# Dose adjustment in Renal Impairment

Dose

Lecture Objectives

After completion of this lecture, student will be able
to:

Explain
dose adjustment based on drug clearance

Explain
dose adjustment based on changes in elimination rate constant

INTRODUCTION

The design of dosage regimens for
uremic patients is based on the pharmacokinetic changes that have occurred as a
result of the uremic condition

Generally, drugs in patients with
uraemia or kidney impairment have prolonged elimination half-lives and a change
in the apparent volume of distribution

In less severe uremic conditions
there may be neither edema nor a significant change in the apparent volume of
distribution

Consequently, the methods for dose
adjustment in uremic patients are based on an accurate estimation of the drug
clearance in these patients

Two general pharmacokinetic
approaches for dose adjustment include methods based on drug clearance and
methods based on the elimination half-life

DOSE ADJUSTMENT BASED ON DRUG CLEARANCE

Methods based on drug clearance try
to maintain the desired Cav after multiple oral
doses or multiple IV bolus injections as total body clearance, Cl T,
changes

The calculation for C av is  (Equation 1)

For patients with a uremic condition
or renal impairment, total body clearance of the uremic patient will change to
a new value, Cl u T

Therefore,
to maintain the same desired Cav, the dose must be
changed to a uremic dose, D u 0 or
the dosage interval must be changed to Tu, as shown in the
following equation 2:

where the
superscripts N and u represent normal and uremic conditions, respectively

Rearranging Equation 1 and solving
for D u 0

If
the dosage interval T  is kept constant, then the uremic dose D u 0 is
equal to a fraction (Cl u T/Cl N T)
of the normal dose, as shown in the equation

For IV infusions the same
desired C SS is maintained both for patients
with normal renal function and for patients with renal impairment

Therefore, the rate of
infusion, R, must be changed to a new value, R u,
for the uremic patient, as described by the equation

DOSE ADJUSTMENT BASED ON CHANGES IN THE ELIMINATION RATE CONSTANT

The
overall elimination rate constant for many drugs is reduced in the uremic
patient

A
dosage regimen may be designed for the uremic patient either by

a)      Reducing
the normal dose of the drug and keeping the frequency of dosing (dosage
interval) constant or

b)      By
decreasing the frequency of dosing (prolonging the dosage interval) and keeping
the dose constant

Doses
of drugs with a narrow therapeutic range should be reduced particularly if the
drug has accumulated in the patient prior to deterioration of kidney function

The
usual approach to estimating a multiple-dosage regimen in the normal patient is
to maintain a desired Cav, as shown in Equation 1

Assuming
the V D is the same in both normal and uremic
patients and is constant, then the uremic dose D u 0 is
a fraction (k u/k N) of the
normal dose:

When the elimination rate constant
for a drug in the uremic patient cannot be determined directly, indirect
methods are available to calculate the predicted elimination rate constant
based on the renal function of the patient

The assumptions on which these
dosage regimens are calculated include the following

The renal elimination rate constant
(k R) decreases proportionately as renal function
decreases

The nonrenal routes of elimination
(primarily, the rate constant for metabolism) remain unchanged

Changes in the renal clearance of
the drug are reflected by changes in the creatinine clearance

The overall elimination rate constant
is the sum total of all the routes of elimination in the body, including the
renal rate and the nonrenal rate constants:

where k nr is
the nonrenal elimination rate constant and k R is
the renal excretion rate constant

Renal clearance is the product of
the apparent volume of distribution and the rate constant for renal excretion:

Rearranging the above equation
gives:

Assuming that the apparent volume of
distribution and nonrenal routes of elimination do not change in uraemia,
then k u nr = k N nr and V u D = V N D

Substitution of the above equation
gives

From the above equation , a change
in the renal clearance, Cl u R, due
to renal impairment will be reflected in a change in the overall elimination
rate constant k u

Because changes in the renal drug
clearance cannot be assessed directly in the uremic patient, Cl u R is
usually related to a measurement of kidney function by the glomerular
filtration rate (GFR), which in turn is estimated by changes in the patient’s creatinine
clearance

Summary

Two general
pharmacokinetic approaches for dose adjustment include methods based on drug
clearance and methods based on the elimination half-life

Dose

Dose
adjustment based on changes in elimination rate constant

Renal clearance is the product of
the apparent volume of distribution and the rate constant for renal excretion

The overall elimination rate
constant is the sum total of all the routes of elimination in the body,
including the renal rate and the nonrenal rate constants

The renal elimination rate constant
(k R) decreases proportionately as renal function
decreases