# Age-Dependent Pharmacokinetics and Dosing Principles

## Overview
Drug handling varies dramatically across the lifespan. Neonates, infants, children, adolescents, adults, and the elderly each present unique pharmacokinetic profiles. The Med-Peds physician must understand these differences to prescribe safely across all age groups.

## Developmental Pharmacokinetics

### Absorption
**Gastric pH**: Neonatal gastric pH is elevated (less acidic) at birth, reaching adult levels by age 2. This increases bioavailability of acid-labile drugs (e.g., penicillin G) and decreases absorption of weak acids (e.g., phenobarbital) **Gastric emptying**: Prolonged and erratic in neonates; reaches adult rates by 6-8 months. **Intestinal motility**: Reduced in neonates, leading to prolonged transit time and increased absorption of some drugs. **Percutaneous absorption**: Dramatically increased in premature neonates due to thin stratum corneum and high surface-area-to-body-weight ratio; risk of systemic toxicity from topical agents (e.g., hexachlorophene, corticosteroids) **Intramuscular absorption**: Variable in neonates due to low muscle mass and poor perfusion; unreliable route in sick neonates. **Rectal absorption**: Relatively reliable in infants and young children; used for diazepam, acetaminophen.

### Distribution
**Total body water (TBW)**: Neonates ~75-80% TBW vs. adults ~55-60%; premature infants up to 85%. Higher Vd for water-soluble drugs in neonates (e.g., aminoglycosides, vancomycin) Requires higher mg/kg dosing to achieve target concentrations. **Body fat**: Lower percentage in neonates; increases through infancy and childhood. Lower Vd for lipophilic drugs in neonates. **Protein binding**: Reduced in neonates due to lower albumin levels, qualitative differences in albumin binding, and competition from endogenous substances (bilirubin, free fatty acids) Increased free fraction of highly protein-bound drugs (phenytoin, valproic acid) Risk of toxicity at "therapeutic" total drug levels. Bilirubin displacement: sulfonamides can displace bilirubin from albumin causing kernicterus. **Blood-brain barrier**: More permeable in neonates; increased CNS drug exposure. **Elderly**: decreased albumin, increased alpha-1-acid glycoprotein, decreased lean mass, increased adipose tissue.

### Metabolism (Biotransformation)

| CYP Enzyme | Developmental Timeline | Clinical Implication |
|-----------|----------------------|---------------------|
| CYP3A7 | Dominant fetal isoform; declines postnatally | Neonatal-specific drug metabolism |
| CYP3A4 | Develops in first weeks; adult activity by 6-12 months | Most drugs metabolized by this pathway need dose adjustment in neonates |
| CYP1A2 | Develops slowly; adult activity by 1-3 years | Caffeine, theophylline clearance delayed in infants |
| CYP2D6 | Present at birth but reduced activity | Codeine toxicity risk (ultra-rapid metabolizers) |
| CYP2C9/2C19 | Develop over first months of life | Phenytoin clearance variable in neonates |

| Phase II Reaction | Neonatal Status | Clinical Example |
|------------------|----------------|-----------------|
| Glucuronidation | Severely deficient | Grey baby syndrome (chloramphenicol) |
| Sulfation | Relatively mature at birth | Compensates for deficient glucuronidation |
| Acetylation | Reduced; adult rates by 1-3 years | INH metabolism slower in neonates |
| Glycine conjugation | Deficient | — |

**Phase I reactions** (CYP enzymes): CYP3A7: dominant fetal isoform, declines postnatally. CYP3A4: develops in first weeks of life, reaches adult activity by 6-12 months. CYP1A2: develops slowly, reaches adult activity by 1-3 years. CYP2D6: present at birth but at reduced activity. CYP2C9/2C19: develop over first months of life. Children aged 2-10 may have HIGHER metabolic capacity per kg than adults (supraadult metabolism), requiring proportionally higher doses of some drugs (e.g., theophylline, carbamazepine) **Phase II reactions** (conjugation): Glucuronidation: severely deficient in neonates (grey baby syndrome from chloramphenicol toxicity) Sulfation: relatively mature at birth, compensates for deficient glucuronidation in neonates. Acetylation: reduced in neonates, reaches adult rates by 1-3 years. Glycine conjugation: deficient in neonates. **Elderly**: CYP activity declines; first-pass metabolism reduced; drug interactions more frequent with polypharmacy.

### Excretion
**Renal function**: GFR at birth is ~2-4 mL/min/1.73m2 in term neonates, even lower in preterm. GFR doubles by 1-2 weeks of age. Reaches adult values by 6-12 months. Tubular secretion matures more slowly than glomerular filtration. Drugs requiring renal dose adjustment in neonates: aminoglycosides, vancomycin, acyclovir. **GFR estimation in children**: Bedside Schwartz equation = 0.413 x height(cm) / serum creatinine. **GFR estimation in adults**: CKD-EPI equation (2021, race-free) **Elderly**: progressive decline in GFR (approximately 1 mL/min/year after age 40); Cockcroft-Gault for drug dosing.

## Dosing Principles Across Ages

### Weight-Based Dosing
Standard in pediatrics: mg/kg or mg/kg/day. Maximum doses should not exceed adult doses regardless of weight. In adults, fixed doses are common but some drugs remain weight-based (anticoagulants, chemotherapy)

### Body Surface Area (BSA) Dosing
Used for chemotherapy, some cardiac medications. BSA calculations: Mosteller formula = sqrt[(height cm x weight kg)/3600]. More closely correlates with metabolic rate and organ function than weight alone.

### Dosing in Obese Pediatric Patients
Controversy: actual body weight (ABW), ideal body weight (IBW), or adjusted body weight (AdjBW)? Most pharmacokinetic data derived from normal-weight children; General guidance:; Hydrophilic drugs: dose closer to IBW or AdjBW to avoid excessive peak levels; Lipophilic drugs: may need ABW due to increased volume of distribution; Drug-specific guidance is often lacking; Examples:; Vancomycin: use ABW (distributes into adipose tissue); Aminoglycosides: use AdjBW (0.4 x [ABW - IBW] + IBW); Enoxaparin: use ABW with dose cap per institutional protocol.

### Dosing in the Elderly
"Start low, go slow" principle; Beers Criteria: potentially inappropriate medications in older adults; STOPP/START criteria for prescribing appropriateness; Polypharmacy management: deprescribing protocols; Anticholinergic burden assessment.

## Therapeutic Drug Monitoring (TDM)
Essential for drugs with narrow therapeutic indices; Key drugs requiring TDM:; Aminoglycosides (peak and trough or AUC-based); Vancomycin (AUC/MIC preferred over trough-based monitoring); Digoxin; Phenytoin (free level if hypoalbuminemia); Valproic acid; Theophylline; Immunosuppressants (tacrolimus, cyclosporine, sirolimus); Population pharmacokinetic models increasingly used for Bayesian dose optimization.

## Special Considerations

### Drug Formulations
Pediatric: liquid formulations, chewable tablets, orally disintegrating tablets, sprinkle capsules. Extemporaneous compounding: stability and bioequivalence concerns. Taste masking is critical for adherence in children. Excipient safety: avoid ethanol, propylene glycol, benzyl alcohol in neonates.

### Off-Label Prescribing
Up to 50-75% of drugs used in neonates and children are prescribed off-label. Pediatric Research Equity Act (PREA) and Best Pharmaceuticals for Children Act (BPCA) have incentivized pediatric drug studies. Despite this, significant knowledge gaps remain for many medications.

### Medication Errors
Weight-based dosing errors are the most common medication error in pediatrics. 10-fold dosing errors are a specific pediatric risk. Electronic prescribing with weight-based dose checking reduces errors. "Tall man" lettering and barcode scanning as safety measures.

<image>A developmental timeline illustration showing the maturation of key pharmacokinetic parameters from birth to adulthood. Four parallel horizontal timelines represent: (1) gastric pH, showing elevated pH at birth declining to adult levels by age 2; (2) CYP enzyme activity, with CYP3A7 declining and CYP3A4 and CYP1A2 rising, showing a supraadult metabolism peak at ages 2-10; (3) GFR, starting very low at birth and reaching adult values by 6-12 months; and (4) total body water percentage, starting at 80% in neonates and declining to 55-60% in adults. Each timeline uses color gradients to indicate the transition periods.</image>

<image>A clinical comparison diagram showing the volume of distribution differences between a neonate, child, adult, and elderly patient for a water-soluble drug (aminoglycoside). Four body silhouettes of different sizes show the proportion of body water (highlighted in blue) relative to total body mass, with corresponding Vd values and resulting dose adjustments. The neonate has the highest proportion of body water and requires the highest mg/kg dose to achieve the same serum concentration.</image>

<image>An infographic showing the dosing challenge in obese pediatric patients. A silhouette of an obese child is shown with three different body weight measurements labeled: actual body weight, ideal body weight (based on 50th percentile BMI), and adjusted body weight. Arrows point to a table showing which weight measure to use for common drugs: vancomycin (ABW), aminoglycosides (AdjBW), enoxaparin (ABW with cap), and midazolam (IBW). A caution symbol highlights the paucity of pharmacokinetic data in this population.</image>

## Clinical Pearls
Neonatal drug dosing cannot simply be extrapolated from adult doses adjusted by weight -- immature hepatic and renal function profoundly alter drug handling. Children aged 2-10 may actually metabolize drugs FASTER per kg than adults due to supraadult hepatic enzyme activity. Never prescribe sulfonamides to neonates with jaundice -- bilirubin displacement from albumin can cause kernicterus. The grey baby syndrome (chloramphenicol toxicity) is the classic example of immature glucuronidation in neonates. When dosing obese children, there is no universal rule -- each drug requires individual consideration based on its pharmacokinetic properties. Free (unbound) drug levels should be measured for highly protein-bound drugs in neonates and patients with hypoalbuminemia. The bedside Schwartz equation (0.413 x height/creatinine) is the standard GFR estimation method in children. Always check that a pediatric weight-based dose does not exceed the standard adult dose. 10-fold dosing errors are the most dangerous medication error unique to pediatrics -- always double-check decimal placement.

## References
- Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology -- drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157-1167.
- Anderson BJ, Holford NHG. Understanding dosing: children are small adults, neonates are immature children. Arch Dis Child. 2013;98(9):737-744.
- Fernandez E, Perez R, Hernandez A, et al. Factors and mechanisms for pharmacokinetic differences between pediatric population and adults. Pharmaceutics. 2011;3(1):53-72.
- Lu H, Rosenbaum S. Developmental pharmacokinetics in pediatric populations. J Pediatr Pharmacol Ther. 2014;19(4):262-276.
- van den Anker J, Reed MD, Allegaert K, Kearns GL. Developmental changes in pharmacokinetics and pharmacodynamics. J Clin Pharmacol. 2018;58(Suppl 10):S10-S25.