Clinical Pharmacology and Therapeutics. Группа авторов
clearance. Thus, digoxin clearance can be estimated from the equation:
The 0.33 in this equation represents the elimination by routes other than the kidney, such as metabolism and clearance by the hepatobiliary system.
An estimate of clearance can then be used to calculate the required dose to achieve a target concentration
where F represents oral bioavailability. Factors that influence clearance are now routinely investigated for all new drugs so that dosage adjustments can be made for patients with a low clearance, who might be at risk from toxicity.
Interpretation of serum concentrations
Serum concentrations can be measured for a number of reasons and it is important to interpret the measured concentration in the light of the clinical situation. If the aim is to assess the patient's maintenance dose requirements, samples should ideally be taken at steady state. However, confirmation of steady state is not necessary if the aim is to confirm toxicity and adherence or to assess the need for a loading dose in a patient who is acutely unwell.
Steady state normally requires that four to five half‐lives elapse since treatment started or since any change in dose. Doses should be given at regular intervals and it is important to confirm that no doses have been omitted. If these conditions can be satisfied and the pharmacokinetics of the drug are linear, clearance depends on the ratio of the dosing rate to the average steady‐state concentration as can be seen by rearranging Eqn 1.2:
(Eqn 1.4)
This means that doses can be adjusted by simple proportion, i.e.
(Eqn 1.5)
Concentrations that are not at steady state cannot be used in this way; although if accurate details of dosage history and sampling time are available, clearance may be estimated with the help of a pharmacokinetic computer package.
It is important to remember that drugs with non‐linear kinetics (such as phenytoin) require special consideration, and different techniques are applied to the interpretation of their concentrations. Successful interpretation of a concentration measurement depends on accurate information. The minimum usually required is:
1 Time of sample collection with respect to the previous dose. Samples taken at inappropriate times may be misinterpreted. Usually, the simplest approach is to measure a trough concentration (i.e. at the end of the dosage interval)
2 An accurate and detailed dosage history – drug dose, times of administration and route(s) of administration. This information can be used to assess whether the sample represents steady state. Samples taken without knowledge of dosage history can result in an inappropriate clinical action or dosage adjustment
3 Patient details such as age, sex, weight, serum creatinine (and estimated glomerular filtration rate) and assessments of cardiac and hepatic function. This information helps to determine expected dose requirements and is necessary for all computerised interpretation methods. Knowledge about the stability of the patient can help to determine the frequency of monitoring, especially if the drug is cleared by the kidneys and renal function is changing
4 Changes in other drug therapy that might influence the pharmacokinetics of the drug being measured
5 The reason for requesting a drug analysis should be considered carefully. ‘On admission’ or ‘routine’ requests are usually of little value and are a waste of valuable resources
Clinical examples of therapeutic drug monitoring
Digoxin
Mr A.R., a 78‐year‐old man weighing 72 kg and with a creatinine clearance of 24 mL/min, has been taking 250 μg digoxin daily to control atrial fibrillation. He presents to his general practitioner with anorexia and nausea a month after starting therapy. A digoxin concentration of 3.6 µg/L (4.6 nmol/L) is measured.
Is this concentration expected?
His expected digoxin clearance can be calculated from Eqn 1.1, i.e.
His average steady‐state concentration can be estimated from 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.