rel="nofollow" href="#ulink_9f584072-7f66-579e-b4e7-b46ef4f2470a">Eqn 1.2, i.e.
The 0.6 is an estimate of the bioavailability of digoxin tablets. The reason the measured concentration is higher than expected should be investigated. In this case, it was found that the sample had been withdrawn 2.5 hours after the dose. Digoxin is absorbed quickly but distributes slowly to the tissues. Samples taken before distribution is complete (i.e. less than 6 hours after the dose) and cannot be interpreted. As concentrations fall only by about 20% from 6 to 24 hours after the dose, samples can be taken at any time during this period.
A further (trough) sample withdrawn 24 hours after the last dose measured 2.4 μg/L (3.1 nmol L). This result is more consistent with the expected concentration but suggests that the dose is too high and may be contributing to his symptoms.
What dose adjustment should be made?
Digoxin has linear pharmacokinetics; therefore, the new dose can be determined by simple proportion. Table 1.5 shows that there are three dosage options for Mr A.R. A reduction to 125 μg/day is the most obvious first choice, but further adjustment (up or down) could be made if necessary on clinical grounds (e.g. poor control of atrial fibrillation or persistence of adverse effects).
Comment. This case illustrates the importance of sampling time for the correct interpretation of digoxin concentrations. Although digoxin is traditionally prescribed to be taken in the morning, changing to a night‐time dose can reduce the chances of samples being withdrawn during the distribution phase. Digoxin has a long elimination half‐life (50–100 hours) and elimination is slow beyond 6 hours after the dose. If samples are taken at steady state, dosage adjustment can be performed by simple proportion.
Gentamicin
Mr J.L., a 64‐year‐old man who weighs 80 kg and has an estimated creatinine clearance of 35 mL/min, requires gentamicin therapy for a suspected Gram‐negative infection. The aim is to achieve a peak concentration around 8 mg/L and a trough around 1 mg/L.
Table 1.5 Predicted steady‐state digoxin concentrations for clinical scenario.
| Dose (μg) | Cssaverage (μg/L) | Csstrough (μg/L) |
|---|---|---|
| 250 | 3.0 | 2.4 |
| 187.5 | 2.2 | 1.8 |
| 125 | 1.5 | 1.2 |
| 62.5 | 0.75 | 0.6 |
What dosage regimen should be prescribed?
Gentamicin is cleared by excretion through the kidneys and its clearance can be approximated by creatinine clearance. The volume of distribution of gentamicin is around 0.25 L/kg. A dosage interval of about three half‐lives will allow the concentration to fall from 8 to 1 mg/L (8 → 4 → 2 → 1). The elimination half‐life can be calculated from Eqn 1.3, i.e.
It will therefore take 3 × 6.6 = 20 hours for the concentration to fall from 8 to 1 mg/L. Because the ‘peak’ is measured 1 hour after the dose, the dosage interval should be 21 hours. A ‘practical’ dosage interval is therefore 24 hours. The dose administered should increase the concentration by 7 mg/L (i.e. from 1 to 8 mg/L). It can be calculated from the volume of distribution, i.e.
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
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 Vmax (the maximum amount of drug that can be metabolised by the enzymes per day) and Km (the concentration at half Vmax). Using average values of Vmax (7.2 mg/kg/day) and Km (4.4 mg/L), Mrs D.L.'s expected concentration can be calculated from the Michaelis–Menten equation:
The
