Treating disorders of the neonatal central nervous system: pharmacokinetic and pharmacodynamic considerations with a focus on antiepileptics

A major consideration in the treatment of neonatal disorders is that the selected drug, dose and dosage frequency is safe, effective and appropriate for the intended patient population. Thus, a thorough knowledge of the pharmacokinetics and pharmacodynamics of the chosen drug within the patient popu...

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Published in:British journal of clinical pharmacology Vol. 81; no. 1; pp. 62 - 77
Main Authors: Donovan, Maria D., Boylan, Geraldine B., Murray, Deirdre M., Cryan, John F., Griffin, Brendan T.
Format: Journal Article
Language:English
Published: England John Wiley and Sons Inc 01.01.2016
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ISSN:0306-5251, 1365-2125, 1365-2125
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Abstract A major consideration in the treatment of neonatal disorders is that the selected drug, dose and dosage frequency is safe, effective and appropriate for the intended patient population. Thus, a thorough knowledge of the pharmacokinetics and pharmacodynamics of the chosen drug within the patient population is essential. In paediatric and neonatal populations two additional challenges can often complicate drug treatment – the inherently greater physiological variability, and a lack of robust clinical evidence of therapeutic range. There has traditionally been an overreliance in paediatric medicine on extrapolating doses from adult values by adjusting for bodyweight or body surface area, but many other sources of variability exist which complicate the choice of dose in neonates. The lack of reliable drug dosage data in neonates has been highlighted by regulatory authorities, as only ~50% of the most commonly used paediatric medicines have been examined in a paediatric population. Moreover, there is a paucity of information on the pharmacokinetic parameters which affect drug concentrations in different body tissues, and pharmacodynamic responses to drugs in the neonate. Thus, in the present review, we draw attention to the main pharmacokinetic factors that influence the unbound brain concentration of neuroactive drugs. Moreover, the pharmacodynamic differences between neonates and adults that affect the activity of centrally‐acting therapeutic agents are briefly examined, with a particular emphasis on antiepileptic drugs.
AbstractList A major consideration in the treatment of neonatal disorders is that the selected drug, dose and dosage frequency is safe, effective and appropriate for the intended patient population. Thus, a thorough knowledge of the pharmacokinetics and pharmacodynamics of the chosen drug within the patient population is essential. In paediatric and neonatal populations two additional challenges can often complicate drug treatment – the inherently greater physiological variability, and a lack of robust clinical evidence of therapeutic range. There has traditionally been an overreliance in paediatric medicine on extrapolating doses from adult values by adjusting for bodyweight or body surface area, but many other sources of variability exist which complicate the choice of dose in neonates. The lack of reliable drug dosage data in neonates has been highlighted by regulatory authorities, as only ~50% of the most commonly used paediatric medicines have been examined in a paediatric population. Moreover, there is a paucity of information on the pharmacokinetic parameters which affect drug concentrations in different body tissues, and pharmacodynamic responses to drugs in the neonate. Thus, in the present review, we draw attention to the main pharmacokinetic factors that influence the unbound brain concentration of neuroactive drugs. Moreover, the pharmacodynamic differences between neonates and adults that affect the activity of centrally‐acting therapeutic agents are briefly examined, with a particular emphasis on antiepileptic drugs.
A major consideration in the treatment of neonatal disorders is that the selected drug, dose and dosage frequency is safe, effective and appropriate for the intended patient population. Thus, a thorough knowledge of the pharmacokinetics and pharmacodynamics of the chosen drug within the patient population is essential. In paediatric and neonatal populations two additional challenges can often complicate drug treatment - the inherently greater physiological variability, and a lack of robust clinical evidence of therapeutic range. There has traditionally been an overreliance in paediatric medicine on extrapolating doses from adult values by adjusting for bodyweight or body surface area, but many other sources of variability exist which complicate the choice of dose in neonates. The lack of reliable drug dosage data in neonates has been highlighted by regulatory authorities, as only ~50% of the most commonly used paediatric medicines have been examined in a paediatric population. Moreover, there is a paucity of information on the pharmacokinetic parameters which affect drug concentrations in different body tissues, and pharmacodynamic responses to drugs in the neonate. Thus, in the present review, we draw attention to the main pharmacokinetic factors that influence the unbound brain concentration of neuroactive drugs. Moreover, the pharmacodynamic differences between neonates and adults that affect the activity of centrally-acting therapeutic agents are briefly examined, with a particular emphasis on antiepileptic drugs.A major consideration in the treatment of neonatal disorders is that the selected drug, dose and dosage frequency is safe, effective and appropriate for the intended patient population. Thus, a thorough knowledge of the pharmacokinetics and pharmacodynamics of the chosen drug within the patient population is essential. In paediatric and neonatal populations two additional challenges can often complicate drug treatment - the inherently greater physiological variability, and a lack of robust clinical evidence of therapeutic range. There has traditionally been an overreliance in paediatric medicine on extrapolating doses from adult values by adjusting for bodyweight or body surface area, but many other sources of variability exist which complicate the choice of dose in neonates. The lack of reliable drug dosage data in neonates has been highlighted by regulatory authorities, as only ~50% of the most commonly used paediatric medicines have been examined in a paediatric population. Moreover, there is a paucity of information on the pharmacokinetic parameters which affect drug concentrations in different body tissues, and pharmacodynamic responses to drugs in the neonate. Thus, in the present review, we draw attention to the main pharmacokinetic factors that influence the unbound brain concentration of neuroactive drugs. Moreover, the pharmacodynamic differences between neonates and adults that affect the activity of centrally-acting therapeutic agents are briefly examined, with a particular emphasis on antiepileptic drugs.
Author Murray, Deirdre M.
Donovan, Maria D.
Griffin, Brendan T.
Boylan, Geraldine B.
Cryan, John F.
AuthorAffiliation 4 Irish Centre for Fetal and Neonatal Translational Research University College Cork and Cork University Maternity Hospital Cork Ireland
1 Pharmacodelivery Group, School of Pharmacy University College Cork Cork Ireland
2 Department of Anatomy and Neuroscience University College Cork Cork Ireland
3 Department of Paediatrics and Child Health University College Cork Cork Ireland
5 Alimentary Pharmabiotic Centre University College Cork Cork Ireland
AuthorAffiliation_xml – name: 1 Pharmacodelivery Group, School of Pharmacy University College Cork Cork Ireland
– name: 2 Department of Anatomy and Neuroscience University College Cork Cork Ireland
– name: 4 Irish Centre for Fetal and Neonatal Translational Research University College Cork and Cork University Maternity Hospital Cork Ireland
– name: 3 Department of Paediatrics and Child Health University College Cork Cork Ireland
– name: 5 Alimentary Pharmabiotic Centre University College Cork Cork Ireland
Author_xml – sequence: 1
  givenname: Maria D.
  surname: Donovan
  fullname: Donovan, Maria D.
  organization: University College Cork
– sequence: 2
  givenname: Geraldine B.
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  fullname: Boylan, Geraldine B.
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Keywords pharmacokinetics
neonate
antiepileptics
patient-specific computational modeling
pharmacodynamics
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Snippet A major consideration in the treatment of neonatal disorders is that the selected drug, dose and dosage frequency is safe, effective and appropriate for the...
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SubjectTerms Anticonvulsants - pharmacokinetics
Anticonvulsants - pharmacology
antiepileptics
Blood-Brain Barrier
Brain - metabolism
Central Nervous System Diseases - drug therapy
Humans
Infant, Newborn
Infant, Newborn, Diseases - drug therapy
Models, Biological
neonate
patient‐specific computational modeling
pharmacodynamics
pharmacokinetics
Review
Reviews
Title Treating disorders of the neonatal central nervous system: pharmacokinetic and pharmacodynamic considerations with a focus on antiepileptics
URI https://onlinelibrary.wiley.com/doi/abs/10.1111%2Fbcp.12753
https://www.ncbi.nlm.nih.gov/pubmed/26302437
https://www.proquest.com/docview/1752583993
https://pubmed.ncbi.nlm.nih.gov/PMC4693568
Volume 81
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