The Logic of laboratory Medicine - page 203

As with all the aminoglycoside antibiotics, amikacin
is eliminated solely by renal excretion. The usual
dose of amikacin is 5 mg/kg given every 8 h. The
dose is scaled according to body weight to account
for the effect of body size upon clearance rate. In
this case, GFR can be estimated so the body weight
scaling is redundant. Therefore, the scaled weight is
multiplied by the average male body weight of 70 kg
to obtain the unscaled usual dose, 350 mg given
every 8 h. The patient’s creatinine clearance rate is
37.5 ml/min using the formula of Cockcroft and
Gault (Table 12.1) so,
individualized Dm = 350 mg 37.5
115 = 114 mg
For a drug cleared primarily by the liver, the
ratio Clindiv /Clavg is approximately equal to the ratio
Clhepatic,indiv/Clhepatic,avg. Unfortunately, there are no
endogenous substances that can be used to estimate
hepatic drug clearance rate reliably. The reason for
this is that the drug elimination capacity of the liver
depends not only upon the number of functioning
hepatocytes but also upon the hepatocellular concen-
tration of the specific enzyme(s) catalyzing the
inactivation of the drug. Drugs are, for the most
part, metabolized by enzyme systems that are not
used to clear endogenous substances so the hepato-
cellular concentration of these enzymes are not
reflected in the clearance rate of endogenous
substances. For drugs that are metabolized by
enzymes that show polymorphisms, it is desirable to
know which of the polymorphic forms of the enzyme
the patient has. A drug dose appropriate for
members of that particular polymorphic population
can then be prescribed. The polymorphic population
to which a patient belongs can be characterized
either by genotyping or by phenotyping (Gonzales
and Idle 1994, Linder et al. 1997). Genotyping is
usually accomplished using restriction fragment
length polymorphism analysis or allele-specific
oligonucleotide hybridization. Phenotyping involves
the administration of a probe drug that is metabo-
lized only by the enzyme of interest. The activity of
the enzyme, and thereby the phenotype, is quantified
by measuring the rate of formation or extent of
formation of drug metabolite. Phenotyping has a
number of disadvantages compared to genotyping
including the difficulty of performing the study, the
risk of an adverse drug reaction to the probe drug,
and a higher rate of misclassification due to the
confounding effects of disease and of concurrent
medications (Linder et al. 1997). So, for those
enzymes for which genotyping is available, and that
now includes most of the clinically relevant drug
metabolizing enzymes that have significant polymor-
phisms, genotyping is preferred over phenotyping.
In patients with diseases of the liver, measurable
reductions in hepatic drug clearance rate are found
only when the disease is severe. Because of the
substantial uncertainty in estimating the magnitude
of the impairment in hepatic clearance rate, careful
monitoring of drug therapy is necessary (Morgan
and McLean 1995).
For a drug eliminated by the kidneys and the
liver, the following formula can be used to calculate
Clindiv/Cl avg,
Cl indiv
Cl avg
= frenal
Cl renal,indiv
Cl renal,avg
+ fhepatic
Cl hepatic ,indiv
Clhepatic,avg
where frenal is the fraction of drug clearance attribut-
able to the kidneys and fhepatic is the fraction contrib-
uted by the liver. Procainamide is a drug that is
eliminated by both the kidneys (freanl, 0.5) and the
liver (fhepatic, 0.5). Consider a patient receiving par-
enteral procainamide for atrial fibrillation following
Drug Therapy 12-9
Table 12.1
Calculation of creatinine clearance rate (Schwartz et al. 1976, Cockcroft and Gault 1976)
Pcr, plasma creatinine concentration in mg/dl; L, length in cm; age, age in years; wt, weight in kg
GFRindiv GFRavg Units
children 0.56 L / Pcr 135 ml/min/1.73 m2
2—12 years
children M 0.73 L / Pcr 140 ml/min/1.73 m2
13—21 years
F 0.56 L / Pcr 125 ml/min/1.73 m2
adults M (1.95 - 0.014 age) wt /Pcr 115 ml/min
F (1.65 - 0.012 age) wt /Pcr 100 ml/min