1. Drug Dosing in Special Populations
Prof. Henny Lucida, PhD, Apt

2. 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

3. 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

4. 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)

5. 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)

6. Equations: 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)

7. 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

8. Equation Cockroft and Gault
CrCl est = estimated creatinine clearance (ml/min)
Age in years
BW = body weight (kg)
Scr = serum creatinine (mg/dl)

9. This equation should be used only in patients:
Age > 18 y
With the weight of 30% of IBW IBW males (kg) = (Ht – 60)
IBW females (kg) = (Ht – 60)
Ht: height in inches
If Scr values were not stable the Cockroft and Gault equation cannot be used

10. Equation Jelliffe and Jelliffe
Ess = the excretion of creatinine
IBW = ideal body weight (kg)
Age (years)

11. Adjusting the CrCl from the Ess

12. Equation Salazar and Corcoran (for obese patients)
Wt = weight (kg), Ht = height (m)
Scr = serum creatinine (mg/dl)

13. Equation for children and young adults
Ht = height (cm) and Scr (mg/dl)

14. Equation Traub & Johnson (children 1 – 18 years)
Height in cm
Scr in mmoles/L

15. 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

16. 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

17. 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

18. 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

19. 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

20. Solution
Estimate CrCl. This patient has a stable Scr and is obese [IBWfemales (kg) = (Ht – 60) = (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

21. 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)
3. Compute new dose to achieve desired serum conc (use the Cssave eq):

22. 60 mg/d or 120 mg every other day
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.

23. 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

24. Renal dysfunction : 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

25. Renal dysfunction: dosage regimen adjustment
Maintenance dose:
(*)
Adjusment may be made by reducing the frequency of administration, or reducing the MD or both.

26. 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)

27. Exp: adjustment of dose of amikacin sulfate
Thus, the maintenance regimen could be:
Dosing interval become 6 x longer, regimen: 500 mg (7.5 mg/kg x 68 kg) every 72 hrs
MD may be reduced by a factor of 6
regimen: 83 mg every 12 hrs
Both dosing interval and MD may be adjusted to reduce average dosing 6x
regimen: 167 mg every 24 hrs

28. 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

29. Welling and Craig Method

30. Giusti-Hayton Method

31. 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.

32. Hepatic Disorders
Most lipid soluble drugs are metabolized to some degree by the liver, the mechanism:
Phase I : oxidation, hydrolysis and reduction; mediated by the cytochrome P-450 enzyme system, occur in hepatocytes
Phase II: conjugation to form glucuronides, acetates, or sulfates; mediated by cytosolic enzymes in hepatocytes

33. Equation for hepatic drug metabolism
LBF = liver blood flow
fB = the fraction of unbound drug in the blood
Clint = intrinsic clearance

34. Two major types of liver disease
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

35. Altered pharmacokinetic parameters
When hepatocytes are damaged Clint decreases hepatic clearance reduces
If the drug has a hepatic first-pass effect BA will increases
A simultaneous effect of (1) and (2) results in extremely large increases in Css for orally administered drugs

36. 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.

37. 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

38. The Child-Pugh score
Consists of 5 laboratory test or clinical symptoms, ie:
- serum albumin
- total bilirubin
- prothrombin time
- ascites
- hepatic encephalopathy

39. 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 encephalopathy
None
Severe

40. 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

41. 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

42. 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