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The clinical significance of clearance is that it determines an individual patient's maintenance dose requirements. Clearance varies between individuals and within an individual in response to changes in his or her clinical condition.

The physiological and pathological factors that affect the clearance of a drug depend mainly on which organ is primarily responsible for its elimination. For example, clearance of the bronchodilator theophylline, a drug that is eliminated by hepatic metabolism, is influenced by age, weight, alcohol consumption, cigarette smoking, other drugs, congestive cardiac failure, hepatic cirrhosis, acute pulmonary oedema and severe chronic obstructive airways disease.

Table 1.3 Examples of target ranges.

Drug	Target range
Mass units	Molar units
Digoxin	0.8–2 μg/L	1–2.6 nmol/L
Carbamazepine	4–12 mg/L	20–50 μmol/L
Phenytoin	10–20 mg/L	40–80 μmol/L
Gentamicin	5–12 mg/L (1 hour post‐dose)
Vancomycin	5–10 mg/L (trough)
Theophylline	5–20 mg/L	28–110 μmol/L

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:

(Eqn 1.1)

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

(Eqn 1.2)

(Eqn 1.3)

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.