Corrected phenytoin for albumin (Sheiner–Tozer)

Adjust a total phenytoin concentration for hypoalbuminaemia, with a separate variant for significant renal impairment.

High-consequence calculationPhenytoin has a narrow therapeutic index and saturable kinetics. An uncorrected concentration in a hypoalbuminaemic patient systematically understates free drug and can lead to a dose increase that precipitates toxicity.

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What is this for?

Phenytoin is about 90% albumin-bound and only the free fraction is pharmacologically active. When albumin falls, the free fraction rises, so a total concentration that looks subtherapeutic may correspond to a normal or even toxic free concentration. The Sheiner–Tozer equation estimates what the total would be at a normal albumin.

How to use it

Enter the measured total phenytoin concentration in mcg/mL.
Enter the serum albumin from the same period.
Select the renal function category — the coefficient changes below a creatinine clearance of 20 mL/min.

Worked example

A patient with an albumin of 2.0 g/dL has a total phenytoin of 8 mcg/mL, which looks subtherapeutic. Should the dose be increased?

Answer: 8 ÷ [(0.2 × 2.0) + 0.1] = 8 ÷ 0.5 = 16 mcg/mL corrected — well within the therapeutic range. Increasing the dose on the uncorrected value would risk toxicity.

Clinical pearls & pitfalls

This is the single most consequential correction in therapeutic drug monitoring. Acting on an uncorrected total in a hypoalbuminaemic patient is a well-documented route to phenytoin toxicity.
Phenytoin follows saturable Michaelis–Menten kinetics in the therapeutic range. A small dose increase near saturation can produce a disproportionately large concentration rise — this is not a drug where a 10% dose increase gives a 10% concentration increase.
Free phenytoin measurement is the definitive test but is not available in every laboratory and has a slower turnaround. Where the decision is urgent and the patient is markedly hypoalbuminaemic, the correction is a reasonable interim step.
Valproate displaces phenytoin from albumin. Co-administration raises the free fraction without raising the total, so the correction does not capture it — measure free phenytoin instead.
Fosphenytoin is dosed in phenytoin sodium equivalents (PE). Confirm which is being reported before applying any correction.

Assumptions & limitations

An estimate only. Validation studies show inconsistent performance, particularly in critical illness, and it can both over- and under-estimate the free concentration.
Does not account for displacement by other highly protein-bound drugs such as valproate, salicylates, or warfarin.
The renal-impairment variant is a coarse adjustment for a spectrum of uraemic displacement; it is not calibrated to the degree of impairment.
Not validated in children, in pregnancy, or in patients with hepatic failure.

References

Sheiner LB, Tozer TN. Clinical pharmacokinetics: the use of plasma concentrations of drugs. In: Melmon KL, Morrelli HF, eds. Clinical Pharmacology. 2nd ed. Macmillan; 1978.
Kane SP, Bress AP, Tesoro EP. Characterization of unbound phenytoin concentrations in neurointensive care unit patients using a revised Winter-Tozer equation. Ann Pharmacother. 2013;47(5):628-636.
Anderson GD, Pak C, Doane KW, et al. Revised Winter-Tozer equation for normalized phenytoin concentrations in trauma and elderly patients with hypoalbuminemia. Ann Pharmacother. 1997;31(3):279-284.