Total body clearance
Total body clearance (ClT) is the sum of individual organ clearances for a drug. For most drugs, total body clearance is equal to hepatic clearance + renal clearance. It is important to remember that the entire apparent volume of distribution must be cleared of drug.
For a drug that follows one-compartment kinetic behaviour, the fraction of the apparent volume of distribution that is cleared of drug at the stated clearance rate is found from the first order elimination rate constant for the drug. For example, if a drug’s apparent volume of distribution is 150 litres and the half-life for elimination is 7 hours then kel, the elimination rate constant (0.693 / 7 hours = 0.1 per hour) tells us that 0.1, or 10%, of the entire volume of distribution will be cleared of drug in 1 hour, and so clearance equals 150 litres x 0.1 per hour = 15 litres/hour.
An alternative method to calculate clearance, which can be used for a drug that follows one-compartment, two-compartment, or any more complex behaviour, is the area under the curve (AUC) method. Total body clearance is calculated from ClT = Dose/AUC0-∞, where AUC0-∞ refers to the area from t=0 to t=infinity, i.e. the point when all drug has been removed from the body. Alternatively, when a drug has reached a steady state concentration during chronic (repeated) dosing, the AUC between two consecutive doses (usually referred to as AUC0-τ) may be used, with the equation becoming ClT = Dose/AUC0-τ (an explanation of this point may be found under the manual entry for area under the curve).
For some drugs with a narrow therapeutic window, it may be necessary to modify a dosing regimen if a patient has a condition affecting total body clearance. For example, a patient with chronic kidney disease, or with hepatic insufficiency, will show reduced clearance for many drugs, and a reduction in dosing rate would be necessary to offset reduced clearance rates. Note, however, that clearance of a drug that is removed predominantly or entirely by the kidneys would be unaffected by hepatic insufficiency, while a lipophilic drug that is cleared by metabolism would see no change in ClT in a patient with renal failure. In neither case would a dosing adjustment be required. For a drug that is cleared partially by the kidneys and partially by hepatic metabolism, a dosing adjustment would be made only for the portion of the dose that is cleared by the organ with compromised function.
Examples
Approximately 60% of an oral dose of digoxin is excreted unchanged in the urine, while the remainder of the dose is metabolised. What dosing adjustment should be made for a patient with stage III CKD (chronic kidney disease), where the glomerular filtration rate (GFR) is reduced by 50%?
In order to achieve the recommended steady state concentration in the renally-compromised patient, the dosing rate must be decreased to the same degree that the clearance rate is decreased (at steady state, rate in = rate out). The 40% of the dose that is metabolised will be unaffected by reduced renal clearance, while the 60% of the dose that is cleared renally would be reduced to the same degree that GFR is reduced. As such, the modified dosing rate would be 40% + (60% × 0.5) = 70% of the original dosing rate.
For an individual with normal renal function who would receive a maintenance dose of digoxin of 250 µg/day, the dosing rate would therefore be reduced to around 175 µg/day in stage III CKD with a 50% reduction in GFR.
