Pharmacokinetics in Children
Pharmacokinetics refers to the processes of drug absorption, distribution, metabolism, and elimination (see Pharmacokinetics).
Absorption from the GI tract is affected by
All these factors are reduced in neonates (full-term and premature) and all may be reduced or increased in an ill child of any age. Reduced gastric acid secretion increases bioavailability of acid-labile drugs (eg, penicillin) and decreases bioavailability of weakly acidic drugs (eg, phenobarbital). Reduced bile salt formation decreases bioavailability of lipophilic drugs (eg, diazepam). Reduced gastric emptying and intestinal motility increase the time it takes to reach therapeutic concentrations when enteral drugs are given to infants < 3 mo. Drug-metabolizing enzymes present in the intestines of young infants are another cause of reduced drug absorption. Infants with congenital atretic bowel or surgically removed bowel or who have jejunal feeding tubes may have specific absorptive defects depending on the length of bowel lost or bypassed and the location of the lost segment.
Injected drugs are often erratically absorbed because of
IM injections are generally avoided in children because of pain and the possibility of tissue damage, but, when needed, water-soluble drugs are best because they do not precipitate at the injection site.
Transdermal absorption may be enhanced in neonates and young infants because the stratum corneum is thin and because the ratio of surface area to weight is much greater than for older children and adults. Skin disruptions (eg, abrasions, eczema, burns) increase absorption in children of any age.
Transrectal drug therapy is generally appropriate only for emergencies when an IV route is not available (eg, use of rectal diazepam for status epilepticus). Site of placement of the drug within the rectal cavity may influence absorption because of the difference in venous drainage systems. Young infants may also expel the drug before significant absorption has occurred.
Absorption of drugs from the lungs (eg, β-agonists for asthma, pulmonary surfactant for respiratory distress syndrome) varies less by physiologic parameters and more by reliability of the delivery device and patient or caregiver technique.
The volume of distribution of drugs changes in children with aging. These age-related changes are due to changes in body composition (especially the extracellular and total body water spaces) and plasma protein binding.
Higher doses (per kg of body weight) of water-soluble drugs are required in younger children because a higher percentage of their body weight is water (see see Figure: Changes in body composition with growth and aging.). Conversely, lower doses are required to avoid toxicity as children grow older because of the decline in water as a percentage of body weight.
Many drugs bind to proteins (primarily albumin, α1-acid glycoprotein, and lipoproteins); protein binding limits distribution of free drug throughout the body. Albumin and total protein concentrations are lower in neonates but approach adult levels by 10 to 12 mo. Decreased protein binding in neonates is also due to qualitative differences in binding proteins and to competitive binding by molecules such as bilirubin and free fatty acids, which circulate in higher concentrations in neonates and infants. The net result may be increased free drug concentrations, greater drug availability at receptor sites, and both pharmacologic effects and higher frequency of adverse effects at lower drug concentrations.
Drug metabolism and elimination vary with age and depend on the substrate or drug, but most drugs, and most notably phenytoin, barbiturates, analgesics, and cardiac glycosides, have plasma half-lives 2 to 3 times longer in neonates than in adults.
The cytochrome P-450 (CYP450) enzyme system in the small bowel and liver is the most important known system for drug metabolism. CYP450 enzymes inactivate drugs via
Phase I activity is reduced in neonates, increases progressively during the first 6 mo of life, exceeds adult rates by the first few years for some drugs, slows during adolescence, and usually attains adult rates by late puberty. However, adult rates of metabolism may be achieved for some drugs (eg, barbiturates, phenytoin) 2 to 4 wk postnatally. CYP450 activity can also be induced (reducing drug concentrations and effect) or inhibited (augmenting concentrations and effect) by coadministered drugs. These drug interactions may lead to drug toxicity when CYP450 activity is inhibited or an inadequate drug level when CYP450 activity is induced. Kidneys, lungs, and skin also play a role in the metabolism of some drugs, as do intestinal drug-metabolizing enzymes in neonates. Phase II metabolism varies considerably by substrate. Maturation of enzymes responsible for bilirubin and acetaminophen conjugation is delayed; enzymes responsible for morphine conjugation are fully mature even in preterm infants.
Drug metabolites are eliminated primarily through bile or the kidneys. Renal elimination depends on
All of these factors are altered in the first 2 yr of life. Renal plasma flow is low at birth (12 mL/min) and reaches adult levels of 140 mL/min by age 1 yr. Similarly, GFR is 2 to 4 mL/min at birth, increases to 8 to 20 mL/min by 2 to 3 days, and reaches adult levels of 120 mL/min by 3 to 5 mo.
Because of the above factors, drug dosing in children < 12 yr is always a function of age, body weight, or both. This approach is practical but not ideal. Even within a population of similar age and weight, drug requirements may differ because of maturational differences in absorption, metabolism, and elimination. Thus, when practical, dose adjustments should be based on plasma drug concentration (however, plasma drug concentration may not reflect the drug concentration in the target organ). Unfortunately, these adjustments are not feasible for most drugs. Studies done as a result of federal legislation (the Best Pharmaceuticals for Children Act of 2001 and the Pediatric Research Equity Act of 2003 [both renewed in 2012]) have provided dosing for > 450 drugs that previously did not have pediatric dosing information.