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Section 2 - Applied Pharmacokinetics

Creatinine clearance(CLcr)

Introduction
Excretion into the urine is a major route of elimination for metabolites and unchanged drug. Impairment of kidney function will have a significant impact on the pharmacokinetic properties of renally excreted drugs. Unlike liver function tests, measures of renal function are simple and relatively accurate. As a result, most of clinical pharmacokinetics deals with drugs which are renally excreted.
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The three main process of renal clearance are:

In renal disease, the three processes are all equally impaired. This is because renal disease results from a decrease in the number of functioning nephrons. The remaining nephrons are entirely functional, that is, secretion, filtration, and reabsorption remain intact.

Creatinine is an endogenous substance which is primarily filtered, not secreted or reabsorbed from the kidney. Therefore, it can readily be used as an estimate of glomerular filtration rate.

Creatinine clearance (CLcr) as an indicator of renal filtration, will parallel any changes in secretion and reabsorption. Therefore, CLcr can be used as an overall estimate of renal function.


Relationship between CLcr and Kel
The relationship between creatinine clearance and overall drug elimination can be easily seen by looking at plots of Kel versus creatinine clearance. These are often referred to at Dettli plots:

Kel vs CLcr plot

If we can determine the relationship between CLcr and Kel from a number of patients, we can then determine the creatinine clearance in a new patient and estimate the elimination rate constant. We can then calculate an optimum dose and dosing interval for this patient.

How do we calculate Kel for a particular drug and patient? For this we need to rely on data previously obtained and published in the literature. With this information we can construct a plot of CLcr versus Kel. This plot may be built into a computer program or nomogram:

The y-intercept(Knr) is the nonrenal elimination rate, or that which occurs with essentially no renal function. The slope(b) of the regression line is the linear relationship between Kel and CLcr.


Calculating creatinine clearance

There is considerable controversy as to which equation is best for estimating CLcr, what weight to use, and whether to round up the serum creatinine in the elderly. Please refer to the publications listed in the reference section for more in-depth discussion of these areas.

The advantages of calculating CLcr from serum creatinine are:

  • Simple, convenient and reproducible.
  • Requires only a single blood sample.
  • Avoids the errors inherent in a timed urine collection.
You should be aware of some pitfalls and precautions when calculating CLcr from serum creatinine:
  1. Liver dysfunction = associated with a significant over prediction of CLcr. Most authorities state that these equations should not be used in patients with liver disease.
  2. Emaciated = have low serum creatinine concentrations secondary to decreased muscle mass, resulting in a significant over prediction of CLcr.
  3. Elderly = may have low serum creatinine concentrations secondary to decreased muscle mass, leading to a possible over prediction of CLcr. Some authorities round up the serum creatinine in the elderly to avoid a falsely elevated CLcr.
  4. Unstable renal function = C&G's method is not reliable in patients with unstable renal function. Jelliffe's multi-step method, which corrects for rising serum creatinine, may be more accurate in these patients.

Jelliffe method
Because Jelliffe's method includes a step to correct for rising serum creatinine, it is more accurate than the Cockroft and Gault method in patients with unstable renal function.

  1. Estimate urinary creatinine excretion rate
      E Males = Wt x (29.305 -[0.203 x (age)])
      E Females = Wt x (25.3 -[0.18 x (age)])

      where:
      Wt = Lean body weight, or Adjusted body weight if obese

  2. Correct for rising serum creatinine
      E = E - [4 x ABW x (SCr1-SCr2)] / D

      where:
      Wt = Lean body weight, or Adjusted body weight if obese
      SCr1 = the latest serum creatinine
      SCr2 = the earlier serum creatinine
      D = the number of days between

  3. Calculate corrected creatinine clearance (CLcr)
      CLcr = (E * 0.12) / (SCr x BSA)

      where:
      SCr = most recent serum creatinine

Cockroft and Gault method

    CLcr Males = Wt(140 - Age) / (SCr x 72)

    CLcr Females = 85% of male value

    where:
    SCr = most recent serum creatinine
    Wt = Lean body weight, or Adjusted body weight if obese

Summary

  • Creatinine clearance (CLcr) can be used as an overall estimate of renal function.
  • The relationship between creatinine clearance and overall drug elimination can be used to predict an optimum dose for a patient.
  • You should be aware of common pitfalls and precautions when calculating CLcr from serum creatinine.

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Section 2 - Applied Pharmacokinetics

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