Transcript Drug Dosing in Special Populations

Drug Dosing in Special
Populations
Prof. Henny Lucida, PhD, Apt
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
failure, removes some medications from
the body although the pharmacokinetic of
other drugs are not changed
• Heart failure, results in low cardiac output,
which decreases blood flow to eliminating
organs
• Obesity, adds excessive adipose tissue to
the body, which may change the way that
drugs distribute in the body and alter the
VD
Common causes of kidney failure
Pyelonephritis
Inflammation and deterioration of the
pyelonephrons due to infection, antigens or other
idiopathic causes
Hypertension
Chronic overloading of the kidney with fluid and
electrolytes may lead to kidney insufficiency
Diabetes mellitus
The disturbance of sugar metabolism and acid-base
balance may lead to or predispose a patient to
degenerative renal disease
Nephrotoxic
drugs/metals
Certain drugs taken chronically may cause irreversible
kidney damage (the aminoglycosides, phenacetin ,
heavy metals such as mercury, lead
Hypovolemia
Any condition that causes a reduction in renal blood
flow will eventually lead to renal ischemia and damage
Neophroallergens
Certain compounds may produce an immune type of
sensitivity reaction with nephritic syndrome. (quartan
malaria nephrotoxic serum)
Renal Disease
• Glomerular filtration is the primary
elimination route for many medications
• The most common method of estimating
glomerular filtration for the purpose of drug
dosing is to measure /estimate Creatinine
Clearance (CrCl)
Equations:
U Cr xVurine
CrCl(ml/mi n) 
SCr xT
• UCr = the urine creatinine concentration
(mg/dl)
• Vurine = the volume of urine collected (ml)
• SCr = the serum creatinine collected at the
midpointof the urine collection (mg/dl)
• T = the time of urine collection (minute)
Problems of routine measurement
of patient’s CrCl:
• Incomplete urine collection
• Serum creatinine concentration obtained
at incorrect times
• Collection times errors
Erroneous measured CrCl values
Equation Cockroft and Gault
CrCl est
CrCl est
•
•
•
•

140  age BW

for males
72  S Cr
0.85140  age BW

for females
72  S Cr
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
• If Scr values were not stable the Cockroft and Gault
equation cannot be used
Equation Jelliffe and Jelliffe
Ess male  IBW29.3  0.203  age 
Ess female  IBW25.1  0.175  age 
• Ess = the excretion of creatinine
• IBW = ideal body weight (kg)
• Age (years)
Adjusting the CrCl from the Ess
Ess corrected  Ess 1.035  0.0337  Scrave 
4IBW Scr2  Scr1 
E  Ess corrected 
Δt
E
2
CrCl(ml/mi n/1.73m ) 
14.4  Scrave
Equation Salazar and Corcoran (for
obese patients)
CrClest(males)

137  age 0.285  Wt   12.1 Ht 2 

CrClest(female s)
51 Scr

146  age 0.287  Wt   9.74  Ht 2 

60  Scr
• Wt = weight (kg), Ht = height (m)
• Scr = serum creatinine (mg/dl)
Equation for children and young
adults
CrCl est (ml/min/1. 73m 2 )  0.45  Ht /S cr ; age0  1year
CrCl est (ml/min/1. 73m 2 )  0.55  Ht /S cr ; age1  20years
• Ht = height (cm) and Scr (mg/dl)
Equation Traub & Johnson
(children 1 – 18 years)
42 x Height
ClCr ml/min/1.7 3m  
S cr
2
Height in cm
Scr in mmoles/L
Renal impairment based on ClCr
Group
Description
Estimated ClCr
(mL/min)
1
Normal renal function
>80 mL/min
2
Mild renal impairment
50 – 80 mL/min
3
Moderate renal impairment
30 – 50 mL/min
4
Severe renal impairment
<30 mL/min
5
End Stage Renal Disease
Required dialysis
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
• When CrCl is <15 ml/min, a substantial
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
available
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
• Estimated pharmacokinetic parameters
are then used in pharmacokinetic dosing
equation to compute initial dose
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 mg/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
digoxin dose that will provide a Css of 1.2
ng/ml
Solution
1.
Estimate CrCl. This patient has a stable Scr and is
obese [IBWfemales (kg) = 45 + 2.3 (Ht – 60) = 45 + 2.3
(65” – 60) = 57 kg]. The Salazar and Corcoran eq. can
be used to estimate CrCl (Ht is converted from inches
to meters(65 in x 2.54 m/in)/(100cm/m) = 1.65 m
Cl est(female s)

146  age 0.287  Wt   9.74  Ht 2 

Cl est(female s)

146  65y 0.287  170kg   9.74  165m 2 

Cl est(female s)  22 ml/min
60  Scr
60  4.7 mg/dl
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 =
mg/L)
Cl  FD/τ /C ss  0.7(125 μg/d /2.5 μg/L  35 L/d
3. Compute new dose to achieve desired serum
conc (use the Cssave eq):
D/τ  (C ss  Cl)/F  (1.2 μg/L  35 L/d)/0.7  60 μg/d
• 60 mg/d or 120 mg every other day. This
would be rounded to digoxin tablets 125
mg every other day.
• The new suggested dose is 125 mg every
other day given as digoxin tablets, to be
started at the next scheduled dosing time.
Since the dosing interval is being
changed, a day should be skipped before
the next dose is given.
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.
• If t½ increase
tss increase, then
dosage must be reduced
Renal dysfunction : estimation of
renal function
• Estimation of renal function:
CL Cr (d)
RF 
CL Cr (t)
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
Renal dysfunction: dosage regimen
adjustment
• Maintenance dose:

MD
τ
(d)

 RF  MD
τ
(*)
(t)
• Adjusment may be made by reducing the
frequency of administration, or reducing the MD
or both.
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
Using equation (*), MD amikacin has to be
reduced by a factor of 6 (or 1/0.17)
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
3. Both dosing interval and MD may be
adjusted to reduce average dosing 6x
regimen: 167 mg every 24 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
suggested
Welling and Craig Method
Giusti-Hayton Method
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
drastically reduced.
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
2. Phase II: conjugation to form glucuronides,
acetates, or sulfates; mediated by cytosolic
enzymes in hepatocytes
Equation for hepatic drug
metabolism
LBF  f B  CL int 
CL H 
LBF  f B  CL int 
LBF = liver blood flow
fB = the fraction of unbound drug in the blood
Clint = 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
2. Cirrhosis; a permanent lost of functional hepatocytes.
Drug dosage schedules usually need to be modified
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)
results in extremely large increases in
Css for orally administered drugs
Altered pharmacokinetic
parameters
4. LBF decreases
depresses hepatic
drug clearance even further
5. The liver produces albumin and a-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
increases.
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
ability of the liver to metabolize the drug is
to determine the Child-Pugh score for a
patient
The Child-Pugh score
• Consists of 5 laboratory test or clinical
symptoms, ie:
- serum albumin
- total bilirubin
- prothrombin time
- ascites
- hepatic encephalopathy
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
Absent
Slight
Moderate
None
Moderate
Severe
Ascites
Hepatic
encephalopathy
• Each of the symptom is given a score of 1
(normal) to 3 (severely abnormal), and the
scores for the five areas are summed.
• The Child-Pugh score for a patient with
normal liver function is 5, whereas for
abnormal (hepatic damage) is 15
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
retaining the normal dosage interval, retain the
usual dose and prolong the dosage interval, or
modify both the dose and dosage interval
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
• VD of some drugs decreases, the alteration in
t½ is difficult to predict in patients with heart
failure