PHAR 4634 - Chapter 16 Page 5

Renal disease considerations

References:

Dettli, Clin.P'col. 16, 274 (1974)

Chow, J.Clin.P'col. 15, 405 (1975)

Welling, Clin.P'col. 18, 45 (1975)

Bennett, Annals Int.Med. 754 (1977)

Getting back to the renal excretion of drugs. If a drug is extensively excreted unchanged into urine, alteration of renal function will alter the drug elimination rate. Fortunately creatinine clearance can be used as a measure of renal function. For most drugs which are excreted extensively as unchanged drug it has been found that there is a good correlation between creatinine clearance and drug clearance or observed elimination rate (since V is usually unchanged).

Dose adjustment

Creatinine clearance

Creatinine is produced in the body by muscle metabolism from creatine phosphate. Creatinine production is dependent on the age, weight, and sex of the patient. Elimination of creatinine is mainly by glomerular filtration with a small percentage by active secretion. With the patient in stable condition the production is like a continuous infusion to steady state with the infusion rate controlled by muscle metabolism and the elimination controlled by renal function. Thus as renal function is reduced serum creatinine concentrations increases. Other compounds such as inulin are also used for GFR measurement. Although inulin GFR values are probably more accurate they involve administration of inulin and careful collection of urine for inulin determination. The major advantage of creatinine is that its formation is endogenous. Determination of creatinine clearance consists of collection of total urine and a plasma/serum determination at the mid-point time. Thus:-

Equation XVI-3 Creatinine Clearance

with serum creatinine expressed as mg/100 ml and creatinine clearance as ml/min. Normal inulin clearance values are 124 ml/min for men and 109 ml/min for women[2]. Because of some small renal secretion of creatinine, normal values of creatinine clearance are slightly higher than GFR measured with inulin. Thus, normal creatinine clearance values are about 120 to 130 ml/min.

Various investigators have developed equations which allow calculation of creatinine clearance using serum creatinine values. Thus a single serum level can used. For example, the equation of Cockcroft and Gault.

Males:

Equation XVI-4 Creatinine Clearance

Females: Use 85% of the value calculated for males. Lean body weight can be used in this equation[3].

Estimation of kel in a patient

The relationship between creatinine clearance and overall drug elimination can be easily seen by looking at plots of kel observed versus creatinine clearance.

Figure XVI-2, Plot of kel versus CLCR (Dettli Plot)

These are often called Dettli plots.

Figure XVI-2 shows the situation with considerable excretion as unchanged drug. i.e. fe 0.5 <--> 0.9

Figure XVI-3, Dettli Plot (fe = 1)

In Figure XVI-3 drug is excreted entirely as unchanged drug. i.e. fe = 1

Figure XVI-4, Dettli Plot (fe = 0)

In Figure XVI-4 drug is excretion only as metabolized drug. i.e. fe = 0

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

The question now arises, how do we calculate kel for a particular drug and patient? For this we need to rely on data previously obtained and published in literature. With this information we can construct a plot of kel versus CLcr. This plot maybe built into a computer program or nomogram.

Figure XVI-5, Dettli Plot Showing kel Observed Versus CL_CR

This is the plot shown before. In the references given earlier there is information useful for calculating kel in patients with impaired renal function.

For example	knr	b
Kanamycin	0.01	0.0024
Sulfadiazine	0.03	0.0005
Tetracycline	0.008	0.00072

As an example these data could be used to calculate the kel for a patient with a CLcr of 10 ml/min compared with normal renal function of 120 ml/min

For kanamycin

kelpatient = knr + b * CLcr = 0.01 + 0.0024 x 10 = 0.01 + 0.024 = 0.034 hr^-1

cf: kel = 0.01 + 0.0024 x 120 = 0.298 hr^-1

For sulfadiazine

kelpatient = 0.03 + 0.0005 x 10 = 0.03 + 0.005 = 0.035 hr^-1

cf: kel = 0.03 + 0.0005 x 120 = 0.09 hr^-1

For tetracycline

kelpatient = 0.008 + 0.00072 x 10 = 0.008 + 0.0072 = 0.0152 hr^-1

cf: kel = 0.008 + 0.00072 x 120 = 0.0944 hr^-1

This page was last modified: 12 February 2001