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

Smits, Anne; Annaert, Pieter; Cruchten, Steven Van; Allegaert, Karel

doi:10.3389/fphar.2020.00587

Cited by 31 publications

(46 citation statements)

References 129 publications

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“…However, such findings need to be integrated with isoenzyme-specific ontogeny in neonates. 12 The sum of excretion in the urine of both the intact substance and metabolites that have been produced by the liver, further metabolisation and excretion into bile, sweat, saliva or milk make up the C L . 12 If, for example, a substance is primarily cleared by excretion in the urine, renal function is the principal determinate of clearance.…”

Section: Open Accessmentioning

confidence: 99%

“…12 The sum of excretion in the urine of both the intact substance and metabolites that have been produced by the liver, further metabolisation and excretion into bile, sweat, saliva or milk make up the C L . 12 If, for example, a substance is primarily cleared by excretion in the urine, renal function is the principal determinate of clearance. The Cochrane systematic review on TH could not observe any significant differences in urine output in neonates who underwent TH compared with those who did not.…”

Section: Open Accessmentioning

confidence: 99%

“…Therefore, the control group are often neonates who do not suffer from HIE, which in turn makes it difficult to disentangle the effect of HIE from TH. 12 Phenobarbital is a relatively old antiepileptic drug, which in adults has been substituted by newer agents. However, it remains one of the most effective antiepileptic drugs for neonatal seizures.…”

Section: Morphinementioning

confidence: 99%

“…This is due to the altered pathophysiology explained by both the disease (asphyxia) and the intervention (TH), and includes renal impairment, altered haemodynamics like cardiac output and blood flow, or altered hepatic function. 12 The aim of this paper is to provide an overview on the effects of TH in neonates suffering from HIE have on the PK of drugs administered during this hypothermic period, and whether dosing regimens need to be adjusted.…”

mentioning

confidence: 99%

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Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review

Lutz

Allegaert

Hoon

et al. 2020

bmjpo

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BackgroundNeonatal hypoxic ischaemic encephalopathy due to perinatal asphyxia, can result in severe neurodevelopmental disability or mortality. Hypothermia is at present the only proven neuroprotective intervention. During hypothermia, the neonate may need a variety of drugs with their specific pharmacokinetic profile. The aim of this paper is to determine the effect that hypothermia for neonates suffering from hypoxic ischaemic encephalopathy has on the pharmacokinetics and to what extent dosing regimens need adjustments.MethodA systematic search was performed on PubMed, Embase and Cochrane Library of literature (2000–2020) using a combination of the following search terms: therapeutic hypothermia, neonate, hypoxic ischemic encephalopathy and pharmacokinetics. Titles and abstracts were screened, and inclusion/exclusion criteria were applied. Finally, relevant full texts were read, and secondary inclusion was applied on the identified articles.ResultsA total of 380 articles were retrieved, and 34 articles included after application of inclusion/exclusion criteria and duplicate removal, two additional papers were included as suggested by the reviewers. Twelve out of 36 studies on 15 compounds demonstrated a significant decrease in clearance, be it that the extent differs between routes of elimination and compounds, most pronounced for renal elimination (phenobarbital no difference, midazolam metabolite −21%, lidocaine −24%; morphine −21% to −47%, gentamicin −25% to −35%, amikacin −40%) during hypothermia. The data as retrieved in literature were subsequent compared with the dosing regimen as stated in the Dutch paediatric formulary.ConclusionDepending on the drug-specific disposition characteristics, therapeutic hypothermia in neonates with hypoxic ischaemic encephalopathy affects pharmacokinetics.

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Section: Open Accessmentioning

confidence: 99%

Section: Open Accessmentioning

confidence: 99%

Section: Morphinementioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review

Lutz

Allegaert

Hoon

et al. 2020

bmjpo

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“…This S cr variability is partly explained by maturational changes (e.g., birth weight, gestational age [GA], postnatal age) and non-maturational changes related to pathophysiology, e.g., perinatal asphyxia, co-medication, congenital anomalies of the kidney and urinary track (CAKUT), cardiac surgery with bypass, or extra-corporeal membrane oxygenation ( 4 , 5 ). Postnatal kidney adaptation is proportional to the nephron number (GA driven) and renal perfusion (postnatal adaptation, mean arterial blood pressure) ( 6 , 7 ). Nephrogenesis evolves as branching morphogenesis, similar to lung, pancreas, vascular tree, or retina.…”

Section: Introductionmentioning

confidence: 99%

Renal Precision Medicine in Neonates and Acute Kidney Injury: How to Convert a Cloud of Creatinine Observations to Support Clinical Decisions

et al. 2020

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Renal precision medicine in neonates is useful to support decision making on pharmacotherapy, signal detection of adverse (drug) events, and individual prediction of short- and long-term prognosis. To estimate kidney function or glomerular filtration rate (GFR), the most commonly measured and readily accessible biomarker is serum creatinine (S cr ). However, there is extensive variability in S cr observations and GFR estimates within the neonatal population, because of developmental physiology and superimposed pathology. Furthermore, assay related differences still matter for S cr , but also exist for Cystatin C. Observations in extreme low birth weight (ELBW) and term asphyxiated neonates will illustrate how renal precision medicine contributes to neonatal precision medicine. When the Kidney Disease Improving Global Outcome (KDIGO) definition of acute kidney injury (AKI) is used, this results in an incidence up to 50% in ELBW neonates, associated with increased mortality and morbidity. However, urine output criteria needed adaptations to broader time intervals or weight trends, while S cr and its trends do not provide sufficient detail on kidney function between ELBW neonates. Instead, we suggest to use assay-specific centile S cr values to better describe postnatal trends and have illustrated its relevance by quantifying an adverse drug event (ibuprofen) and by explaining individual amikacin clearance. Term asphyxiated neonates also commonly display AKI. While oliguria is a specific AKI indicator, the majority of term asphyxiated cases are non-oliguric. Asphyxia results in a clinical significant—commonly transient—mean GFR decrease (−50%) with a lower renal drug elimination. But there is still major (unexplained) inter-individual variability in GFR and subsequent renal drug elimination between these asphyxiated neonates. Recently, the Baby-NINJA (nephrotoxic injury negated by just-in-time action) study provided evidence on the concept that a focus on nephrotoxic injury negation has a significant impact on AKI incidence and severity. It is hereby important to realize that follow-up should not be discontinued at discharge, as there are concerns about long-term renal outcome. These illustrations suggest that integration of renal (patho)physiology into neonatal precision medicine are an important tool to improve contemporary neonatal care, not only for the short-term but also with a positive health impact throughout life.

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Physiologically based pharmacokinetic modelling of acetaminophen in preterm neonates—The impact of metabolising enzyme ontogeny and reduced cardiac output

Olafuyi

Abbasi

Allegaert

2021

Biopharm & Drug Disp

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In preterm neonates, physiologically based pharmacokinetic (PBPK) models are suited for studying the effects of maturational and non-maturational factors on the pharmacokinetics of drugs with complex age-dependent metabolic pathways like acetaminophen (APAP). The aim of this study was to determine the impact of drug metabolising enzymes ontogeny on the pharmacokinetics of APAP in preterm neonates and to study the effect of reduced cardiac output (CO) on its PK using PBPK modelling. A PBPK model for APAP was first developed and validated in adults and then scaled to paediatric age groups to account for the effect of enzyme ontogeny. In preterm neonates, CO was reduced by 10%, 20%, and 30% to determine how this might affect APAP PK in preterm neonates. In all age groups, the predicted concentration-time profiles of APAP were within 5th and 95th percentile of the clinically observed concentration-time profiles and the predicted Cmax and AUC were within 2-folds of the reported parameters in clinical studies. Sulfation accounted for most of APAP metabolism in children, with the highest contribution of 68% in preterm neonates. A reduction in CO by up to 30% did not significantly alter the clearance of APAP in preterm neonates. The model successfully incorporated the ontogeny of drug metabolising enzymes involved in APAP metabolism and adequately predicted the PK of APAP in preterm neonates. A reduction in hepatic perfusion as a result of up to 30% reduction in CO has no effect on the PK of APAP in preterm neonates.

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

Cited by 31 publications

References 129 publications

Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review

Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review

Renal Precision Medicine in Neonates and Acute Kidney Injury: How to Convert a Cloud of Creatinine Observations to Support Clinical Decisions

Physiologically based pharmacokinetic modelling of acetaminophen in preterm neonates—The impact of metabolising enzyme ontogeny and reduced cardiac output

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