Pediatric Pharmacokinetics

## 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