Pharmacokinetics

1. Pediatric Dosing of
Aminoglycosides and
Vancomycin Based on
Pharmacokinetic Concepts
Marie Varela, Pharm.D., BCPS
Sherene Samu, Pharm.D.
1

2. Objectives
 Describe basic pharmacokinetic parameters for
vancomycin and aminoglycosides in pediatric patients
 Outline dosing strategies for aminoglycosides based
on pharmacokinetic principles
 Outline dosing strategies for vancomycin based on
pharmacokinetic principles
 Select a monitoring plan for vancomycin and
aminoglycosides in pediatric patients
 Select an adjusted dosing regimen based on serum
concentrations for vancomycin and aminoglycosides in
pediatric patients
2

3. Pharmacokinetics
Definition:
 The study of the time course of a drug and its
metabolites in the body
 The study of the ADME of a drug and its
metabolites in the body
 Absorption
 Distribution
 Metabolism
 Excretion
 Varies greatly with age groups (pediatrics,
geriatrics)
3

4. Volume of Distribution
4

5. Excretion
 Because of the PK and PD characteristics
of vancomycin and aminoglycosides, the
clearance of these drugs is closely
correlated to creatinine clearance
5

6. Estimation of Creatinine Clearance
Schwartz Estimate
Estimates creatinine clearance
from serum creatinine, the
patient's height, and a
proportionality constant
CrCl = (k * Ht) / Cr
(Caution: formula tends to
overestimate the actual
creatinine clearance and
should be used with caution.)
http://www-users.med.cornell.edu
Ht height in
centimeters
Cr serum creatinine
K Constant:
(see below)
Infant (LBW < 1
year)
0.33
Infant (Term < 1
year)
0.45
Child or Adolescent
Girl
0.55
Adolescent Boy 0.70
6

7. Elimination Half-life (t½)
 Associated with first-order kinetics (serum
concentration diminishes logarithmically
over time)
 Time it takes for plasma concentration to
reach half of a previous concentration
 Affected by metabolism and excretion
 Most drugs follow first-order kinetics
(including aminoglycosides and vanco)
7

8. Steady State
 Equilibrium reached:
Rate of drug in=Rate of drug out
 Time to reach steady state is a function of t½
t½ % of Steady State Achieved
1 50%
2 75%
3 87.5%
4 93.75%
5 100% 8

9. Graph of Multiple Dosing
Q6h dosing
t½ = 6 hours
9

10. Pharmacodynamic Concepts Affecting
Dosing and Monitoring of
Aminoglycosides and Vancomycin
 Organism (Gram + vs. Gram -)
 MIC of organism
 Site of infection
 Dose-response relationships of Abx
 Concentration vs. time dependent bactericidal
activity
 PAE
10

11. Concentration Dependent
 Aminoglycosides
 CONCENTRATION dependent killing
 Maximize INTENSITY of exposure
 As concentration at site ↑, antimicrobial action ↑
 More pronounced responses to dosage
adjustments
11

12. Gentamicin/Tobramycin
Initial Dosing Pediatrics
12
Conventional Dosing Extended Interval Dosing
2-2.5 mg/kg/dose q8h 4.5-7.5 mg/kg/dose q24h
CF: 3.3 mg/kg/dose q8h CF: 10-12 mg/kg/dose q24h
Gram + synergy: 1 mg/kg/dose q8h N/A
Lexicomp 1978-2013

13. Gentamicin/Tobramycin
Initial Neonatal Dosing SBUH
PMA (weeks) Postnatal (days) Dose
(mg/kg)
Interval
(hours)
≤ 29 0 to 7
8 to 28
> 28
5
4
4
48
36
24
30 to 34 0 to 7
> 7
4.5
4
36
24
≥ 35 ALL 4 24
Reference: Neofax 13

14. Gentamicin/Tobramycin
Expected Half-Life
(Population Statistics)
Age t½
Neonates < 1wk 3 to 11.5 hrs
Neonates 1wk-1mo 3 to 6 hrs
Infants 4 ± 1 hrs
Children 2 ± 1 hrs
Adolescents 1.5 ± 1 hrs
Adults Normal Renal Function: 2 to 3 hr
Functionally Anephric: 30 to 60 hr
Clearance approximately equal to CrCl (≈ 5% metabolized)
14

15. Aminoglycosides Target Goals
 Tobramycin/Gentamicin
Target Serum Concentrations
Parameter
Serum
Concentration
Condition
Peak
4-5 mcg/mL
•UTI
•Gram (+) synergy
6-8 mcg/mL
•Pneumonia (within 24
to 48 hours)
Trough <2 mcg/mL to minimize toxicities
15

16. Time Dependent
 Vancomycin
 TIME dependent killing
 Maximize DURATION of exposure
 More pronounced responses to interval
adjustments
16

17. Vancomycin
Initial Dosing Pediatrics
 10-15 mg/kg/dose q6-8 hours
 Renal impairment
 GFR 30-50: 10 mg/kg/dose q12h
 GFR 10-29: 10 mg/kg/dose q18-24 hours
 GFR < 10: 10 mg/kg/dose; re-dose based on
serum concentrations
17
Lexicomp 1978-2013

18. IV Vancomycin
Initial Neonatal Dosing SBUH
PMA
(weeks)
Postnatal (days) Interval
≤ 29 0 to 14
> 14
18
12
30 to 36 0 to 14
> 14
12
8
37 to 44 0 to 7
> 7
12
8
> 44 All 6
Dose: 10 to 15 mg/kg/dose*
(*This dosing strategy targets a trough of 5-15, therefore 15 mg/kg/dose is preferred.)
Reference: Neofax

19. Vancomycin
Expected Half-Life
(Population Statistics)
Age t1/2
Neonates 6 to 10 hrs
Infants 3 to 4 hrs
Children 2.2 to 3 hrs
Adults Normal renal function: 5-11 hr
End stage renal: 5 to 7 days
Clearance approximately equal to CrCl (≈ 5% metabolized)
19

20. IV Vancomycin
 Target Serum Concentrations
Trough
Goal
Condition
10-15 mcg/mL •General
15-20 mcg/mL •Peritonitis
•Osteomyelitis
•MRSA pneumonia
•CNS infections
20
Maintain trough in therapeutic range; peak inconsequential

21. IV Vancomycin
 Dosing Strategies
 Due to pharmacodynamic characteristics,
optimal give more frequently
 Want trough to remain in therapeutic range;
peak inconsequential
 For renal impairment, reduce frequencies
21

22. Why Monitor?
 Constant changes in Vd and clearance
 Optimize therapeutic effects
 Minimize toxicity
22

23. When to Monitor?
 At presumed steady state
 Upon initiation of therapy
 After a dosage/frequency adjustment
 Upon significant change in weight, fluid status, renal
function
 After addition of a medication that may affect renal
function (i.e. Ibuprofen)
 Every week after achieving therapeutic serum
concentrations
 For vancomycin doses of > 15 mg/kg/dose q6h or > 3 g
per day, recheck first therapeutic trough in 2-3 days.
(Then follow above monitoring strategy thereafter.)
23

24. Time to Draw
 Peak (aminoglycosides only)
30 minutes after dose completely infused
 Trough (all drugs)
30 minutes before the next dose is due
24

25. How to Interpret Lab Results
 Questions to ask yourself
 Was the initial dosing appropriate? (considering renal
function etc.)
 Was the trough drawn at presumed steady state?
 For unexpected high concentrations, was it possible
the trough was drawn after the start of the infusion or
from a line that may not have been flushed?
 Was it actually drawn at the time documented in the
system?
 Should the level be redrawn?
25

26. Gentamicin Conventional Dosage
Adjustment Guidelines
26
If Peak is
High
(>10
mcg/mL)
Trough is High
Proportional DECREASE in DOSE to
bring peak to desired number.
Check to see how this change
affects trough.
If trough is still high (above
range) with this dosage
decrease, DECREASE the
FREQUENCY.
Trough is in range
Proportional DECREASE in DOSE to
bring peak to desired number.
Trough is low
(<0.5 mcg/mL)
Proportional DECREASE in DOSE to
bring peak to desired number and
INCREASE the dosing frequency.
If Peak is
Low
(less
than
target)
Trough is High
Proportional INCREASE in DOSE to
bring peak to desired number. Must
also DECREASE the dosing
frequency
Trough is in Range
Proportional INCREASE in DOSE to
bring peak to desired number.
Check to see how this change
affects the trough.
If the change will cause the
trough to be high (above
range), also DECREASE the
FREQUENCY.
Trough is low
Proportional INCREASE in DOSE to
bring peak to desired number.
Check to see how this change
affects trough.
If the change will cause the
trough to be high (above
range), also DECREASE the
FREQUENCY.

27. Gentamicin Dosage
Adjustment Guidelines
27
•If peak is in desired range and trough is
high, DECREASE THE FREQUENCY.
•After rechecking serum
concentrations, may be necessary to
increase dose with next adjustment.
•If peak is in desired range and trough is
low, most likely no adjustment is
necessary.

28. Vancomycin Dosage
Adjustment Guidelines
28
If trough
comes back
HIGH
If trough is in toxic
range, hold and draw
random serum
concentrations until
below 15 mcg/mL.
May calculate patient
half-life using formula if
there are 2
concentrations after a
dose and one value is at
least twice the other.
When
concentration is
below 15
mcg/mL,
recalculate
dose and
restart.
If half-life is
greater than
dosing interval,
increase dosing
interval to greater
than or equal to
one half-life
If trough
comes back
LOW
If trough is less than
half of target,
increase the
frequency. If the
frequency is already
Q6H, increase the
dose to 15 mg/kg. If
trough is still low,
increase the dose in
small increments
(i.e. 2 mg/kg per
dose)
If trough is more than
half of target, increase
the dose based on a
linear relationship;
calculate as a
proportional ratio to
trough. Maximum
increase of 50% at one
time.
Note: Q6h hours in the maximum frequency

29. Common Myth
 Adjust the dose by 10%
 Is this an appropriate recommendation?
 In what situation, if ever, would this apply?
29

30. Calculating Actual Half-Life
to choose best dosage interval
K = ln C1
C2
Δ Time
t½ = 0.693/K
K=elimination rate constant
Δ Time = hours
•Can be done from random levels if spaced far enough apart
(one number at least twice the other)
•Can be done from peak and trough if at steady state
30

31. Communication
 Verbal
 Progress notes
 Sign outs
31

32. Case 1
Female
20 years old
ABW 76.6 kg
IBW 52.4 kg
SCr 0.6
CrCl 123 mL/min
 Reason for visit
 Chronic CSF leak
 Comes to ER with symptoms of bending
down, having rhinorrhea
 Started on vancomycin
 Trough goal = 15-20 mcg/mL
32

33. Case 1
Date Dosing Schedule Dose Received Time
2/3/10 1 g x1 STAT 1 g 1629
2/4/10
1.5 g Q12H 1.5 g 0400
1 g Q12H 1 g 1520
2/5 /10
VANCOMYCIN TROUGH
10.1 mcg/mL
0330
1 g Q12H
1 g 0400
1 g 1530
33

34. Case 1
 Pharmacy recommendation on 2/5/10
 Draw a level on 2/6/10 AM
 If level ≤ 10 mcg/mL, give 1 g Q8H
 If level 11-12 mcg/mL, give 1.5 g Q12H
 If 13-15 mcg/mL, give 1.2 g Q12h
34

35. Case 1
Date Dosing Schedule Dose Received Time
2/6/10
VANCOMYCIN TROUGH 11 mcg/mL 0300
1 g Q12H 1 g 0330
1.5 g Q12H 1.5 g 1530
2/7/10 1.5 g Q12H
1.5 g 0330
1.5 g 1530
2/8/10
VANCOMYCIN TROUGH
17.5 mcg/mL
0300
35

36. Case 2
Female
2 years old
ABW 17.5 kg
IBW 17.3 kg
SCr 0.3
CrCl 177 mL/min
 Reason for admission
 Lethargy
 Mental status changes
 Fever
 Started on gentamicin
 R/O sepsis (gram negative coverage)
36

37. Case 2
 Target Serum Concentrations
 Peak: 6-10 mcg/mL
 Trough: < 2 mcg/mL
 Gentamicin Dose: 2.5 mg per kg q8h
37

38. Case 2
Date Dosing Schedule Dose Received Time
1/27/10 43 mg Q8H 43 mg 22:00
1/28/10
43 mg Q8H 43 mg 06:00
43 mg Q8H 43 mg 14:00
1/28/10 Gentamicin Peak 5.2 mcg/mL 15:00
Gentamicin Trough 1.3 mcg/mL 21:30
1/28/10 43 mg Q8H 43 mg 22:00
38

39. Case 2
 Dosage Adjustment
 Want peak 6 or greater
If 43 mg yields peak of 5.2, what dose
would bring it to 6?
Use linear proportion as long as interval is
unchanged
39

40. Case 2
 Dosage Adjustment Continued
 What effect would that have on trough (if
dose was increased to 49 mg q8h)?
If 43 mg yields a trough of 1.3 mcg/mL, 49
mg would bring it to what trough?
40

41. Case 2
 What if trough calculated to greater than 2?
 Answer: increase the interval
 Monitoring
 After dosage change, repeat peak and trough
around 3rd dose of the new regimen
41

42. Case Study
 Term neonate
 DOB: 1/25/12
 Diagnosis: chorioamnionitis
 Weight 3.65 kg
 Start antibiotics: ampicillin
gentamicin
42

43. Case 3 ( 1) Gentamicin
43
Gentamicin ordered: 14.6 mg q 24 hours
Dosed at 4 mg per kg

44. Questions:
 Was this dosed properly?
 What criteria are used to determine if this
was dosed properly?
 What level(s) will be drawn to properly
monitor this drug?
 What serum concentrations are we
targeting?
44

45. Gentamicin Dosing
45
PMA (weeks)
Postnatal
(days)
Dose
(mg/kg)
Interval
(hours)
≤ 29 0 to 7
8 to 28
> 28
5
4
4
48
36
24
30 to 34 0 to 7
> 7
4.5
4
36
24
≥ 35 ALL 4 24
PMA is the equivalent to Gestational Age plus Postnatal Age

46. Case 3 (2) Gentamicin
46
Dose given each morning for 3 doses

47. Question:
 What time should the peak be drawn?
 What time should the trough be drawn?
47

48. Case 3 (3) Gentamicin
48

49. Case 3 (4) Gentamicin
49

50. Question:
 What is your evaluation of this peak?
 How do we proceed from here?
50

51. 51
Date Dosage
Regimen
Admin
Time
Time
of
Blood
Draw
Peak,
Trough
or
Random
Result Serum
Creat
Comments
1/25/12 Gent
14.6 mg
q24
9:00 No serum creatinine.
Wt= 3.65 kg 4 mg/kg
1/26/12 “ 8:08
1/27/12 “ 8:08 9:00
(11:09)
Peak 33.7
Mcg/mL
If you “believe” these
numbers,
t ½ =1.88
12:39
(12:55)
Random 9.3
Mcg/mL
Expected t ½ in
neonate=3-6 hours
Aminoglycoside Pharmacokinetic
Monitoring
Drug: Gentamicin

52. Case 3 (5) Gentamicin
52

53. 53
Date Dosage
Regimen
Admin
Time
Time
of
Blood
Draw
Peak,
Trough
or
Random
Result Serum
Creat
Comments
1/25/12 Gent
14.6 mg
q24
9:00 No serum creatinine.
Wt= 3.65 kg 4 mg/kg
1/26/12 “ 8:08
1/27/12 “ 8:08 9:00
(11:09)
Peak 33.7
Mcg/mL
If you “believe” these
numbers,
t ½ =1.88
12:39
(12:55)
Random 9.3
Mcg/mL
Expected t ½ in
neonate=3-6 hours
1/28/12 8:15 Trough 1.6
Mcg/mL
Aminoglycoside Pharmacokinetic
Monitoring
Drug: Gentamicin

54. Question:
 Next step?
 Give a dose (4 mg/kg dose) now (9AM) and
draw a peak 30 minutes after it is infused
54

55. Case 3 (6)
55

56. Evaluation
 Check initial dosing for correctness
 Evaluate the credibility of the laboratory values
 Identify possible reasons for serum
concentration to be different than what is
expected
 Confirm that all doses were given as scheduled
 Confirm that blood was drawn at the correct time
 Repeat lab work if necessary
 Make adjustments based on pharmacokinetic
relationships
56

57. Case 4 (1) Vancomycin
57
Dosed at 10 mg/kg per dose every 8 hours.
Premature infant is 3 weeks old when vancomycin
is added..

58. Case 4 (2) Vancomycin
58

59. Case 4 (3) Vancomycin
59
4th dose

60. Case 4 (4) Vancomycin
60

61. What is the next step?
 Evaluate the initial dosing strategy
 Evaluate the lab result
 Target trough?
 Adjust dose or change the frequency?
61

62. Summary
 Basic knowledge of pharmacokinetics will
optimize prescribing by insuring:
Maximal therapeutic benefits
Minimal adverse effects
Cost effectiveness
Decreased blood sampling
62

63. CE Question #1
 A patient is on vancomycin every 8 hours
and his half life is 6 hours. What is the
earliest you would expect him to be at
steady state?
a) 12 hours
b) 6 hours
c) 18 hours
d) 24 hours
63

64. CE Question #2
 A patient is on gentamicin being treated
for a gram negative pneumonia. What is
the target serum concentrations?
a) Peak 4; Trough <2
b) Peak 15; Trough <2
c) Peak 7; Trough <2
d) Peak 5; Trough <2
64

65. CE Question #3
 A 4 year old female child with normal renal
function (Wt = 18 kg; Ht = 40 inch) is admitted
for presumed meningitis. What would be
the appropriate starting dose of
vancomycin?
a) 1g q12h
b) 15 mg/kg/dose q6h
c) 5 mg/kg/dose q8h
d) 750mg q6h
65

66. CE Question #4
 There is a 10 kg patient that is on vancomycin 150mg
q8h being treated for cellulitis. The trough comes back
at 5 at presumed steady state with all doses given at the
appropriate times. The resident calls down to the
pharmacy and asks you for a dosage adjustment. What
would be an appropriate recommendation?
a) Increase the dose by 10%
b) Change the frequency to q6h at the same dose
c) Increase the dose to 170mg at the same q8h frequency
d) Switch to linezolid because you don’t know how to adjust
vancomycin
66

67. Questions?
67

68. References
1. Harriet Lane Handbook. 17th ed. Robertson, J and Shilkofski, N Editors.
Philadelphia: Mosby, Inc., 2005.
2. Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics. 3rd
ed. Appleton & Lange, 1993.
3. Thomson MICROMEDEX. 1974 - 2008 MICROMEDEX(R) Thomson
Healthcare
4. Winter ME. Basic Clinical Pharmacokinetics. 4th ed. Baltimore: Lippincott
Williams & Wilkins, 2004.
5. http://www-users.med.cornell.edu
6. www.merck.com. Merck Manual on-line
7. Young, TE and Mangum, B. Neofax. 18th ed. Acorn Publishing, Raleigh,
2005.
8. Taketomo, Hoddong and Kraus. Pediatric Dosage Handbook. Lexi-comp.
2003-2004. 68