Pharmacokinetic Considerations in Pediatric Patients

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Pharmacokinetic Considerations in Pediatric
Patients

• Jennifer King, Pharm.D.
• Assistant Professor
• University of Alabama at Birmingham School of
  Medicine

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Outline

• Review definitions of pharmacokinetic parameters
• Review basic principles of clinical
  pharmacokinetics
• Describe how pharmacokinetic processes differ
  between adults and children

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Pharmacokinetic Definitions

• Area under the concentration time curve (AUC)
• Overall amount of drug in the body
• Drug concentrations are graphed versus time after
  the dose that the blood samples were collected
• Maximum Concentration (Cmax)
• The highest drug concentration (in blood) after a
  dose
• Usually occurs within a few hours of drug intake

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Pharmacokinetic Definitions

• Tmax time at which Cmax occurs
• Minimum Concentration (Cmin)
• The lowest drug concentration in blood after a
  dose
• Typically the last concentration of the dosing
  interval
• Half-life (t1/2)
• The time for blood drug concentration to fall by
  50
• 4-5 half-lives for drug elimination

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Factors Affecting Oral Absorption

• Bioavailability
• Stability
• Permeability
• First Pass Metabolism

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Bioavailability

• The fraction of drug that reaches the systemic
  circulation after oral ingestion
• Absolute bioavailability
• Determined by comparing blood concentrations of
  drug after IV dosing with those after dosing by
  oral route
• Relative bioavailability
• Is a term used to compare different formulations
  of the same medication

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Stability

• Rate of release of drug from pharmaceutical
  preparation
• Blood flow to site of absorption
• Surface area in contact with drug
• Destruction of drug at or near site of absorption

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Drug Absorption
absorption
hepatic metabolism
dissolution
disintegration
gastric emptying rate
intestinal metabolism
intestinal transit rate
dissolution
absorption
disintegration
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P1066 Raltegravir PK
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Drug Absorption

• Drugs may be more absorbed more slowly in
  neonates
• Approaches adult values by 6-8 months
• Diarrhea decreases absorption in small intestine
• In preterm neonate, gastric pH is elevated due to
  immature acid secretion

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Intestinal Bacterial Flora

• Crucial component of enterohepatic circulation
• Metabolites conjugated in the liver and excreted
  in the bile are deconjugated in the intestine by
  bacterial enzymes, then absorbed across the
  mucosa and returned to the liver in the portal
  circulation.
• Flora in children may not inactive drugs as
  readily as in adults
• A small secondary peak following the Cmax
  suggests enterohepatic circulation

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First Pass Metabolism

• Concentration of drug is greatly reduced before
  it reaches systemic circulation
• Can occur when drug absorbed from the small
  intestine is transported first via the portal
  system to the liver
• Some drugs more extensively metabolized in the
  intestine than in the liver

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First Pass Metabolism Intestinal Drug
Metabolizing Enzymes and Transporters
CYP

Blood (basolateral)

GI tract (apical)
Fletcher CV. Medscape 2005
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Factors Affecting Distribution

• Cardiac output/regional blood flow
• Organ perfusion
• Permeability of cell membranes/drug transporters
• Body Composition
• Total and extracellular water
• Fat
• Degree of protein binding

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Developmental Changes in Distribution Sites
Adapted from Kearns, et al NEJM 2003

• Neonates and infants usually display
• ? Vd for hydrophilic drugs because of excess
  body water
• ?Vd for lipophilic drugs because of decreased
  body fat

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Degree of Protein Binding

• Neonatal serum contains 80 as much protein as
  adults
• Many ? at birth and during infancy, but approach
  adult values about 1 years of age
• ? endogenous substances (bilirubin and free fatty
  acids) capable of displacing drug from binding
  sites

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Factors Affecting Metabolism

• Hepatic blood flow
• Ability of the liver to extract the drug from the
  blood
• Drug binding in the blood
• Hepatic Enzymes

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Inhibition of Hepatic Enzymes
SQV/RTV 800/100 mg bid
SQV 1200 mg tid
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Appearance of Phase I Enzymes

• Total CYP450 content in fetal liver is 30-60 of
  adult values
• CYP3A7
• Peaks shortly after birth then ? rapidly to
  levels undetectable in most adults
• CYP3A4, 2D6, and 2C
• Appear during the first week of life
• CYP1A2
• One to three months of life

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Appearance of Phase II Enzymes

• Sulfation enzymes are well developed even in
  premature infant
• Glucuronosyltransferases have unique maturation
  profiles
• APAP (UGT1A6 and 1A9) glucoronidation is
  decreased in newborns and young children compared
  with adolescents and adults
• UGT1A1 is absent from fetal liver and reaches
  adult values by 6 months of life

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Factors affecting Excretion

• Renal blood flow
• Concentrating and acidifying ability
• Glomerular Filtration
• Tubular Function
• Secretion
• Reabsorption

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Drug Excretion

• Renal clearance of drugs significantly decreased
  compared with adults
• Both GFR and secretory pathways decreased in
  relative function
• Normalized values for GFR and secretion
  approximate adult values at 1 year
• Absolute values dont reach adult values until
  10 years of age

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Conclusions

• Many factors affect the pharmacokinetics of drugs
• Understanding these factors can help us predict
  pharmacokinetic properties of new agents
• Physiological changes with age should be
  considered when predicting pharmacokinetic
  properties of drugs in children