Paediatric Clinical Pharmacology

Evelyne Jacqz-Aigrain, Imti Choonara, Evelyne Jacqz-Aigrain, Imti Choonara

• Publisher: CRC Press
• Year: 2021
• ISBN:
  9781000416251
• Edition: 1
• Topic: Medizin
• Subtopic: Pädiatrische Medizin

The treatment of children with medicinal products is an important scientific area. It is recognized that many medicines that are used extensively in pediatric patients are either unlicensed or off-label. This textbook will help pediatric health professionals effectively treat children with the most appropriate medicine with minimal side effects.

Paediatric clinical pharmacology

2.1
The effect of age on drug metabolism

Saskia de Wildt¹, Trevor N. Johnson², Imti Choonara³

¹Dept, of Paediatrics, Erasmus University & Sophia Childrens Hospital, Rotterdam, The Netherlands

²Academic Unit of Molecular Pharmacology & Pharmacogenetics, University of Sheffield and Pharmacy Department, Children’s Hospital, Sheffield, UK

³Academic Division of Child Health, University of Nottingham, Derbyshire Children’s Hospital, Uttoxeter Road, Derby, UK

2.1.1 INTRODUCTION

There are many factors that affect drug metabolism. There is currently considerable interest in the field of pharmacogenetics, i.e. the effect of genetic make up in relation to the capacity to metabolise different drugs. We wish to give a brief overview of the effect of age on drug metabolism from birth through childhood to adolescence.

The major site of drug metabolism is within the liver. The gastrointestinal tract, blood cells and other organs are also involved in drug metabolism. The biological purpose of drug metabolism is to convert lipophilic (fat soluble) compounds into more polar and thus more water soluble substances that are more readily excreted into bile or urine. The enzymes involved in drug metabolism are not only involved in the breakdown of medicines but also the numerous other chemicals that humans ingest or inhale either deliberately or unwittingly.

The major pathways involved in drug metabolism are divided into phase 1 and phase 2 reactions. Phase 1 involves oxidation, reduction, hydrolysis and hydration reactions. The major pathway is oxidation which involves the cyto-chrome P450 dependent (CYP) enzymes. The major CYP enzymes are CYP1A2, CYP2B6, CYP2C8–10, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 and 5. The major pathways for phase 2 involve glucuronidation, sulphation, methylation, acetylation and glutathione conjugation.

We plan to highlight the changes that have been previously described in relation to some of the major metabolic pathways and review enzyme activity in paediatric patients of different ages. Specifically we will review the development of CYP1A2 and CYP3A4 as examples of phase 1 and glucuronidation and sulphation as examples of phase 2 metabolism.

We have used the age classification accepted by both the European Medicines Evaluation Agency and also the recent International Conference on Harmonisation [1]. This classification divides paediatric patients into 5 age groups; preterm neonates, full-term neonates, infants from 1 month up to 24 months of age, children between the ages of 2 and 11 years and adolescents from 12 to 17 years.

2.1.2 GENERAL TRENDS IN THE DEVELOPMENT OF PHASE 1 DRUG METABOLISM IN CHILDREN

Total cytochrome P450 content in the fetal liver is between 30 and 60% of adult values and approaches adult values by 10 years of age [2]. Different developmental patterns have been identified for CYPs involving activity in the fetal liver (CYP3A7), minimal activity in the fetal liver but with rapid increase hours after birth (CYP2D6 & CYP2E1) and development in infancy (CYP1A2) [3–6].

For many CYP drug substrates, weight corrected clearance values are often low at birth, but then increase rapidly reaching a maximum by 2 years of age. Hepatically metabolised drugs that exhibit a higher systemic weight normalised clearance in children compared to adults include theophylline [7], diclofenac [8], teniposide [9], phenytoin [10], carbamazepine [11] and omeprazole [12]. Possible reasons for increased hepatic clearance in children include an increased liver volume normalised to body weight [13,14] or a higher concentration of catalytically active CYPs. A recent study failed to detect increased intrinsic CYPs 1A2, 2C8, 2E1 and 3A4/5 activity in paediatric livers in comparison to adult livers [15].

2.1.3 CYP3A4

The CYP3A subfamily is the most abundantly expressed CYP subfamily in the human adult and newborn liver. Moreover, this subfamily is involved in the metabolism of more than half of all drugs, including cyclosporin, tacrolimus, cisapride, midazolam, fentanyl, lidocaine, nifedipine, indinavir and verapamil.

The CYP3A subfamily consists of at least 4 enzymes: CYP3A4, CYP3A5, CYP3A7 and CYP3A43. CYP3A4/CYP3A5 account for 30 to 40% of total CYP content in the adult liver and intestine. CYP3A4 and CYP3A5 are differentially expressed, but have largely overlapping substrate specificity. CYP3A7 is the main CYP isoform in the human fetal and newborn liver. From the few studies available, it appears that the substrate specificity of CYP3A7 is different from CYP3A4.

In vitro studies have shown that CYP3A7 activity is high directly after birth, while CYP3A4 activity is very low [3]. During the first days after birth, a transition occurs from mainly CYP3A7 activity to CYP3A4 activity. Finally, adult levels of CYP3A4 are reached during the first years of life. This developmental pattern of CYP3A4 is reflected by the change in clearance rate of midazolam [16–19] at different ages (Table 1). Midazolam clearance is reduced in infants under the age of 2 years. Although the median plasma clearance reaches adult levels in children over the age of 2 years, it is important to recognise the considerable inter-individual variation [17] (up to 100 fold in one study [18]).

Table 1 Age and midazolam clearance

Age group	Number of patients	Mean or median plasma clearance (ml/min/kg)	Range	Ref.
preterm neonates	24	1.8	0.7 – 6.7	16
	?	1.2	?	17
term neonates	?	1.8	?	17
infants 1–24 months	25	3.0	0.5 – 25.8	18 ^*
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