Drug Dosing in Special Populations

Drug Dosing in Special

Populations

Patient conditions that may altered

the dosing of most drugs:

• Renal or hepatic disease, may decrease the elimination or metabolism of the

majority of drugs and change the clearance

• Dialysis procedures, conducted using artificial kidneys in patients with renal

• Heart failure, results in low cardiac output, which decreases blood flow to eliminating organs

Renal Disease

• Glomerular filtration is the primary

elimination route for many medications • The most common method of estimating

Equations:

• U_Cr = the urine creatinine concentration (mg/dl)

• V_urine = the volume of urine collected (ml) • S_Cr = the serum creatinine collected at the

midpointof the urine collection (mg/dl) • T = the time of urine collection (minute)

xT S

xV U

n) CrCl(ml/mi

Cr

urine Cr

Problems of routine measurement

of patient’s CrCl:

• Incomplete urine collection

• Serum creatinine concentration obtained at incorrect times

• Collection times errors

Equation Cockroft and Gault

• CrCl est = estimated creatinine clearance (ml/min) • Age in years

• BW = body weight (kg)

• Scr = serum creatinine (mg/dl)

This equation should be used only in patients:

• Age > 18 y

• With the weight of 30% of IBW

IBW males (kg) = 50 + 2.3 (Ht – 60) IBW females (kg) = 45 + 2.3 (Ht – 60) Ht: height in inches

Equation Jelliffe and Jelliffe

Equation Salazar and Corcoran (for

obese patients)

• Wt = weight (kg), Ht = height (m) • Scr = serum creatinine (mg/dl)

Equation Traub & Johnson

(children 1 – 18 years)

Height in cm Scr in _moles/L





cr 2

S

Height

x

42

3m

ml/min/1.7

Estimation of drug dosing using

CrCl

• renal clearance of drug is smaller in patients with reduced GFR

• All drug excreting by tubular secretion and

reabsorption decline in parallel with glomerular filtration

• When CrCl is <50 – 60 ml/min, a possible modest decrease in drug doses

• When CrCl is <25 – 30 ml/min, a moderate decrease in drug doses

Modifying Doses for patients with

renal impairment

• It is possible to decrease the drug dose and retain the usual dosage interval,or • Retain the usual dose and increase the

dosage interval, or

• Both decrease the dosage and prolong the dosage interval

• The choice was made depend on the route of drug administration, the dosage forms

For drugs with narrow therapeutic

index

• Measured or estimated CrCl may be used to estimate pharmacokinetic parameters for a patient based on prior studies

conducted in other patients with renal dysfunction

Problem

• OI is a 65 yo, 170 kg (5’5”) female with Class III heart failure. Her current serum creatinine is 4.7 mg/dl and is stable. A

digoxin dose of 125 _g/d given as tablets was prescribed and expected to achieve Css equal to 1 ng/ml. After 3 weeks of therapy, the Css was measured and equalled 2.5 ng/ml. Calculate a new

Solution

This patient has poor renal function, but can be expected to be at Css with regard to digoxin

serum conc after 3 weeks of treatment.

2. Compute drug clearance (digoxin conc in ng/ml =

g/L)

• 60 _g/d or 120 _g every other day. This would be rounded to digoxin tablets 125

g every other day.

• The new suggested dose is 125 _g every other day given as digoxin tablets, to be started at the next scheduled dosing time. Since the dosing interval is being

Renal dysfunction

• Urinary excretion of drugs decreased due to a decrease in renal function (exp:

cephalosporine) drug accumulation (exp: amikacin in patient with 17% renal function) • Drug accumulation depends on frequency

of adm and t½ elimination.

Renal dysfunction : estimation of

renal function

• Estimation of renal function:

CLCr (d) = creatinine clearance in the patient with renal

dysfunction

CLCr (t) = creatinine clearance in the typical 55 year-old

and 70 kg patient RF = renal function

(t)

CL

(d)

CL

RF

Cr Cr

Renal dysfunction: dosage regimen

adjustment

• Maintenance dose:

(*)

• Adjusment may be made by reducing the

frequency of administration, or reducing the MD or both.





_(d)

_RF



MD

_τ



_(t)

τ

Exp: adjustment of dose of

amikacin sulfate

• Usual dose regimen: 7.5 mg/kgBW im every 12 hrs

• The dose for 23 year-old, 68 kg patient with CLCr 13 mL/min would be:

CLCr expected for typical patient = 77 mL/ min

RF (d) = 13/77 = 0.17

Exp: adjustment of dose of

amikacin sulfate

Thus, the maintenance regimen could be: 1. Dosing interval become 6 x longer,

regimen: 500 mg (7.5 mg/kg x 68 kg) every 72 hrs

2. MD may be reduced by a factor of 6 regimen: 83 mg every 12 hrs

Confirmation by TDM

• t½ amikacin in typical patient = 2 hr • t½ amikacin in (d) patient = 12 hr

• TDM results in:

– Regimen with 72 hrs interval showed >>> fluctuations

– Changing MD reduced fluctuation but inconvenience of frequent im injection

– Change interval & MD, reduced fluctuation and inconvenience : the most appropriate – Loading dose: same usual LD for amikacin

General guidelines for dosage

adjustment in (d) patient

• As long as fraction of drug unbound eliminated by renal route (fe) is 0.30 or less and

metabolites are inactive no change in a regimen is called for based on RF

• Regardless of the contribution of the renal route

if RF is 0.70 x typical value no

change is needed

• If RF approach zero fe(t) approach 1 CLt

reduced dosing rate must be

Hepatic Disorders

• Most lipid soluble drugs are metabolized to some degree by the liver, the mechanism:

1. Phase I : oxidation, hydrolysis and reduction; mediated by the cytochrome P-450 enzyme system, occur in hepatocytes

Equation for hepatic drug

metabolism

LBF = liver blood flow

fB = the fraction of unbound drug in the blood

Cl_int = intrinsic clearance

Two major types of liver disease

1. Hepatitis

- Patients with hepatitis inflammation of the liver decreased ability of hepatocytes or die

- Acute hepatitis: mild, transient decreases in drug

metabolism required no or minor changes in drug dosing

- Chronic hepatitis: irreversible hepatocytes damage required drug dosage changes. Patients with long term hepatocytes damage can progress to

hepatic cirrhosis

Altered pharmacokinetic

parameters

1. When hepatocytes are damaged

Clint decreases hepatic clearance

reduces

2. If the drug has a hepatic first-pass effect BA will increases

3. A simultaneous effect of (1) and (2)

Altered pharmacokinetic

parameters

4. LBF decreases depresses hepatic

drug clearance even further

5. The liver produces albumin and _-1-acid glycoprotein in the blood. The production of these proteins decline in patient with cirrhosis

free fraction of drugs in the blood. 6. Since clearance decreases and VD usually

increases the t½ almost always

Measurement of liver function

• No single laboratory test to assess the

liver function (not like CLCrest to measure

renal function)

• The most common way to estimate the

The Child-Pugh score

• Consists of 5 laboratory test or clinical symptoms, ie:

- serum albumin - total bilirubin

- prothrombin time - ascites

Table: Child-Pugh scores for patients with liver disease

Test/symptom Score 1 point Score 2 points Score 3 points

Total bilirubin

(mg/dl) < 2.0 2.0 – 3.0 >3.0

Serum albumin

(g/dl) > 3.5 2.8 – 3.5 < 2.8

Prothrombin time (seconds prolonged over control)

< 4 4 – 6 > 6

Ascites Absent Slight Moderate

Hepatic

• Each of the symptom is given a score of 1 (normal) to 3 (severely abnormal), and the scores for the five areas are summed.

Dosage adjusment

• A Child-Pugh score of 8 – 9 : a moderate

decrease (+ 25%) in initial daily drug dose for agents that are primarily (> 60%) metabolized hepatically

• A Child-Pugh score of > 10 : a significant

decrease in initial daily dose (+ 50%) is required for drugs that are mostly liver metabolized

• It is possible to decrease the dose while

Heart Failure

• Is accompanied by a decrease in cardiac output results in lower liver and renal blood flow

• Decreased drug bioavailability has been

reported, due to collection of edema fluid in the GI tract difficult absorption and

decreased blood flow to GI tract