Pediatric Pharmacokinetics Refresher for Pharmacists

FEBRUARY 25, 2016
Pharmacokinetic differences in newborns and infants affect drug selection and dosing. Therefore, an understanding of basic pharmacokinetics in the pediatric population is essential for positive therapeutic outcomes.
 
Age classifications hold critical significance when discussing pediatric populations. Premature is considered before 37 weeks of gestation, while term is considered at 37 weeks or more. Neonates are younger than 1 month (28 days), infants are between 1 and 12 months, and a child is between 1 and 11 years.
 
Pharmacist awareness of the characteristics expressed in pediatric patients is crucial, as these distinctions affect bioavailability, serum concentrations, and ultimately therapeutic or toxic outcomes. This punctuates a need for basic understanding of pediatric pharmacokinetics and careful selection of drug, dose, and form. 
 
Drug Absorption
Pediatric patients differ in terms of gastric pH, gastric emptying time, intestinal motility, and gastric enzymes.
 
Gastric pH
With the exception of a low gastric pH during the first 24 to 48 hours after birth, neonates have near-neutral pH in their first 1 to 2 weeks of life. As gastric acid production begins, gastric pH slowly declines until about age 2, when it approaches adult levels of 1 to 3.1
 
Weakly acidic drugs like phenytoin, phenobarbital, and acetaminophen are best absorbed in their nonionized form. In a neonate or infant’s alkaline gastric environment, these drug molecules generally remain unprotonated, decreasing absorption and subsequent therapeutic effects.
 
The opposite holds true for weakly basic drugs like ampicillin and nafcillin. They are less ionized and better absorbed.
 
Gastric Emptying Time
Gastric emptying time is significantly slower in neonates and infants until about 6 months of age.2 It can vary due to both gestational age and disease states.  
 
Intestinal Motility
Lowered motility and peristalsis in neonates and infants lead to decreased medication transit time.3 The longer amount of time that drugs spend in the stomach of a newborn further reinforces the increased absorption of penicillins.2
 
Motility patterns are variable across not only pediatric age groups, but also individual newborns. These patterns also depend on gestational age and affect the rate and extent of absorption. Lowered intestinal surface area and transit times allow for less absorption.4
 
Gastric Enzymes
Neonates have reduced levels of gastric and pancreatic enzymes and biliary excretions. The presence of these compounds may be required for solubilization, cleavage, or protonation and deprotonation for absorption of certain drug molecules.4
 
Drug Distribution
Distribution is dependent on the drug’s chemical properties and the body’s composition.
 
At birth, a neonate is about 80% water.5 Water-soluble drug dosing in a neonate requires a higher mg/kg amount for comparable plasma concentration. That goes for drugs like morphine, gentamicin, and vancomycin.
 
Plasma concentration is also affected by protein binding. Compounds bind mainly to albumin if they are acidic, and alpha1-acid glycoprotein if they are basic.4,6 Because protein concentrations and affinity are both decreased in the first year of life,7 newborns exhibit lowered binding to drugs like penicillin and phenytoin.
 
Clinicians must also be wary of drugs that displace bilirubin binding from albumin. A vulnerable blood-brain barrier in newborns combined with increased levels of bilirubin can cause brain damage onset by kernicterus. 
 
Drug Metabolism                                                                                          
Metabolism is principally hepatic, comprising of phase 1 and phase 2 reactions. Respectively, these are either changes in the drug’s molecular structure or conjugation with other moieties.
 
Phase 1 reactions include cytochrome P450 (CYP450) enzymes and add functional groups that result in a small increase in water solubility, while phase 2 reactions generally result in a large increase in water solubility. Both phases are immature at birth.
 
Keep in mind the following generalizations:
  • Dealkylation is normal in neonates.
  • Conjugation with acetyl coenzyme A is reduced in the first month of life.
  • Glucuronidation is normalized by 3 to 6 months.
  • Oxidation is reduced and normalizes to the adult process by 6 to 12 months.
  • Hydroxylation and esterification activity are reduced.
Usually, differences in the drug metabolism process in neonates do not hold significance with regard to antibiotics that are excreted unchanged via the kidney.8
 
The following table is useful for generalizing CYP differences. Use caution, as activity levels can fluctuate. For example, CYP1A2 activity is barely detectable in neonates, 30% at 1 to 3 months, 50% at year 1, and 81% at year 2.9
 
 
Drug Excretion
  • Systemic excretion can be credited to the kidneys.
  • Glomerular filtration rate (GFR), tubular secretion, and tubular reabsorption are all decreased in the newborn.
  • GFR in the newborn is about 40 mL/min/173 m2. It approaches adult values of 100 mL/min/173 m2 at about 3 months of age. Afterwards, it may surpass adult values.8
  • Tubular secretion depends on renal blood flow and increases until age 6 to 12 months. This can decrease clearance of penicillins, aminoglycosides, and cephalosporins.  
 
Key Takeaways
1. Do not linearly extrapolate from adult values.
2. Some levels and processes in the newborn can initially be nonexistent, low, or high. Keep in mind that these can change rapidly in the first few weeks or months of life.
3. Use caution with all drugs in pediatric patients, but pay special attention to drugs with narrow therapeutic windows.

References 
1. Lu H, Rosenbaum S. Developmental Pharmacokinetics in Pediatric Populations. The Journal of Pediatric Pharmacology and Therapeutics. 2014;19(4): 262-276.
2. Koren G. Therapeutic drug monitoring principles in the neonate. Clinical Chemistry. 1997;43(1):222-227.
3. Bartelink I. Rademaker C, Schobben A, can den Anker J. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clinical Pharmacokinetics. 2006;45(11): 1077-1097.
4. Alcorn J, McNamara PJ. Pharmacokinetics in the newborn. Advanced Drug Delivery Reviews. 2003;55(5): 667-686.
5. Rane A, Wilson JT. Clinical pharmacokinetics in infants and children. Clinical Pharmacokinetics. 1976;1:2–24
6. Fernandez E, Perez R, Hernandez A, Tejada P, Arteta M, Ramos JT. Factors and Mechanisms for Pharmacokinetic Differences between Pediatric Population and Adults.  Pharmaceutics. 2011;3(1): 53-72.
7. Kanakoudi F, Drossou V, Tzimouli V, Diamanti E, Konstantinidis T, Germenis A, Kremenopoulos G. Serum concentrations of 10 acute-phase proteins in healthy term and preterm infants from birth to age 6 months Clinical Chemistry. 1995;41: 605–608.
8. Routledge PA. Pharmacokinetics in children. Journal of Antimicrobial Chemotherapy. 1994;34(A): 19-24.
9. Strolin Benedetti M, Baltes EL. Drug metabolism and disposition in children. Fundamental and Clinical Pharmacology. 2003;17(3): 281-299.

Jola Mehmeti, PharmD, MBA
Jola Mehmeti, PharmD, MBA
Jola Mehmeti is a 2018 PharmD graduate from the UConn School of Pharmacy. She is a CITI-certified researcher with investigative and work experience at a large tertiary care center in Hartford, Connecticut. Connect with her on LinkedIn or send a message to contact@jolamehmeti.com.
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