Body Surface Area (BSA)

Most literature values for clearance are expressed as volume/kg/time or as volume/70 kg/time. There is some evidence, however, that drug clearance is best adjusted on the basis of BSA rather than weight.

The patient’s BSA can be obtained from a nomogram, estimated from below:

BSA in m2 = [(Patient’s Weight in Kg / 70 kg)^0.7]*(1.73 m2)

or

BSA in m2 = (W^0.425)(H^0.725)*0.007184

The following formulas can be used to adjust the clearance values reported in the literature for specific patients. There are other equations one can use depending on units used in the literature for clearance.

• Patient’s Cl = (Literature Cl per m2)(Patient’s BSA)
• Patient’s Cl = (Literature Cl per 70 kg) (Patient’s BSA / 1.73 m2)
• Patient’s Cl = (Literature Cl per 70 kg)(Patient’s Weight in Kg / 70 kg)
• Patient’s Cl = (Literature Cl per kg)(Patient’s Weight in kg)

When patients do not differ significantly from 70 kg, the difference between using weight versus BSA becomes less significant.

The underlying assumption in using weight or BSA to adjust clearance is that the patient’s liver and kidney size (and hopefully function) vary in proportion to these physical measurements. This may not always be the case; therefore, clearance values derived from the patient populations having a similar age and size should be used whenever possible. If the patient’s weight is reasonably close to 70 kg (BSA = 1.73 m2), the patient’s calculated clearance will be similar whether weight or BSA are used to calculate clearance. If, however, the patient’s weight differs significantly from 70 kg, then the use of weight or surface area is likely to generate substantially different estimates of the patient’s clearance. When a patient’s size is substantially greater or less than the standard 70 kg, or 1.73 m2, a careful assessment t should be made to determine if the patient’s body stature is normal, obese, or emaciated. In obese and emaciated patients, neither weight nor surface area is likely to be helpful in predicting clearance, since the patient’s body size will not reflect the size or function of the liver and kidney.

Plasma Protein Binding

For highly protein-bound drugs, diminished plasma protein binding is associated with a decrease in reported steady-state plasma drug concentrations (total of unbound plus free drug) for any given dose that is administered. It would be misleading, however, to assume that because the calculated clearance is increased, the amount eliminated per unit of time has increased. Actually the amount eliminated per unit of time equals is the production of both Cl and C. In summary, when the same daily dose of a drug is given in the presence of diminished protein binding, an amount equal to that dose will be eliminated from the body each day at steady state despite a diminished steady-state plasma concentration and an increase in the calculated clearance. This is one way to explain the un-changed RE (rate of elimination). In another way to explain, when Css ave changes, the free or unbound fraction of drug in the plasma generally increases (even though Css ave decreases) with diminished plasma protein binding. As a result, the amount of free drug eliminated per unit of time remains unchanged.

And also what is important is that the pharmacologic effect achieved will be similar to that produced by the higher serum concentration observed under normal protein binding conditions. This example re-emphasizes the principle that clearance alone is not a good indicator of the amount of drug eliminated per unit of time (RE).

Extraction Ratio

The direct proportionality between calculated clearance and fraction unbound (fu) does not apply to drugs that are so efficiently metabolized or excreted that some (perhaps all) of the drug bound to plasma protein is removed as it passes through the eliminating organ. In this situation the plasma protein acts as a “transport system” for the drug, carrying it to the eliminating organs, and clearance becomes dependent on the blood or plasma flow to the eliminating organ. To determine whether the clearance for a drug with significant plasma binding will be influenced primarily by blood flow or plasma protein binding, its extraction ratio is estimated and compared to its fu value.

The extraction ratio is the fraction of the drug presented to the eliminating organ that is cleared after a single pass through that organ. It can be estimated by dividing the blood or plasma clearance of a drug by the blood or plasma flow to the elimination organ. At rest, the blood flow to the liver via the portal vein is at a rate of 1300 mL/min, and the other 500 mL/min is suppled by the hepatic artery. If the extraction ratio exceeds the free fraction (fu), then the plasma proteins are acting as a transport system and clearance will not change in proportion to fu. If, however, the extraction ratio is less than fu, clearance is likely to increase by the same proportion that fu changes. This approach does not take into account other factors that may affect clearance such as red blood cell binding, elimination from red blood cells, or changes in metabolic function.

Renal and Hepatic Function

Drugs can be eliminated or cleared as unchanged drug through the kidney (renal clearance) and by metabolism in the liver (metabolic clearance). These two routes of clearance are assumed to be independent of one another and additive.

Clt = Clm + Clr (total Cl = metabolic CI + renal Cl)

Because the kidneys and liver function independently, it is assumed that a change in one does not affect the other. Thus, Clt can be estimated in the presence of renal or hepatic failure or both. Because metabolic function is difficult to quantitate, Clt is most commonly adjusted when there is decreased renal function:

A clearance that has been adjusted for renal function can be used to estimate the maintenance dose for a patient with diminished renal function. This adjusted clearance equation, however, is only valid if the drug’s metabolites are inactive and if the metabolic clearance is indeed unaffected by renal dysfunction as assumed. A decrease in the function of an organ of elimination is most significant when that organ serves as the primary route of drug elimination. However, as the major elimination pathway becomes increasingly compromised, the “minor” pathway becomes more significant because it assumes a greater proportion of the total clearance. For example, a drug that is usually 67% eliminated by the renal route and 33% by the metabolic route will be 100% metabolized in the event of complete renal failure; the total clearance, however, will only be one-third of the normal value.

As an alternative to adjusting Clt to calculate dosing rate, one can substitute fraction of the total clearance that is metabolic and renal for Clm and Clr. Using this technique the equation below can be derived.

The Dosing Rate Adjustment Factor can be used to adjust the maintenance dose for a patient with altered renal function.

Most pharmacokinetic adjustments for drug elimination are based on renal function because hepatic function is usually more difficult to quantitate. Elevated liver enzymes do reflect liver damage but are not a good measure of function. Hepatic function is often evaluated using the prothrombin time (or INR), serum albumin concentration, and serum bilirubin concentration. Unfortunately, each of these laboratory tests is affected by variables other than altered hepatic function. For example, the serum albumin may be low due to decreased protein intake or increased renal or GI loss, as well as decreased hepatic function. Although liver function tests do not provide quantitative data, pharmacokinetic adjustments must still take into consideration liver function because this route of elimination is important for a significant number of drugs.

Cardiac Output

Cardiac output also affects drug metabolism. Hepatic or metabolic clearances for some drugs can be decreased by 25% to 50% in patients with congestive heart failure. For example, the metabolic clearances of theophylline and digoxin are reduced by approximately one-half in patients with congestive heart failure. Since the metabolic clearance for both of these drugs is much lower than the hepatic blood or plasma flow (low extraction ratio), it would not have been predicted that their clearances would have been influenced by cardiac output or hepatic blood flow to this extent. The decreased cardiac output and resultant hepatic congestion must, in some way, decrease the intrinsic metabolic capacity of the liver.