Special Populations: Renal Impairment, Hepatic Impairment, Elderly, Paediatrics

Standard pharmacokinetic parameters derived from healthy adult volunteers may be profoundly altered in special populations. Prescribing without considering these differences is a major source of preventable adverse drug events. Four key populations require systematic pharmacokinetic consideration: renal impairment, hepatic impairment, the elderly, and paediatrics.

Renal impairment reduces the clearance of renally eliminated drugs in proportion to the decline in GFR. The dose adjustment factor is: dose fraction = (CL in renal failure / CL normal) = (fu × GFR_patient / fu × GFR_normal) for drugs cleared by filtration alone. In practice, dose adjustments are made using published nomograms or dosing equations. The critical drugs requiring renal dose adjustment include: aminoglycosides (reduce dose or extend interval), vancomycin (reduce dose and extend interval), digoxin (reduce dose), metformin (reduce at eGFR <45, stop at <30), lithium (reduce dose, increase monitoring), NSAIDs (avoid at eGFR <30 — risk of further reduction and hyperkalaemia), direct oral anticoagulants (dabigatran contraindicated at eGFR <30; apixaban/rivaroxaban dose adjustments per datasheet), and gabapentin/pregabalin. Renal impairment also affects protein binding (albumin lower, uraemic toxins displace acidic drugs) and Vd (oedema increases Vd of water-soluble drugs, increasing loading dose requirements).

Hepatic impairment is more complex to manage because no single test predicts hepatic drug metabolism capacity analogous to eGFR for renal function. The Child-Pugh score (incorporating bilirubin, albumin, prothrombin time, ascites, and encephalopathy) stratifies liver disease into Child-Pugh A (mild), B (moderate), and C (severe). Drug manufacturer datasheets provide guidance based on these classes. Hepatic impairment reduces CYP enzyme activity, glucuronidation, and sulfation capacity, decreasing clearance of high-extraction and capacity-limited drugs. Additionally, porto-systemic shunting in cirrhosis increases oral bioavailability of high-extraction drugs (morphine, propranolol) because gut-absorbed drug bypasses the liver. Hypoalbuminaemia increases free fraction of highly protein-bound drugs. Avoid NSAIDs (risk of hepatorenal syndrome), aminoglycosides (increased nephrotoxicity), and opioids (increased CNS sensitivity and reduced metabolism). The MELD score is increasingly used in clinical practice for prognosis.

Pharmacokinetics in the elderly (>65 years) is governed by physiological changes accompanying ageing: reduced GFR (CKD-EPI overestimates GFR in older patients — use Cockcroft-Gault for dose adjustment), reduced hepatic blood flow (↓ clearance of high-extraction drugs), reduced hepatic mass and CYP activity (↓ first-pass, ↑ oral bioavailability of high-extraction drugs), reduced albumin (↑ free fraction of acidic drugs), reduced body water (↑ Cp of water-soluble drugs for same dose), increased body fat (↑ Vd and prolonged t½ of lipophilic drugs — benzodiazepines, amiodarone), and reduced GI motility (slowed absorption). The STOPP/START criteria and Beers Criteria identify potentially inappropriate medicines in the elderly. In NZ, this is relevant to reducing falls risk (benzodiazepines, anticholinergics, opioids) and avoiding anticholinergic burden.

Paediatric pharmacokinetics are not simply scaled adult values. Neonates and infants differ fundamentally: reduced GFR (reaches adult values by 6–12 months), immature CYP enzymes (CYP3A4 and CYP2D6 mature by 3–12 months; CYP1A2 by 4 months), reduced albumin and protein binding in neonates, higher total body water as a proportion of weight (↑ Vd for water-soluble drugs), and reduced fat stores in neonates. Doses are typically expressed per kilogram, but the relationship is not linear — allometric scaling (dose ∝ weight^0.75) better describes clearance across the paediatric age range. Critical paediatric drug issues include: chloramphenicol grey baby syndrome (immature glucuronidation), morphine sensitivity in neonates (immature blood-brain barrier and CYP3A4), and codeine toxicity risk in ultra-rapid CYP2D6 metabolisers (Medsafe contraindicated codeine in children under 12 following deaths).