1. Evaluation of Methods Used to Estimate Vancomycin Pharmacokinetic Parameters
By Hanh Huynh, PSIII

2. Outline Meet MJ Vancomycin background
The relationship between CLvanco & CLcr
Comparison between methods of estimating CLvanco based on CLcr
Kinetidex® vs. Matzke method

3. Meet MJ 62 y/o M Height=175cm, weight = 81.8kg Relapsed AML.
Received first allogeneic sibling-related stem cell transplantation in 2006
Currently admitted for a second allogeneic sibling-related transplantation from his brother (on 3/21)
PMH:
Nephrectomy d/t renal cell carcinoma in March 1998
History of benign prostate hypertrophy
History of inguinal hernia repair
History of appendectomy
History of osteonecrosis with bilateral hip replacement

4. Meet MJ Since 3/12 Pt on Ancef & Fortaz since 4/12 3/22: Day +1
Spiking temp: Tmax = 39.4oC
SCr: 1.03 mg/dL
Hemodynamically stable
Ancef and Fortaz D/C
Meropenem was started
Vancomycin 1,200mg IVPB Q24H was started
Concurrent nephrotoxic medications:
Tacrolimus 1mg daily
What is the estimated trough for this patient?

5. Vancomycin Background
Tricyclic glycopeptide
Used to treat gram-positive infections
MOA: exhibits bactericidal activity by blockage of the glycopeptide polymerization in the bacterial cell wall.
Largely excreted unchanged in the urine
 Dose/dosing frequency needs to be adjusted for patients with reduced renal function
Common adverse reactions: hyptotension, flushing, erythematous rash, and chills
Serious adverse reactions: ototoxicity, nephrotoxicity

6. Vancomycin Pharmacokinetic Parameters
Half life:
Adult with normal renal function: 8 hours
Adult with renal failure: hours
Burns: 4 hours
Obesity (>%30 over IBW): 3-4 hours
Volume of distribution: 0.5 – 1 L/kg
Commonly used: 0.7L/kg

7. Poll Time
How do you estimate CLvanco based on CLcr? CLvanco = _________ CLcr
100%
80% - 99%
70% - 89%
60 – 69%
59% or less
Other

8. What is the relationship between the CLvanco & CLcr?

9. Rodvold, K. Vancomycin pharmacokinetics in Patients with Various Degrees of Renal Function
Purpose:
Characterize the pharmacokinetics of vancomycin in patients with various degrees of renal function.
Evaluate the influence of age, protein binding, and renal function on vancomycin distribution and elimination.
Patient population:
37 adults
Age
Method:
Pharmacokinetic parameters obtained by stripping the serum concentration-time data with RSTRIP (pharmacokinetic computer software)
These estimated parameter used to generate a best fit of the data using both two- and three- compartment models
Result:
CLvanco = 0.79 x CLcr

10. Birt, JK. Using clinical data to determine vancomycin dosing parameter
Patient population:
22 patients,
Unknown characteristics
Method:
Geometric regression analysis used to determine the correlation between CLvanco and CLcr
Results:
CLvanco = x CLcr

11. Burton, M.E. Evaluation of a Bayesian method for predicting vancomycin dosing.
Purpose:
Evaluate the performance of a vancomycin dosing program
Method:
Population estimates of vancomycin’s Vd and CL used to predict dosing.
These estimates individualized by a Bayesian algorithm that used dosing and serum vancomycin concentration
Results:
Demonstrate the accuracy and lack of bias in individualized dosing predictions using the Bayesian dosing method
CLvanco (mL/min/kg) =([CLcr (mL/min) x ] );
Ability of revised pharmacokinetic parameter estimates to improve performance.
CLvanco (L/hr) = CLcr (mL/min) x 0.048

12. Matzke, G. et. al. Pharmacokinetics of Vancomycin in Patients with Various Degrees of Renal Function
Purpose
To assess the relationship between renal function and vancomycin pharmacokinetics
Develop a nomogram for vancomycin dosage in patients with various degrees of renal function
Patient Population:
56 patients
Age 17-85
With different degrees of renal functions
Method:
Postinfusion log vancomycin concentration in serum-time profiles analyzed by linear least-squares regression technique
Elimination rate constant and the serum concentration at the end of infusion period estimated
CLs and Vd calculated based on ke and Cmax
Result:
No significant relationship between the steady-state volume of distribution and CLCR
Observed relationship between ke and CLCR
Ke = x CLCR
Observed relationship between CLS (serum clearance) and CLCR:
CLS = x CLCR

13. Matzke, et. al.

14. Matzke, et. al.

15. Kinetidex®
Comprehensive tool to optimize drug therapy for vancomycin, gentamicin, tobramycin, amikacin, theophylline, digoxin and valproic acid
Calculate kinetic parameter
Dosing recommendations
Graphic representations
Use Matzke method to calculate ke
Ke = x CLcr
Vd = 0.6L/kg

16. Text books Ambrose. Basic clinical pharmacokinetics.
CLvanco (mL/min) = CLcr
Bauer, L. Applied Clinical Pharmacokinetics
CLvanco (mL/min/kg)
= (0.695 x CLcr [mL/min/kg]

17. Murphy, J. et. Al. Predictability of Vancomycin Trough Concentrations Using Seven Approaches for Estimating Pharmacokinetic Parameter
Purpose:
Seven methods for estimating vancomycin pharmacokinetic parameter were studied
Determine which method best predicted measured concentrations for patients at a community teaching hospital

18. Murphy, J. et. Al. Patient population: Methods: Results:
189 patients who were given vancomycin and had at least one trough vancomycin concentration measured
Methods:
Data reviewed retrospectively
Patient information and data were entered into an Excel spreadsheet and steady state troughs were calculated
Precision (root mean-squared error) – how close predicted concentration are to the measured concentration
Bias (mean error) – prediction are, on average, higher or lower than the measured concentrations.
Results:
The Matzke method had the best combination of the least bias and best precision.
CLvanco (mL/min) = (CLcr x 0.689)
V=0.72L/kg if CLcr is >60mL/min; V=0.89L/kg if CLcr is mL/min; V=0.9L/kg if CLcr is <10mL/min

19. Murphy, J. et. Al. – Pharmacokinetic parameter prediction methods
Matzke method
CLvanco (mL/min) = (CLcr x 0.689)
Cockcroft-Gault method, ABW
V=0.72L/kg if CLcr is >60mL/min;
V=0.89L/kg if CLcr is mL/min;
V=0.9L/kg if CLcr is <10mL/min
ABW
Rodvold method
CLvanco (mL/min) = (CLcr x 0.79)
V=0.5L/kg if CLcr is >70mL/min/70kg;
V=0.59L/kg if CLcr is 40-70mL/min/70kg;
V=0.64L/kg if CLcr is 10-39mL/min/kg
Birt method
CLvanco (mL/min) = x CLcr ;
V=0.54L/kg
ABW = Actual Body Weight, IBW = Ideal Body Weight

20. Murphy, J. et. Al. – Pharmacokinetic parameter prediction methods
Ambrose method
CLvanco (mL/min) = CLcr
Cockcroft-Gault, ABW
V(L) = (0.17 x [age in years]) + (0.22 x [ABW in kg]) +15
ABW
Burton method
CLvanco (mL/min/kg) =([CLcr (mL/min) x ] )
V = 0.47 L/kg
(*)
Burton revised method
CLvanco (L/hr) = CLcr (mL/min) x 0.048
V = L/kg
Bauer method
CLvanco (mL/min/kg) = (0.695 x CLcr [mL/min/kg]
(**)
V = 0.7L/kg
(*)Use AdjBW if ABW>IBW; ABW if <=IBW, IBW = 0.73 x height(cm) – 59.42
(**) Cockcroft-Gault with ABW up to ABW/IBW = 1.3, after that IBW is used.

21. Practical Population Pharmacokinetic Parameters
Vd = 0.7L/kg
CLvanco = 0.7 x CLcr
Closed to Bauer and Matzke method
Used to quickly estimate CLvanco

22. Pharmacokinetic Parameters Comparison Among Models
Estimate CLvanco based on the CLcr
Estimate Vd
Estimate Ke based
Estimate the trough level based on
The dose given to patients
Above Ke
Bolus model

23. Methods Comparison Methods Equation Kinetidex ®
(Ke = x CLcr )
Matzke method
CLvanco (mL/min) = (CLcr x 0.689)
Cockcroft-Gault method, ABW
V=0.72L/kg if CLcr is >60mL/min;
V=0.89L/kg if CLcr is mL/min;
V=0.9L/kg if CLcr is <10mL/min
ABW
Bauer method
CLvanco (mL/min/kg) = (0.695 x CLcr [mL/min/kg]
(**)
V = 0.7L/kg
Practial method
Using Vd=0.7L/kg
CLvanco = 0.7 x CLcr
(**) Cockcroft-Gault with ABW up to ABW/IBW = 1.3, after that IBW is used.

24. Back to MJ Vancomycin 1200mg IV daily Trough (mcg/mL) Measured level
6.7
Kinetidex
6.8
Matzke method
5.6
Bauer method
Using Vd=0.7L/kg and CLvanco = 0.7 x CLcr 6

25. Additional Patients Patient Gender Age Height Weight(kg) SCr (mg/dL)
CrCL (ml/min) GF M 49
67”
103.6
0.86
119.2 FR 47
66” 79
1.25
102.7 NK F 46
63”
67.8
0.66
98.5 ML 38
56.3
0.59
102.2 MG 44
64”
55.2
0.64
96.8 CR 31
72” 88
0.93
126.3 JR 34 50
1.06
69.4 MJ 62
69”
81.1
1.03
74.4

26. Trough Level Comparison between Methods
Patient
Dose
Measured Trough (mcg/mL)
Kinetidex
(mcg/mL)
Matzke method
Bauer method
Practical Method GF
1000mg q12h
7.9
9.9*
7.2*
9.8*
7.3* FR
8.2
21.7
15.5
17.6
16.4 NK
900mg q12h
8.5
15.6
7.8*
9.6*
8.1* ML 9
15.8
7.4*
8.8*
7.6* MG
500mg q12h
9.3*
4.8 5 CR
6.5
8.3* JR
750mg q12h
10.2
24.1
11.6*
12.4* MJ
1200mg q24h
6.7
6.8*
5.6*
6.7* 6*
Total *
4 out of 8
6 out 8
6 out of 8
*: estimated trough level within 30% of measured trough level

27. Difference between Vancomycin Pharmacokinetic models
Vancomycin parameters vary among models
Matzke, Bauer and practical methods yield more troughs close to measured troughs than Kinetidex®
The difference between the measured trough and estimated trough may be due to:
Trough level drawn before steady state (yield lower measured trough)
Increasing SCr (yield higher measured trough)

28. Kinetidex® vs. Matzke method
Kinetidex® - Matzke equation 1
Ke = x CLcr
Matzke method – Matzke equation 2
CLvanco (mL/min) = (CLcr x 0.689)
Both from the same study

29. Kinetidex® vs. Matzke Patient CLcr Ke (1/hr) GF 97.1 0.085 152.3 0.087
Matzke method
CLcr
(ml/min) Ke
(1/hr) GF
97.1
0.085
152.3
0.087 FR
65.9
0.059
81.6
0.063 NK
88.1
0.078
114
0.101 ML
106.9
0.093
115
0.123 MG
96.9
97.7
0.107 CR
0.109
143.2
0.097 JR
69.4
0.062
0.086 MJ
74.4
0.066
85.3
0.064

30. Kinetidex® vs. Matzke Why are the ke values different? Kinetidex®
IBW in CLcr calculation
Vd = 0.6L/kg
Matzke (recommended by Murphy, et. al.)
ABW in both Vd and CLcr calculation
V=0.72L/kg if CLcr is >60mL/min;
V=0.89L/kg if CLcr is mL/min;
V=0.9L/kg if CLcr is <10mL/min

31. Trough Level Comparison between Methods
Patient
Dose
Measured Trough (mcg/mL)
Kinetidex®
(mcg/mL)
Matzke method
Bauer method
Practical Method GF
1000mg q12h
7.9
9.9*
7.2*
9.8*
7.3* FR
8.2
21.7
15.5
17.6
16.4 NK
900mg q12h
8.5
15.6
7.8*
9.6*
8.1* ML 9
15.8
7.4*
8.8*
7.6* MG
500mg q12h
9.3*
4.8 5 CR
6.5
8.3* JR
750mg q12h
10.2
24.1
11.6*
12.4* MJ
1200mg q24h
6.7
6.8*
5.6*
6.7* 6*
Total *
4 out of 8
6 out 8
6 out of 8
*: estimated trough level within 30% of measured trough level

32. Kinetidex® vs. Matzke Kinetidex® Matzke method
4 out of 8 estimated troughs within 30% measured troughs
The other 4 estimated trough: % of measured troughs
Matzke method
6 out of 8 estimated troughs within 30% measured troughs
The other 2 estimated trough: one lower and one higher than trough.

33. Matzke, et. al. study No height listed for patients’ demographic
AdjBW or IBW not mentioned
ABW assumed to be used in CLcr calculation
Future investigation: clarification for which weight (ABW, IBW or AdjBW) being used in the study
Average Vd reported in the study
V=0.72L/kg if CLcr is >60mL/min;
V=0.89L/kg if CLcr is mL/min;
V=0.9L/kg if CLcr is <10mL/min

34. Conclusion
Variation in population pharmacokinetic parameters used to estimate trough level
Reasonable to use parameters: Vd = 0.7L/kg and CLvanco = 70%CrCL in estimating trough level.
Measured trough level still required for optimizing vancomycin therapy.

35. Limitation Small number of patients used in assessment.
Measured trough levels may not at steady state.
Bolus model used in calculation.
Patient with unstable SCr
RF: 1.25mg/dL (Vancomycin start date) -> 0.88 mg/dL (trough date)
Measured trough 8.2mcg/mL vs. 15.5mcg/mL (Matzke) or 21.7 (Kinetidex)
Cockroft- Gault method: is it good method to calculate CrCL for oncology patients?

36. Reference
Birt JK, Chandler MH. Using clinical data to determine vancomycin dosing parameters. Ther Drug Monit. 1990; 12:206–9.
Matzke GR, McGroy RW, Halstenson CE et al. Pharmacokinetics of vancomycin in patients with various degrees of renal function. Antimicrob Agents Chemother. 1984; 25:433–7.
Burton ME, Gentle DL, Vasko MR. Evaluation of a Bayesian method for predicting vancomycin dosing. DICP. 1989; 23:294–300.
Rodvold KA, Blum RA, Fischer JH et al. Vancomycin pharmacokinetics in patients with various degrees of renal function. Antimicrob Agents Chemother. 1988; 32:848–52.
Ambrose PJ, Winter ME. Vancomycin. In: Winter ME. Basic clinical pharmacokinetics, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2004:451–76.
Bauer LA. Applied clinical pharmacokinetics. New York: McGraw Hill, Medical Publishing Division; 2001:180–261.
Murphy, J. et. Al. Predictability of Vancomycin Trough Concentrations Using Seven Approaches for Estimating Pharmacokinetic Parameter. American Journal of Health-System Pharmacy :63(23)