In some hospitals, high aminoglycoside doses (e.g. gentamicin doses of 5–7 mg/kg) are given at intervals of 24–48 hours and the normal target peak and trough ranges do not apply. Samples are usually taken 6–14 hours after the dose and the dose is adjusted (if necessary) according to a nomogram.
Clearance in any individual is most accurately determined from concentration measurements. However, in many cases, relationships between clearance and clinical factors have previously been established. For example, the average value for theophylline clearance is 0.04 L/h/kg and this is modified according to the patient's clinical characteristics by multiplying by the factors shown in Table 1.4. This means that on average, smokers require 1.6 times the theophylline dose of non‐smokers and patients with cirrhosis require half the dose of patients without cirrhosis.
Table 1.4 Factors influencing theophylline clearance and therefore dose requirements.
| Factor | Adjustments required |
|---|---|
| Smoking | ×1.6 |
| Congestive cardiac failure | ×0.4 |
| Hepatic cirrhosis | ×0.5 |
| Acute pulmonary oedema | ×0.5 |
| Severe chronic obstructive airways disease | ×0.8 |
For drugs primarily excreted by the kidney, e.g. digoxin and gentamicin, creatinine clearance closely reflects drug 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
