**Dose
adjustment in Renal Impairment**

__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 *C*_{av} 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 *C*_{av}, the dose must be

changed to a uremic dose, *D* ^{u} _{0} or

the dosage interval must be changed to T^{u}, 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 *C*_{av}, 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

adjustment based on drug clearance

• 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

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