Drug Dosing in Special Populations

  Drug Dosing in Special Populations

  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

• 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

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 xV _{Cr urine} CrCl(ml/mi n)

   S xT _Cr

• U = the urine creatinine concentration _Cr (mg/dl)
• V = the volume of urine collected (ml) _urine
• S = the serum creatinine collected at the _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 140 age BW 

    CrCl for males _est 

  

72 S

 _Cr 0.85 140 age BW 

    CrCl for females _est 

  72 S  _Cr

• CrCl est = estimated creatinine clearance (ml/min)
• Age in years
• BW = body weight (kg)

  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

  IBW 29.3 0.203 age    male

      Ess

  IBW 25.1 0.175 age    female

     

• Ess = the excretion of creatinine
• IBW = ideal body weight (kg)
• Age (years)

  Adjusting the CrCl from the Ess Ess Ess 1.035 0.0337 Scr    corrected

   ave  

  

  4IBW Scr Scr  

  2 1  E Ess   corrected

  Δt E

  

2

CrCl(ml/mi n/1.73m ) 

  14.4 Scr  ave

  

Equation Salazar and Corcoran (for

obese patients)

      

   

  

  

  

   _cr ² _{s) est(female} ^{cr 2 est(males)} S

  60 Ht

  9.74 Wt 0.287 age 146 CrCl S

  51 Ht

  12.1 Wt 0.285 age 137 CrCl     

        

• Wt = weight (kg), Ht = height (m)

      20years age1 ; /S Ht 0.55 ) 73m (ml/min/1. CrCl

  Equation for children and young adults

  1year age0 ; /S Ht 0.45 ) 73m (ml/min/1. CrCl cr ^{2 est cr 2 est}

       

• Ht = height (cm) and Scr (mg/dl)

  Equation Traub & Johnson (children 1 – 18 years)

  Height in cm Scr in moles/L

    cr

  Height x

  42 3m ml/min/1.7 ClCr 

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

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

  

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

  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 ₂ 146 age 0.287 Wt

  9.74 Ht    

    

      Cl _{est(female s)} 

  60 S  _{cr 2}

146 65y 0.287 170kg

9.74 165m    

    

      Cl

  

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) Cl F D/τ /C 0.7(125 μg/d /2.5 μg/L

  35 L/d   

    ss    

  3. Compute new dose to achieve desired serum conc (use the C eq): ssave

  D/τ (C Cl)/F (1.2 μg/L

  35 L/d)/0.7 60 μg/d     

• 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 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 t increase, then dosage

  _ss

  Renal dysfunction : estimation of renal function

• Estimation of renal function:

  CL (d) Cr

  RF  CL (t)

  Cr CL (d) = creatinine clearance in the patient with renal _Cr dysfunction CL (t) = creatinine clearance in the typical 55 year-old _Cr and 70 kg patient

  

Renal dysfunction: dosage regimen

adjustment

• Maintenance dose:

  (*)

      (t) (d)

  τ MD

RF

τ

  MD

 

• Adjusment may be made by reducing the frequency of administration, or reducing the MD

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

  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 CL _t 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

  2. Phase II: conjugation to form glucuronides, acetates, or sulfates; mediated by cytosolic enzymes in hepatocytes

  Equation for hepatic drug

metabolism

LBF f CL  

   B int  CL 

  H LBF f CL  

   B int 

  LBF = liver blood flow f = the fraction of unbound drug in the blood _B

Two major types of liver disease

• 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.

Altered pharmacokinetic parameters

  1. When hepatocytes are damaged Cl _int 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

  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 CLCr to measure _est 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
Table: Child-Pugh scores for patients with liver disease

  Test/symptom Score 1 point Score 2 points Score 3 points Total bilirubin < 2.0 2.0 – 3.0 >3.0 (mg/dl) Serum albumin > 3.5 2.8 – 3.5 < 2.8 (g/dl) Prothrombin < 4 4 – 6 > 6 time (seconds prolonged over control)

• 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

Heart Failure

• • Is accompanied by a decrease in cardiac output