Clinical Pharmacology and Therapeutics. Группа авторов

      Mr J.L. was started on a daily dose of 140 mg and after 2 days of therapy his peak concentration (1 hour post‐dose) was 6 mg/L and his trough (24 hours post‐dose) was 0.5 mg/L.

      Has steady state been reached?

      Mr J.L.'s estimated elimination half‐life is 6.6 hours; therefore, steady state should be reached in 5 × 6.6 = 33 hours. He will be at steady state after 2 days of therapy.

      How should the dose be adjusted?

      The peak is slightly lower than the target and the trough is satisfactory. As these represent steady‐state concentrations and gentamicin has linear pharmacokinetics, the dose can be adjusted by proportion. Increasing the dose to 200 mg/day should achieve a peak of (200/140) × 6 = 8.6 mg/L and a trough of (200/140) × 0.5 = 0.7 mg/L.

Comment. Elimination half‐life is a useful guide to dosage interval and is particularly important when the target concentration–time profile includes both peak and trough concentrations. In this case, because the peaks and troughs were both low, the dose can be adjusted by direct proportion. If the trough had been high, an increase in the dosage interval would also have been necessary.

      Phenytoin

      

Clinical scenario

      Mrs D.L., a 38‐year‐old woman who weighs 55 kg, was prescribed phenytoin at a dose of 300 mg/day (5.5 mg/kg/day) after carbamazepine failed to control her epilepsy. She attended the outpatient clinic 3 weeks later and her 24‐hour post‐dose trough phenytoin concentration was 6 mg/L (24 μmol/L). As her seizures were not well controlled, her dose was increased to 350 mg/day (6.4 mg/kg/day). She presented to her general practitioner 2 weeks later complaining of fatigue and difficulty in walking properly. Her trough phenytoin concentration was 28 mg/L (112 mol/L).

      Why was the first concentration so low?

      There are two possibilities: the dose was too low, or she was not adhering to her prescribed dose. As patients generally require phenytoin maintenance doses in the range 4.5–5 mg/kg/day, both doses were higher than average. Phenytoin has non‐linear pharmacokinetics at concentrations normally seen clinically, and standard pharmacokinetic equations cannot be used. The relationship between dose rate and average steady‐state concentration is controlled by V_max (the maximum amount of drug that can be metabolised by the enzymes per day) and K_m (the concentration at half V_max). Using average values of V_max (7.2 mg/kg/day) and K_m (4.4 mg/L), Mrs D.L.'s expected concentration can be calculated from the Michaelis–Menten equation:

      The measured concentration of 6 mg/L is much lower than expected and suggests poor adherence with therapy.

      Why was the second concentration so high?

      The predicted concentration on her increased dose can be calculated as before, i.e.

      In this case, the measured concentration was reasonably consistent with the predicted value and her actual V_max can therefore be estimated from the measured concentration, i.e.

Using her actual V_max and a K_m of 4.4 mg/L, average steady‐state concentrations can be predicted for various doses (Table 1.6). Note that a small change in the dose produces a disproportionately large increase in concentration, especially at higher concentrations.

Table 1.6 Predicted steady‐state phenytoin concentrations for clinical scenario.

Dose (mg/day)	Steady‐state concentration
(mg/L)	(μmol/L)
225	6	24
250	7	28
275	9	36
300	13	52
325	18	72
350	28	112
375	55	220

      It is known that a concentration of 6 mg/L does not control her seizures and she experiences toxicity with 28 mg/L. Her ideal dose is therefore likely to lie in the range 275–325 mg/day. It would be sensible to start with 300 mg/day and adjust the dose (if necessary) according to her response. It would also be useful to emphasise to the patient that she must comply with her prescribed dose in order to obtain the maximum benefit

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