PharmacologyTier 1Medical Sciences concept

Dose adjustment calculation from clearance changes

Core concept

Only the renally cleared fraction of a drug needs adjusting - the hepatic fraction is unaffected

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fe = fraction excreted unchanged in urine

RF = patient's renal function as a fraction of normal (e.g. CrCl 25/100 = 0.25)

Dose adjustment factor Q = 1 - fe x (1 - RF)

Adjusted dose = Normal dose x Q

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Worked example: fe = 0.4, renal function 25% of normal
- Q = 1 - 0.4 x (1 - 0.25) = 1 - 0.4 x 0.75 = 0.7
- A normal 50 mg dose becomes 35 mg
Two limiting cases
- fe = 1 (entirely renal, e.g. gentamicin, vancomycin, lithium) -> Q = RF - dose falls in direct proportion to renal function
- fe = 0 (entirely hepatic) -> Q = 1 - no adjustment needed

The loading dose does NOT change - it depends on Vd, not clearance
- Only the maintenance dose (or the interval) is adjusted
Two ways to apply Q, with different consequences

Strategy	Effect
Reduce the dose, keep the interval	Smoother levels, lower peak - suits time-dependent drugs (beta-lactams)
Extend the interval, keep the dose	Preserves the peak, longer trough - suits concentration-dependent drugs (aminoglycosides)

Use Cockcroft-Gault CrCl for drug dosing, not CKD-EPI eGFR (which is body-surface-area indexed) - especially at extremes of weight and in the elderly
Assumptions the formula makes, and when they break
- Metabolites are inactive - false for morphine (M6G), pethidine (norpethidine), allopurinol (oxypurinol), procainamide (NAPA)
- Non-renal clearance is unchanged - false in uraemia, which also reduces hepatic metabolism and protein binding
- Steady state - in AKI, renal function is a moving target and the formula is unreliable; use levels
- Protein binding is unchanged - false for phenytoin in uraemia (dec binding -> falsely low total level)
Dialysis restores clearance intermittently - dose after dialysis for dialysable drugs, or supplement post-session

DOACs - each has its own creatinine clearance thresholds and dose reductions; dabigatran (fe ~80%) is the most renally dependent
Drugs where getting this wrong is dangerous: digoxin, DOACs, gabapentin/pregabalin, metformin, opioids (morphine, codeine, oxycodone), aciclovir, colchicine, sotalol, allopurinol, methotrexate, aminoglycosides, vancomycin, lithium
Gabapentinoid accumulation in CKD presents as sedation, myoclonus and confusion - very commonly missed
In AKI, recalculate every day and use therapeutic drug monitoring wherever available - a creatinine still rising means the true GFR is lower than the number suggests
Round to a practical dose and formulation; the arithmetic serves the prescription, not the other way round

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