Paediatric pharmacology
Children are not small adults. Age-dependent changes in body composition, organ maturation, and enzyme expression profoundly alter how drugs behave from the neonatal period through adolescence. This guide covers developmental pharmacokinetics, dosing principles, regulatory requirements (FDA PREA/BPCA, EMA PIP), and specific safety issues in paediatric patients. Key references: FDA paediatric drug information ↗ and EMA paediatric medicines ↗.
Paediatric age groups and PK relevance
Regulatory and PK definitions divide the paediatric population into subgroups with distinct physiological characteristics. ICH E11 (paediatric clinical trials) and EMA ICH E11 guidance ↗ define the following age bands:
| Group | Age range | Key PK characteristics |
|---|---|---|
| Preterm neonate | <37 weeks GA | Most immature organ function; extreme PK variability; very limited trial data |
| Term neonate | 0–27 days | Rapid GFR maturation; immature CYP enzymes; high % body water |
| Infant | 1–23 months | CYP3A4, CYP2D6 activity surpasses adult by ~6–12 months; CYP2C9/19 mature by 1–2 y |
| Child | 2–11 years | Higher weight-normalised clearance than adults for many drugs; liver/body weight ratio larger |
| Adolescent | 12–17 years | Puberty affects Vd (body composition), and CYP activity may peak then normalise; approaching adult PK |
Developmental changes in ADME
Gastric pH is near-neutral at birth (6–8) then falls to adult levels (~2) by 2–3 years. Acid-labile drugs (e.g. ampicillin, penicillin) have higher oral bioavailability in neonates. Gastric emptying is slow (~6–8 h in neonates vs ~2 h adults), delaying tmax. IM absorption is erratic in neonates due to poor muscle perfusion. Skin is thinner and more hydrated → higher transdermal absorption risk. NCBI developmental pharmacology review ↗.
Total body water (TBW) is ~85% of body weight in premature neonates vs ~60% in adults → larger Vd for hydrophilic drugs (aminoglycosides, vancomycin) → require higher mg/kg doses. Plasma albumin and AAG (alpha-1-acid glycoprotein) are lower at birth → higher free fraction of highly bound drugs (phenytoin, diazepam). Bilirubin competes with drugs for albumin binding in neonatal jaundice.
CYP enzyme maturation is highly isoform-specific: CYP3A7 (foetal predominant form) → CYP3A4 (adult form) over weeks. CYP2D6 appears at 1 week, reaches adult activity by 3–5 years. CYP1A2 matures by 4–6 months. Phase II (glucuronidation via UGT) is particularly immature — codeine, morphine, and chloramphenicol glucuronidation are severely reduced in neonates. NCBI CYP enzyme maturation table ↗.
GFR at birth is ~5 mL/min in term neonates, reaching adult values (~120 mL/min/1.73 m²) by 1–2 years. Tubular secretion matures over 6–12 months. Renally cleared drugs (aminoglycosides, vancomycin, penicillins, gabapentin) require substantially longer dosing intervals in neonates. Gentamicin is given every 48 h in premature neonates vs every 24 h in children and every 8–12 h in adults.
Dosing principles
Weight-based dosing (mg/kg)
The most common approach; adjusts for differences in Vd between children and adults. Effective for many drugs across the paediatric age range. Limitations: overestimates metabolic capacity in very young infants; does not account for maturation effects. Use actual body weight for most children; for obese children, dosing at true IBW or adjusted weight may be preferable.
Allometric scaling
Metabolic processes scale with body weight to the power of 0.75 (not proportionally). Allometric scaling (dose ∝ WT0.75) is incorporated into population PK models and FDA PK extrapolation guidance. It explains why older children often need higher mg/kg doses than adults for CYP-metabolised drugs. FDA paediatric PK extrapolation guidance ↗.
Body surface area (BSA) dosing
Used for anticancer drugs (methotrexate, cytarabine) where therapeutic index is narrow. BSA (m²) estimated by Mosteller formula: BSA = √(height × weight / 3600). BSA correlates better than weight with renal function and cardiac output. However, BSA dosing still requires maturation corrections for neonates.
Flat/fixed dosing (age-band)
Used when weight is not available or for self-administered OTC products. Age-band dosing (e.g. "2–5 years: 5 mL") is practical but less precise. FDA requires manufacturers to justify flat dosing with population PK simulations showing acceptable target attainment across the specified weight range.
Regulatory framework for paediatric studies
PREA & BPCA (FDA)
The Paediatric Research Equity Act (PREA) ↗ requires paediatric studies when an adult indication may also apply to children. The Best Pharmaceuticals for Children Act (BPCA) ↗ offers 6-month exclusivity extension for voluntary paediatric studies. Together they have generated >1,000 paediatric labelling updates since 2000.
Paediatric Investigation Plan (PIP) — EMA
All new medicines or new indications require a Paediatric Investigation Plan (PIP) ↗ agreed with EMA's Paediatric Committee (PDCO) before submission — unless a waiver or deferral is granted. The PUMA pathway provides 10-year data exclusivity for paediatric-only marketing authorisations of off-patent drugs.
The ICH E11 guideline (Clinical Investigation of Medicinal Products in the Paediatric Population) ↗ and its 2017 addendum (ICH E11A) on paediatric extrapolation provide the scientific framework for both FDA and EMA paediatric development programmes.
Paediatric drug safety: key concerns
Codeine is converted to morphine by CYP2D6. CYP2D6 ultra-rapid metabolisers (URM) generate toxic morphine concentrations. FDA contraindicated codeine in children <12 years in 2017 ↗ following post-tonsillectomy deaths in URM children.
Neonates lack mature UGT enzymes to glucuronidate chloramphenicol. Accumulation causes the "grey baby syndrome" — cardiovascular collapse, hypothermia, and grey ashen colour. Historically caused many deaths before the mechanism was understood. Highlights the danger of inadequate paediatric dose adjustment for UGT substrates.
Animal models showed fluoroquinolone-induced cartilage damage in weight-bearing joints in juvenile animals. FDA restricts systemic fluoroquinolones in paediatric patients except for specific indications (complicated UTI, inhalation anthrax, plague) where the benefit outweighs risk. FDA fluoroquinolone safety communications ↗.
Aspirin use in children with viral illness (influenza, varicella) is associated with Reye's syndrome — a rare but life-threatening encephalopathy and hepatic failure. The CDC Reye's syndrome page ↗ and FDA labelling strongly warn against aspirin in children <18 years with fever-producing illnesses.
Frequently asked questions
Why can't we simply give children proportionally smaller adult doses?
Body weight-proportional scaling ignores age-dependent changes in absorption, distribution, metabolism, and excretion. A neonate has lower GFR (~5% of adult), immature CYP enzymes (CYP3A4 ~30% of adult at birth), different body composition (higher % body water), and lower plasma albumin — all altering drug PK independently of weight. Allometric scaling (dose ∝ weight^0.75) is more physiologically appropriate for metabolic parameters, but even this does not capture all maturation effects.
What is the "therapeutic orphan" problem in paediatrics?
Until the US Paediatric Research Equity Act (PREA) and Best Pharmaceuticals for Children Act (BPCA), most drugs were approved only in adults and used off-label in children — earning them the name "therapeutic orphans." PREA (2003) requires companies to study drugs in paediatric populations when the adult indication applies to children. FDA publishes a list of approved paediatric studies and labelling updates at the Written Requests list.
What is the Paediatric Use Marketing Authorisation (PUMA) in Europe?
PUMA (EU) is a regulatory pathway allowing companies to obtain authorisation specifically for paediatric indications of off-patent products, without having to prove benefit in adults. It provides 10 years of data protection as an incentive. The European Paediatric Investigation Plan (PIP) must be agreed with EMA before adult marketing authorisation is granted (analogous to FDA PREA). EMA's Paediatric Committee (PDCO) evaluates PIPs.
What is FDA Orphan Drug exclusivity vs Paediatric exclusivity?
Paediatric exclusivity (PE) is a 6-month extension of existing patents or exclusivity periods granted to manufacturers who conduct paediatric studies requested by FDA under BPCA. It applies to all existing formulations of the drug. Orphan Drug exclusivity provides 7 years of market exclusivity for drugs treating rare diseases (<200,000 US patients). These are distinct programmes and can interact — a drug can receive both orphan and paediatric exclusivity.
What special safety concerns exist for drug use in neonates?
Neonates (<28 days) have: near-zero renal drug clearance at birth (GFR ~1 mL/min maturing to adult-equivalent by ~2 years), immature BBB (drugs enter the CNS more readily), high body water content leading to larger Vd for hydrophilic drugs, reduced plasma albumin and AAG (more free drug), and immature hepatic conjugation (glucuronidation matures slowly — explaining chloramphenicol "grey baby syndrome"). Benzyl alcohol (a preservative) causes "gasping syndrome" in premature neonates — many parenteral formulations must be preservative-free for neonates.