Intensive and prolonged urine collection in preterm infants reveals three distinct indomethacin metabolic patterns: potential implications for drug dosing

Lewis, Tamorah; Haandel, Leon van; Scott, Allison; Leeder, J. Steven

doi:10.1038/s41390-018-0051-7

Cited by 7 publications

(12 citation statements)

References 5 publications

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“…More recently, a similar observation on rapidly maturing fentanyl (also CYP3A) clearance in preterm neonates has been described, and this resulted in the need to adapt body‐weight fentanyl dosing to achieve comparable exposure over time . Along the same line, these fast maturational changes may also affect the routes of elimination and the urinary metabolic ratios over time, as has been observed for indomethacin and acetaminophen …”

Section: Specific Issues Beyond Ontogeny Also Contribute To the Variamentioning

confidence: 82%

“…Intriguingly, CYP2C9 polymorphisms (rs2153628 and rs179985) were also associated with differences in the likelihood to response to indomethacin among preterm neonates with a patent ductus arteriosus, so that altered indomethacin metabolism may explain some of the variability in indomethacin disposition and response . This puts the earlier mentioned paper of Lewis et al on the relevance of prolonged urine collection to assess drug metabolism into additional perspective.…”

Section: Specific Issues Beyond Ontogeny Also Contribute To the Variamentioning

confidence: 96%

“…31 Along the same line, these fast maturational changes may also affect the routes of elimination and the urinary metabolic ratios over time, as has been observed for indomethacin and acetaminophen. 32,33 Issues Related to Pediatric Critical Illness Several factors will affect drug disposition and response in critically ill children, but altered phase I enzyme activity is one of these factors. The underlying mechanism related to this are likely the downregulation effects of cytokines on these drug-metabolizing enzymes.…”

Section: Specific Issues Beyond Ontogeny Also Contribute To the Variamentioning

confidence: 99%

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Ontogeny of Phase I Metabolism of Drugs

Allegaert

Anker

2019

The Journal of Clinical Pharma

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Capturing ontogeny of enzymes involved in phase I metabolism is crucial to improve prediction of dose‐concentration and concentration‐effect relationships throughout infancy and childhood. Once captured, these patterns can be integrated in semiphysiologically or physiology‐based pharmacokinetic models to support predictions in specific pediatric settings or to support pediatric drug development. Although these translational efforts are crucial, isoenzyme‐specific ontogeny‐based models should also incorporate data on variability of maturational and nonmaturational covariates (eg, disease, treatment modalities, pharmacogenetics). Therefore, this review provides a summary of the ontogeny of phase I drug‐metabolizing enzymes, indicating current knowledge gaps and recent progresses. Furthermore, we tried to illustrate that straightforward translation of isoenzyme‐specific ontogeny to predictions does not allow full exploration of scenarios of potential variability related to maturational (non–age‐related variability, other isoenzymes or transporters) or nonmaturational (disease, pharmacogenetics) covariates, and necessitates integration in a “systems” concept.

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Section: Specific Issues Beyond Ontogeny Also Contribute To the Variamentioning

confidence: 82%

Section: Specific Issues Beyond Ontogeny Also Contribute To the Variamentioning

confidence: 96%

Section: Specific Issues Beyond Ontogeny Also Contribute To the Variamentioning

confidence: 99%

See 1 more Smart Citation

Ontogeny of Phase I Metabolism of Drugs

Allegaert

Anker

2019

The Journal of Clinical Pharma

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“…For example, SNPs in CYP2C9 have been associated with indomethacin response for PDA closure [3]. With further research, we may find that dose modification is required dependent on an infant's genetically determined drugmetabolizing capacity [4]. Need for opiate medications for pain control during mechanical ventilation is associated with OPRM1 and COMT genotype in preterm infants [5].…”

Section: Editorial Lewis and Leedermentioning

confidence: 99%

“…Now, we are moving away from assessing only the disappearance of the parent compound and toward a more comprehensive characterization of various PK processes. The quantification of changing contributions from various metabolic pathways through the longitudinal measurement of metabolites reveals the potential intersection of ontogeny and pharmacogenetics [4]. The next advance was population PK (PopPK) models, allowing for identification of important covariates in drug clearance and distribution using sparse sampling designs.…”

Section: Editorial Lewis and Leedermentioning

confidence: 99%

Pharmacogenomics and Implementation of Precision Therapeutics in the Neonatal ICU: a New Frontier?

Lewis

Leeder

2018

Pharmacogenomics

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Neonatal medicine has progressed rapidly in the past 50 years, with major advances in nutrition, ventilation strategies, surgical techniques and infection control practices. These advances have allowed the intact survival of increased numbers of extremely preterm and critically ill full-term neonates. However, one key area lagging in medical advance is pharmacologic therapy for neonatal diseases. Certain diseases and drug classes are common in the neonatal ICU (NICU), and there are conditions that are unique to the neonatal population. Patent ductus arteriosus (PDA) is treated with nonsteroidal anti-inflammatory drugs or acetaminophen. Persistent pulmonary hypertension of the newborn (PPHN) is treated with inhaled nitric oxide or off-label vasodilators. Hypoxic ischemic encephalopathy (HIE) has no approved pharmacologic therapies, but drugs including erythropoietin are being researched. Bronchopulmonary dysplasia (BPD) is treated off-label with diuretics, steroids and β-agonists. Necrotizing enterocolitis (NEC) is treated with anti-infectives and at times, vasopressors for septic shock. In addition to these unique conditions, neonates are also treated for nonunique pathophysiology including seizures, hypotension, sepsis and pain.With the exception of surfactant and inhaled nitric oxide, no targeted drugs have been developed for neonatal conditions. Neonatologists often adapt currently approved drug therapies from other patient populations to treat NICU pathology. Thus, neonates are considered 'therapeutic orphans' in that meaningful drug development is scarce in this population. In a comprehensive review published in 2013, the ten most commonly used drugs in the NICU were anti-infectives (ampicillin, gentamicin, vancomycin), surfactant (beractant and calfactant), caffeine, furosemide, dopamine, fentanyl and midazolam. None of these drugs currently have actionable pharmacogenomic guidelines, thus the potential impact of pharmacogenomics in the neonatal population may appear very limited. Yet, there are certain diseases with such wide variability in phenotype (newborn opiate withdrawal, bronchopulmonary dysplasia) and response to drug therapy (PDA, pain and agitation) that there seems to be an urgent need to understand the underlying sources of variability, including genetics.A treating neonatologist faces many challenges in drug therapy, including uncertainties about variability in drug exposure and drug response. All of the typical pharmacokinetic (PK) processes are heterogeneous and rapidly changing in our patient population: absorption (developing acid production, villous development and variable amount of enteral feedings), distribution (transporter ontogeny, large fluid shifts in first weeks of life and variable fat content based on in utero environment), metabolism (immature enzyme expression) and elimination (rapidly developing glomelular filtration and biliary clearance). In addition, a neonatologist can rarely be sure that a certain drug target is adequately expressed and often-times, the goal drug exposu...

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Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life

Krzyzanski

Stockard

Gaedigk

et al. 2022

CPT Pharmacom & Syst Pharma

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Indomethacin is used commonly in preterm neonates for the prevention of intracranial hemorrhage and closure of an abnormally open cardiac vessel. Due to biomedical advances, the infants who receive this drug in the neonatal intensive care unit setting have become younger, smaller, and less mature (more preterm) at the time of treatment. To develop a pharmacokinetics (PK) model to aid future dosing, we designed a prospective cohort study to characterize indomethacin PK in a dynamically changing patient population. A population PK base model was created using NONMEM, and a covariate model was developed in a primary development cohort and subsequently was tested for accuracy in a validation cohort. Postnatal age was a significant covariate for hepatic clearance (CL H ) and renal clearance (CL R ). The typical value of the total clearance (CL, the sum of CL R and CL H ) was 3.09 ml/h and expressed as CL/WT median = 3.96 ml/h/kg, where WT median is the median body weight. The intersubject variability of CL R and CL H were 61% and 207%, respectively. The typical value of the volume of distribution V p = 366 ml (V p /WT median = 470 ml/kg), and its intersubject variability was 38.8%.Half-life was 82.1 h. Compared with more mature and older preterm populations studied previously, indomethacin CL is considerably lower in this contemporary population. Model-informed precision dosing incorporating important covariates other than weight alone offers an opportunity to individualize dosing in a susceptible patient undergoing rapid change. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?With current weight-based dosing, indomethacin exposure is variable, and clinical response is unpredictable in preterm infants.

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Intensive and prolonged urine collection in preterm infants reveals three distinct indomethacin metabolic patterns: potential implications for drug dosing

Cited by 7 publications

References 5 publications

Ontogeny of Phase I Metabolism of Drugs

Ontogeny of Phase I Metabolism of Drugs

Pharmacogenomics and Implementation of Precision Therapeutics in the Neonatal ICU: a New Frontier?

Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life

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