Special populations

Paediatrics

Size and maturation are separate

Body size alone explains paediatric clearance well from roughly 2 years upward. Below that, enzyme and renal maturation dominate, and size-only scaling overpredicts clearance — in a neonate by several fold.

CL_child = CL_adult * (WT/70)^0.75 * MF
MF = PMA^Hill / (TM50^Hill + PMA^Hill)              Anderson & Holford

Generic clearance values: TM50 ≈ 54.2 weeks post-menstrual age, Hill ≈ 3.92. Drug-specific ontogeny is much better where it exists, because individual enzymes mature on very different schedules.

Use post-menstrual age (gestational + postnatal), not postnatal age. A 4-week-old born at 28 weeks and a 4-week-old born at term have very different eliminating capacity.

Enzyme ontogeny, in outline:

ICH E11A pediatric extrapolation

Step 4 adopted 21 August 2024, effective 25 January 2025. It formalises a framework for using adult (or other-population) data to support paediatric conclusions:

• Build a pediatric extrapolation concept from the similarity of disease, response to treatment, and exposure-response between the source and target populations.
• Quantify the assumptions and the residual uncertainty; the amount of new paediatric data required scales inversely with confidence in the extrapolation.
• Where exposure matching is the basis, the standard applies the 90% CI to 80-125% bounds for AUC and Cmax — but a model-informed approach using dose-response or exposure-response parameters (Emax, EC50, slope) within acceptable limits is an accepted alternative.
• Modelling and simulation, including popPK and PBPK, are central rather than supportive.

The practical consequence: paediatric dose selection is expected to be model-informed, with a prospective plan, not a mg/kg extrapolation from the adult label.

Other paediatric points

• Volume of distribution per kg is higher in neonates (greater total body water), so a loading dose per kg is often larger while maintenance is smaller.
• Protein binding is lower in neonates (less albumin, less alpha-1-acid glycoprotein, and competition from bilirubin), raising the unbound fraction.
• Oral absorption differs: higher gastric pH, slower gastric emptying, immature biliary function.

Renal impairment

Classified by eGFR (mL/min/1.73 m²): normal ≥ 90, mild 60-89, moderate 30-59, severe 15-29, kidney failure < 15.

• The relevant question is not only whether the parent drug is renally cleared, but whether an active or toxic metabolite is. Morphine-6-glucuronide accumulating in renal failure is the standard example.
• Renal impairment also reduces some non-renal clearance pathways — uraemic toxins inhibit CYP and transporter activity — so a low fe does not guarantee no effect.
• Protein binding falls in uraemia for acidic drugs, raising unbound fraction; total concentrations then understate the change in unbound exposure.
• Dialysis is a separate question with its own study: whether the drug is removed depends on molecular size, protein binding and volume of distribution, and the dosing implication is about timing relative to the session as much as about dose.
• Cockcroft-Gault (creatinine clearance) versus CKD-EPI (eGFR, normalised to 1.73 m²) matters. For dosing, de-normalise eGFR to the individual's body surface area; using a normalised eGFR as if it were an individual clearance misdoses people at the extremes of size.

Hepatic impairment

Child-Pugh A/B/C is the conventional classification, though it is a crude proxy for drug-metabolic capacity and correlates poorly with any specific enzyme.

• Effects include reduced enzyme content, reduced hepatic blood flow, portosystemic shunting (raising oral bioavailability of high-extraction drugs sharply), reduced albumin, and altered transporter expression.
• For a high-extraction drug given orally, the dominant effect is loss of first-pass extraction, and exposure can rise many-fold — much more than clearance alone would suggest.
• Reduced albumin raises the unbound fraction; for a low-extraction, highly bound drug the unbound concentration may be nearly unchanged while total concentration falls. Interpreting total concentrations alone gives the wrong dose adjustment.

Obesity

Which size descriptor to scale by depends on the parameter and the drug:

Fixed allometric exponents derived across species do not automatically apply within a species across the obesity range. Fitting the descriptor and letting the data choose is legitimate here.

Pregnancy

Physiological changes across gestation are large and progressive: plasma volume up ~50%, GFR up ~50%, albumin down, CYP3A4 and CYP2D6 induced, CYP1A2 and CYP2C19 inhibited. A single "pregnancy" covariate is inadequate — the effect is gestational-age dependent. PBPK with a pregnancy population model is the usual approach, since dedicated PK studies in pregnancy are rare.

Geriatric

Age effects are mostly mediated: declining renal function, reduced hepatic blood flow and mass, changed body composition (less water, more fat), lower albumin. Include the mediators as covariates rather than age itself where possible — a model with age standing in for renal function will mispredict a fit 80-year-old and a frail 60-year-old in opposite directions.

Organ impairment study design

Both regulators accept a reduced ("staged") design: study severe impairment first, and if exposure is unchanged, the intermediate categories can often be waived. A full design covers each category against matched controls. Match on age, weight and sex; unmatched controls are the usual reason an organ-impairment study is uninterpretable.