In this presentation, I have tried to explain in brief and precisely about drugs that require renal dose adjustments in Chronic Kidney Disease or Acute Kidney Injury (renal failure).

1. DRUG THAT NEED DOSE
ADJUSTMENT IN RENAL FAILURE
[or]
RENAL DOSE ADJUSTMENTS
KEVIN JOHN, PHARM.D
1

2. AIM
i. Therapeutic plasma drug concentration must be maintained
similar in renal failure and normal people.
ii. Renal failure patients must have Cavg with normal people after
oral administration of the drug.
iii. Same average steady state concentration must be maintained in
I.V Infusion.
iv. Minimization of morbidity caused by excessive dosing.
v. Save the cost and
vi. Prevent drug-related toxicity
2

3. Why Dose Adjustments?
i. Majority of the drugs are eliminated by the kidneys.
ii. It is mandatory to make appropriate dosage modification when
renal function deteriorates to prevent drug toxicity.
3

4. 4
Urine Urine
Drug input Drug output Drug input Drug output
Excretion Of Drug

5. Stepwise approach to adjust drug dosage
regimens for patients with CKD and AKI
Step 1 Obtain history and
relevant
demographic/clinical
information
Assess demographic information, past medical history including history of renal
disease, and current clinical and laboratory information to asses the current clinical needs
of the patient
Step 2 Estimate GFR Use most appropriate tool to assess eGFR or CLcr for the patient based on age, body size,
ethnicity, and concomitant disease states
Step 3 Review current
medications
Identify drugs for which individualization of the treatment regimen will be necessary
Step 4 Calculate individualized
treatment regimen
Determine treatment goals; calculate dosage regimen based on pharmacokinetic
characteristics of the drug and the patient’s volume status and eGFR or CLcr
Step 5 Monitor Monitor parameters of drug response and toxicity; monitor drug levels if available/
applicable
Step 6 Revise regimen Adjust regimen based on drug response or change in patient status (including renal
function) as warranted
5
2011 International Society of Nephrology

6. 6

7. Pharmacokinetic Considerations
Uremic patients may exhibit pharmacokinetic changes in:-
• Bioavailability
• Volume of distribution
The oral bioavailability of a drug in severe uremia may be decreased as a result
of disease-related changes in:
• Gastrointestinal motility
• pH that are caused by nausea, vomiting, and diarrhea
• Mesenteric blood flow may also be altered.
7
• Clearance

8. The apparent volume of distribution depends largely on
• Drug–protein binding in plasma or tissues
• Total body water.
Renal impairment may alter the distribution of the drug as a result of
• Changes in fluid balance,
• Drug–protein binding, or
• Other factors that may cause changes in the apparent volume of
distribution
8
Pharmacokinetic Considerations

9. Phenytoin
9
Lactic acid
Phenytoin
Uric Acid
Hippuric acid
Albumin
Phenytoin sodium that is poorly bound to
albumin in CRF- may be estimated to be below
therapeutic levels in total plasma and increase in the
dose of phenytoin sodium based on this report
would lead to toxicity.
But in chronic kidney disease organic acids,
normally excreted in the urine, accumulate and
compete with phenytoin for binding sites on
albumin molecules.
Uremia also changes the shape of albumin
molecules, affecting phenytoin attachment.

10. Phenytoin
10
Lactic acid
Phenytoin
Uric Acid
Hippuric acid
Albumin
Phenytoin sodium that is poorly bound to
albumin in CRF- may be estimated to be below
therapeutic levels in total plasma and increase in the
dose of phenytoin sodium based on this report
would lead to toxicity.
Limited binding of phenytoin to
albumin and greater distribution
of the drug to other tissues

11. CrCl vs. Conc. Renally Elimated Drug
11

12. Example of Drugs that are eliminated
exclusively by the kidney are:
• Benzyl penicillin
• Ampicillin
• Acyclovir
• Gentamicin
• Sotalol
• Atenolol
• Tetracycline
12

13. 13
Example of Drugs that are almost entirely
metabolized by kidney:
• Clindamycin
• Propranolol
• Rifampicin
• Lorazepam
• Doxycycline
• Nortriptyline
• Warfarin

14. Drugs That Do Not Require Dosage
Adjustments
14

15. 15

16. How to adjust the dosing regimen
i. Reduce the dose of
the drug
ii. Dosing interval is
constant
16
i. Dose of the drug
constant
ii. Dosing interval is
increased

17. 17
Basis Of Renal Dose Adjustment
Normal person Renal Failure patient
C av C av
C ss C ss

18. 18
Dose Adjustment Based On Drug
Clearance
Calculation for C av
C av = Do
Cl T

19. 19
Dose Adjustment Based On Drug
Clearance
Calculation for C av
C av = Do
Cl T
Dose
Total Clearance Dosing Interval

20. For patients with renal impairment, total body clearance
will change to Clu
T
Therefore, to maintain the same desired C avg, the dose must be
changed to a uremic dose, Do
u
or the dosage interval must be changed to u
20
Dose Adjustment Based On Drug
Clearance

21. 21
For patients with renal impairment, total body clearance will
change to Clu
T
Therefore, to maintain the same desired C avg, the dose
must be changed to a uremic dose, Do
u
or the dosage interval must be changed to u
Dose Adjustment Based On Drug
Clearance

22. Cont…
22
C av = Do
N
Cl N
T
Do
Cl T
N
U
U U
=
[ⅱ]
C av = Do
Cl T
[ⅰ]

23. Cont…
23
If dosing interval is kept constant
For Oral administration

24. For IV
For IV Infusions, the same desired Css is
maintained both for patients with normal renal
function and for patients with renal impairment.
24
Therefore, the rate of infusion “R” , must be
changed to a new value, R
u for the uremic
patients.

25. 25
For IV

26. Loading dose Maintenance dose
Basis Of Renal Dose Adjustment
(based on elimination of the drug)
Depends on the Volume of
Distribution (Vd)
Vd not altered in RF =>
So Loading doses usually do
not need to be
adjusted in patients with chronic
kidney disease.
Depends on the clearance of the
drugs
Due to decreased excretion =>
decreased clearance of drugs
Therefore drug dose
adjustments required.
26

27. 27
Loading dose Maintenance dose
Basis Of Renal Dose Adjustment
(based on elimination of the drug)
Depends on the Volume of
Distribution (Vd)
Vd not altered in RF =>
So Loading doses usually do
not need to be
adjusted in patients with chronic
kidney disease.
Depends on the clearance of the
drugs
Due to decreased excretion =>
decreased clearance of drugs
Therefore drug dose
adjustments required.
As the Vd of drugs, especially
hydrophilic antibiotics, including b-
lactams, cephalosporins, and penems,
are significantly increased in the
presence of AKI, the administration of
aggressive loading doses (25–50%
greater than normal) are highly
recommended.
International Society of Nephrology

28. Estimation of eGFR or
Creatinine Clearance
28
Indirect Method
 Only Blood sample is required.
 No need of urine sample.
 Here creatinine levels in blood is estimated and,
from that determines the creatinine in urine.

29. GFR Estimation In Children And Adults
 Counahan-Barratt
 Schwartz equations.
 MDRD Study [Modification of diet in renal disease]
 Cockcroft-Gault equation.
29
In Children
In Adults

30. Counahan-Barratt
GFR (ml/min/1.73m2) = ( 0.43 x height ) / Scr
30
GFR - Glomerular Filtration Rate
Scr - Serum Creatinine
Height in cm.

31. Schwartz equation
CrCl (ml/min/1.73m2) = [height(cm) x k] / Scr
31
Patient population:
Infants over 1 week old through adolescence (18 years old)
k = 0.33 for infants 1 to 52 weeks old
k = 0.45 for children 1 to 13 years old
k = 0.55 for adolescent females 13-18 years old
k = 0.7 for adolescent males 13-18 years old

32. Modification of Diet in Renal Disease
(MDRD) study equation…
GFR = 186 x (Serum Cr)- 1.154 x (age) - 0.203
x 1.212 (if patient is black) x 0.742 (if female)
32
Note:- Does not require weight because the results are reported normalized
to 1.73 m2 body surface area, which is an accepted average adult surface
area.

33. Cockroft and Gault equation
Creatinine Clearance =
(140 – Age in years) x weight (kg)
Serum creatinine (mg/dl) x 72
33

34. Cockroft and Gault equation
Creatinine Clearance =
(140 – Age in years) x weight (kg)
Serum creatinine (mg/dl) x 72
34
For males

35. Cockroft and Gault equation
Creatinine Clearance =
(140 – Age in years) x weight (kg)
Serum creatinine (mg/dl) x 72
35
For males
For females
Multiply with 0.85 for females

36. Cockroft and Gault equation
36




37. Cockroft and Gault equation
37



IBW (Male, Kg)
= 50 + (2.3 x Ht in
inches over 5 feet)
IBW (Female, Kg)
= 45.5 + (2.3 x Ht in
inches over 5 feet)
1 feet = 12 inch
1 inch = 2.54 cm

38. If the weight of the patient is 75kg and height of 5’6”
38
IBW= 50 + (2.3 x Ht in inches over 5 feet)
50+(2.3 x 6)
50 + 13.8
63.8
For example:
IBW * 1.3 = 62.8 *1.3 = 82.94

39. Estimation of GFR in Obese Patients
using Salazar Corcoran Equation
39

40. Sanaka et al (1996) equation – for
malnourished and debilitated patient.
Creatinine clearance (ml/min) =
0.0884 x (19 x serum albumin (g/l) + 320) x weight (kg)
40
In men:
Serum creatinine (μmol/l)
Creatinine clearance (ml/min) =
0.0884 x (13 x serum albumin (g/l) + 290) x weight (kg)
In female:
Serum creatinine (μmol/l)

41. Estimation of eGFR or
Creatinine Clearance
41
Direct Method
 Here urine sample is required. (24hrs)
 Serum Creatinine directly from urine.
 Patient blood sample is also required.
 Since both are to be take, not used clinically.

42. Equation for this method…
Urine Creatinine Concentration (Μmol/L)
x Total Volume Of Urine (ml/min)
Serum Creatinine Concentration (Μmol/L).
42
Creatinine Clearance =

43. Calculations For Dosage Regimen
Using “Fe”
Step 1: Find the creatinine clearance [from above equations]
43
Step 2: Calculate the Renal Function
Step 3: Find out the “Fe” of the drug
Step 4: Calculate the Dose Adjustment Factor “Q”
Step 5: Dosing interval if needed

44. Step 2: Calculate the Renal Function
Renal Function [RF] =
44
Creatinine Clearance of Renal Impaired Patient (Clcr uremic)
Creatinine Clearance of Normal person (Clcr)
x (from lab investiga𝑡𝑖𝑜𝑛𝑠)
125 𝑚𝑙/ min
=

45. Step 3: Find out the “Fe” of the drug
 (Fe) = Fraction of the drug excreted through urine unchanged.
 Available in various literatures.
 Or else you can find them using the terminal half life of the drug:-
45
𝒇𝒆 = 𝟏 −
𝑻𝒆𝒓𝒎𝒊𝒏𝒂𝒍 𝒉𝒂𝒍𝒇 𝒍𝒊𝒇𝒆 𝒐𝒇 𝒕𝒉𝒆 𝒅𝒓𝒖𝒈 𝒊𝒏 𝑵𝒐𝒓𝒎𝒂𝒍 𝒑𝒆𝒓𝒔𝒐𝒏
𝑻𝒆𝒓𝒎𝒊𝒏𝒂𝒍 𝒉𝒂𝒍𝒇 𝒍𝒊𝒇𝒆 𝒐𝒇 𝒕𝒉𝒆 𝒅𝒓𝒖𝒈 𝒊𝒏 𝒓𝒆𝒏𝒂𝒍 𝒊𝒎𝒑𝒂𝒊𝒓𝒆𝒅 𝒑𝒂𝒕𝒊𝒆𝒏𝒕
𝒇𝒆 = 𝟏 −
𝒕 𝟏/𝟐
𝒕 𝟏/𝟐
(Of the drug in Normal Renal Function)
(Of the drug in Renal Impaired patient)

46. 46

47. 47

48. 48

49. 49

50. 50

51. Step 4: Calculate the Dose Adjustment
Factor “Q”
51
Dose Adjustment Factor “Q” = 1 - [ fe * (1-RF) ]
fe = fraction of the drug excreted in the urine unchanged
RF = Renal Function

52. Problem: 1
RI is a 38 year old woman who was admitted to the ICU after a gunshot wound. She is
5’ 6” and weights 65kg. She is on the following medications: Piperacillin 4g IV every
6 hour and I.V Ciprofloxacin 500 mg PO every 12 hour. She has suddenly gone into
renal failure and has a Serum Creatinine of 3mg/dl. Any dose regimen changes?
Fe of piperacillin is 0.8, Fe for ciprofloxacin is 0.5
52

53. 53
Problem: 1
RI is a 38 year old woman who was admitted to the ICU after a gunshot wound. She is
5’ 6” and weights 65kg. She is on the following medications: Piperacillin 4g IV every
6 hour and I.V Ciprofloxacin 500 mg PO every 12 hour. She has suddenly gone into
renal failure and has a Serum Creatinine of 3mg/dl. Any dose regimen changes?
Fe of piperacillin is 0.8, Fe for ciprofloxacin is 0.5
Age: 38 year old
Weight: 65 kg
Height: 5 feet 6 inches
Piperacillin dose: 4g every 6 hours
Ciprofloxacin dose: 500mg every 12 hours.
(140 – Age in years) x weight (kg)
Serum creatinine (mg/dl) x 72

54. 54
Problem: 1
RI is a 38 year old woman who was admitted to the ICU after a gunshot wound. She is
5’ 6” and weights 65kg. She is on the following medications: Piperacillin 4g IV every
6 hour and I.V Ciprofloxacin 500 mg PO every 12 hour. She has suddenly gone into
renal failure and has a Serum Creatinine of 3mg/dl. Any dose regimen changes?
Fe of piperacillin is 0.8, Fe for ciprofloxacin is 0.5
Age: 38 year old
Weight: 65 kg
Height: 5 feet 6 inches
Piperacillin dose: 4g every 6 hours
Ciprofloxacin dose: 500mg every 12 hours.
(140 – Age in years) x weight (kg)
Serum creatinine (mg/dl) x 72
IBW
IBW (Male, Kg)
= 50 + (2.3 x Ht in
inches over 5 feet)
IBW (Female, Kg)
= 45.5 + (2.3 x Ht in
inches over 5 feet)
1 feet = 12 inch
1 inch = 2.54 cm

55. 55
Problem: 1
(140 – 38) x 59.3 * (0.85)
3 x 72
= 23.80 ml/min
Clcr =
23.80 ml/min
125 ml/min
𝑅𝐹
(𝑟𝑒𝑛𝑎𝑙 𝑓𝑢𝑛𝑐𝑡𝑖𝑜𝑛)
=
0.19
=

56. 56
Problem: 1
Q 1 - [ fe * (1-RF) ]
=
1 - [ 0.8 * (1-0.19) ]
Piperacillin
=
0.35
=
Adjusted Dose
Normal Dose * Q
=
= 4000 * 0.35
= 1,400 mg ~ 1.4 g
every 6 hour
Normal Dose * Q

57. 57
Problem: 1
Piperacillin
Adjusted Interval
Normal interval
Q
=
17 hrs ~ 12 hrs
6
0.35
=

58. 58
Problem: 1
Q 1 - [ fe * (1-RF) ]
=
1 - [ 0.5 * (1-0.19) ]
Ciprofloxacin
=
0.595
=
Adjusted Dose
=
= 500 * 0.595
= 297 mg
Normal Dose * Q

59. 59
Adjusted Interval
Normal interval
Q
=
20 hrs ~ 24 hrs
12
0.595
=
Problem: 1
Ciprofloxacin

60. 60
Problem: 2
A 34-year-old, 110-lb female patient is to be given tobramycin for sepsis. The usual dose
of tobramycin is 150 mg twice a day by intravenous injection. The creatinine clearance in
this patient has decreased to a stable level of 50 mL/min. The fraction of tobramycin
excreted unchanged is 0.9. Calculate the appropriate dose of tobramycin for this patient.
50 ml/min
Clcr =
50 ml/min
𝑅𝐹
(𝑟𝑒𝑛𝑎𝑙 𝑓𝑢𝑛𝑐𝑡𝑖𝑜𝑛)
= 0.4
=
125 ml/min

61. 61
Problem: 2
Q 1 - [ fe * (1-RF) ]
=
1 - [ 0.9 * (1-0.4) ]
=
= 0.46
Adjusted Dose
=
= 150 * 0.46
= 69 mg twice a day
Normal Dose * Q

62. 62
Adjusted Interval
Normal interval
Q
=
26 hrs
12
0.46
=
Problem: 2

63. Giusti–Hayton Method…
Assumes that the effect of reduced kidney function on the renal portion - of
the elimination constant can be estimated from the ratio of the uremic
creatinine clearance to the normal creatinine clearance.
63

64. Problem: 3
An adult male patient (52 years old, 75 kg) whose serum creatinine is 2.4 mg/dL is to be given
gentamicin sulfate for a confirmed Gram-negative infection.
The usual dose of gentamicin in adult patients with normal renal function is 1 mg/kg every 8
hours by multiple IV bolus injections. Gentamicin sulfate is available in 2-mL vials containing 40
mg of gentamicin sulfate per milliliter.
Calculate
(a) the Clcr in this patient by the Cockcroft–Gault method and
(b) the appropriate dosage regimen of gentamicin sulfate for this patient in mg and mL
64

65. Problem: 3
Using Cockcroft–Gault method using Equation,
65
(140 – 52) x 75
72 x 2.4
= 38.19 mL/min
Clcr =
(a)
The fraction of dose excreted unchanged in the urine, fe = 0.98 for gentamicin sulfate
+ Normal creatinine clearance taken as 100 ml/min.
(b)

66. Problem: 3
66
Reduce the dose by keeping dosing interval constant
Uremic dose = KU * Normal dose
Uremic dose = 0.39 * 75 = 29.25 ~ 30mg every 8 hours
___
KN
Increasing the dosing interval and keeping the maintenance dose constant
u = 2.564 × 8 = 20.5 h

67. 67
Aminoglycoside dosing and interval

68. 68

69. Thank you
69