 were found to have a hemodynamically significant PDA. Pulse pressure showed no correlation (p = 0.266) with the degree of ductal patency, whereas diastolic BP was best correlated with ductal severity (p < 0.001). Conclusion We found that low diastolic pressures are better correlated with ductal patency and severity than is pulse pressure in preterm neonates during the first week of life.

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