Pediatric Pharmacokinetics
How drug absorption, distribution, metabolism, and excretion change from birth through adolescence, and implications for pediatric dosing.
Children Are Not Small Adults
Pediatric pharmacokinetics vary dramatically across developmental stages. The same drug may require vastly different weight-normalized doses in a premature neonate versus a 10-year-old. Understanding the maturational timeline is essential for safe prescribing.
Age-Based Developmental Stages
| Stage | Age | Key PK Features |
|---|---|---|
| Premature neonate | < 37 weeks GA | Extreme organ immaturity, highest risk |
| Term neonate | 0-28 days | Rapid physiological transitions |
| Infant | 1-12 months | Rapid enzyme and renal maturation |
| Child | 1-12 years | Often higher weight-normalized clearance than adults |
| Adolescent | 12-18 years | Approaching adult PK parameters |
Absorption
- Gastric pH is near neutral at birth (pH 6-8) and reaches adult acidity (pH 1-3) by age 2. Acid-labile drugs (penicillin G) have higher oral bioavailability in neonates.
- Gastric emptying is prolonged and erratic in neonates, normalizing by 6-8 months.
- Intestinal motility is irregular, affecting drug transit time and absorption window.
- Rectal absorption is more reliable in young children, making this route practical for diazepam in seizures and acetaminophen when oral dosing is refused.
Distribution
- Total body water decreases from ~80% in premature neonates to ~60% in adults. Water-soluble drugs (aminoglycosides, vancomycin) have larger Vd per kg, requiring higher mg/kg doses.
- Body fat is low in neonates (~1% in premature, ~15% in term), increasing to adult proportions during puberty. Lipophilic drug distribution varies accordingly.
- Protein binding is reduced in neonates due to lower albumin and alpha-1-acid glycoprotein levels plus competition from fetal albumin and bilirubin. Free fractions of phenytoin, diazepam, and bilirubin are higher.
- Blood-brain barrier is more permeable in neonates, allowing greater CNS drug exposure.
Metabolism
Enzyme maturation follows different timelines:
- CYP3A7: predominant at birth, declines over weeks
- CYP3A4: reaches adult activity by 6-12 months
- CYP1A2: matures by 4-6 months; reaches peak activity at 1-2 years
- CYP2D6: present at birth but full activity by 3-5 years
- UGT (glucuronidation): severely deficient at birth; reaches adult levels by 2-3 years
- Sulfation: relatively mature at birth, compensating for immature glucuronidation
Children aged 1-10 years often have higher weight-normalized clearance than adults due to a relatively larger liver mass relative to body weight. Theophylline clearance in 1-year-olds can be twice the adult value per kg.
Excretion
GFR at birth is 2-4 mL/min/1.73 m² in term neonates. It increases rapidly in the first weeks, reaches 50-60 mL/min/1.73 m² by 2 weeks, and adult values (~120 mL/min/1.73 m²) by 6-12 months. Aminoglycoside dosing intervals are extended in neonates (q24-36h vs q8h in older children) accordingly.
Key Takeaways
- Pediatric PK parameters change rapidly, especially in the first year of life
- Neonates have higher body water, lower protein binding, and immature enzymes
- Children aged 1-10 often require higher mg/kg doses than adults due to faster clearance
- Enzyme maturation follows enzyme-specific timelines over months to years
- Renal function is immature at birth and reaches adult levels by 6-12 months