Dose adjustment in Renal Impairment

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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