Evaluation of Methods Used to Estimate Vancomycin

Pharmacokinetic Parameters

By Hanh Huynh, PSIII

Outline

• Meet MJ

• Vancomycin background

• The relationship between CLvanco & CLcr

• Comparison between methods of estimating CLvanco based on CLcr

• Kinetidex® vs. Matzke method

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:

o Nephrectomy d/t renal cell carcinoma in March 1998o History of benign prostate hypertrophyo History of inguinal hernia repairo History of appendectomyo History of osteonecrosis with bilateral hip replacement

  

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

o What is the estimated trough for this patient?

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 urineo  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

Vancomycin Pharmacokinetic Parameters

• Half life:– Adult with normal renal function: 8 hours– Adult with renal failure: 120-140 hours– Burns: 4 hours– Obesity (>%30 over IBW): 3-4 hours

• Volume of distribution: 0.5 – 1 L/kg– Commonly used: 0.7L/kg

Poll Time

• How do you estimate CLvanco based on CLcr? CLvanco = _________ CLcr

a. 100%b. 80% - 99%c. 70% - 89%d. 60 – 69%e. 59% or lessf. Other

What is the relationship between the CLvanco & CLcr?

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 26 - 87

• 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 + 15.7

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 = 0.674 x CLcr + 13.45

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 0.0075] + 0.04);

– Ability of revised pharmacokinetic parameter estimates to improve performance.

• CLvanco (L/hr) = CLcr (mL/min) x 0.048

Matzke, G. et. al. Pharmacokinetics of Vancomycin in Patients with Various Degrees of Renal Function• Purpose

o To assess the relationship between renal function and vancomycin pharmacokinetics o 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: o No significant relationship between the steady-state volume of distribution and CLCR

o Observed relationship between ke and CLCR

o Ke = 0.00083 x CLCR + 0.0044o Observed relationship between CLS (serum clearance) and CLCR:

o CLS = 0.689 x CLCR + 3.66

Matzke, et. al.

Matzke, et. al.

Kinetidex®

• Comprehensive tool to optimize drug therapy for vancomycin, gentamicin, tobramycin, amikacin, theophylline, digoxin and valproic acido Calculate kinetic parametero Dosing recommendationso Graphic representations

• Use Matzke method to calculate ke• Ke = 0.00083 x CLcr + 0.0044• Vd = 0.6L/kg

 

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] + 0.05

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

Murphy, J. et. Al.

• Patient population: – 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) + 3.66– V=0.72L/kg if CLcr is >60mL/min; V=0.89L/kg if CLcr is 10 -60 mL/min;

V=0.9L/kg if CLcr is <10mL/min

Murphy, J. et. Al. – Pharmacokinetic parameter prediction methods

Matzke method

CLvanco (mL/min) = (CLcr x 0.689) + 3.66 Cockcroft-Gault method, ABW

V=0.72L/kg if CLcr is >60mL/min;

V=0.89L/kg if CLcr is 10 -60 mL/min;

V=0.9L/kg if CLcr is <10mL/min

ABW

Rodvold method

CLvanco (mL/min) = (CLcr x 0.79) + 15.7 Cockcroft-Gault method, ABW

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

ABW

Birt method

CLvanco (mL/min) = 0.674 x CLcr + 13.45; Cockcroft-Gault method, ABW

V=0.54L/kg ABW

ABW = Actual Body Weight, IBW = Ideal Body Weight

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 0.0075] + 0.04) Cockcroft-Gault, ABW

V = 0.47 L/kg (*)

Burton revised method

CLvanco (L/hr) = CLcr (mL/min) x 0.048 Cockcroft-Gault, ABW

V = 0.706 L/kg (*)

Bauer method

CLvanco (mL/min/kg) = (0.695 x CLcr [mL/min/kg] + 0.05 (**)

V = 0.7L/kg ABW

(*)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.

Practical Population Pharmacokinetic Parameters

• Vd = 0.7L/kg

• CLvanco = 0.7 x CLcr

– Closed to Bauer and Matzke method

– Used to quickly estimate CLvanco

Pharmacokinetic Parameters Comparison Among Models

1. Estimate CLvanco based on the CLcr

2. Estimate Vd

3. Estimate Ke based

4. Estimate the trough level based on • The dose given to patients• Above Ke • Bolus model

Methods ComparisonMethods Equation

Kinetidex ® (Ke = 0.00083 x CLcr + 0.0044)

Matzke method

CLvanco (mL/min) = (CLcr x 0.689) + 3.66 Cockcroft-Gault method, ABW

V=0.72L/kg if CLcr is >60mL/min;

V=0.89L/kg if CLcr is 10 -60 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] + 0.05

(**)

V = 0.7L/kg ABW

Practial method

Using Vd=0.7L/kg

CLvanco = 0.7 x CLcr

ABW

(**) Cockcroft-Gault with ABW up to ABW/IBW = 1.3, after that IBW is used.

Back to MJ

Vancomycin 1200mg IV daily Trough (mcg/mL)

Measured level 6.7

Kinetidex 6.8

Matzke method 5.6

Bauer method 6.7

Using Vd=0.7L/kg and CLvanco = 0.7 x CLcr 6

Additional PatientsPatient Gender Age Height Weight

(kg)SCr (mg/dL)

CrCL (ml/min)

GF M 49 67” 103.6 0.86 119.2

FR M 47 66” 79 1.25 102.7

NK F 46 63” 67.8 0.66 98.5

ML F 38 63” 56.3 0.59 102.2

MG F 44 64” 55.2 0.64 96.8

CR M 31 72” 88 0.93 126.3

JR M 34 66” 50 1.06 69.4

MJ M 62 69” 81.1 1.03 74.4

Trough Level Comparison between Methods

Patient Dose Measured Trough

(mcg/mL)

Kinetidex(mcg/mL)

Matzke method

(mcg/mL)

Bauer method

(mcg/mL)

Practical Method(mcg/mL)

GF 1000mg q12h 7.9 9.9* 7.2* 9.8* 7.3*

FR 1000mg q12h 8.2 21.7 15.5 17.6 16.4

NK 900mg q12h 8.5 15.6 7.8* 9.6* 8.1*

ML 1000mg q12h 9 15.8 7.4* 8.8* 7.6*

MG 500mg q12h 8.2 9.3* 4.8 4.8 5

CR 1000mg q12h 6.5 7.8* 7.2* 8.3* 7.2*

JR 750mg q12h 10.2 24.1 11.6* 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 8 6 out of 8

*: estimated trough level within 30% of measured trough level

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)

Kinetidex® vs. Matzke method

• Kinetidex® - Matzke equation 1

– Ke = 0.00083 x CLcr + 0.0044

• Matzke method – Matzke equation 2

– CLvanco (mL/min) = (CLcr x 0.689) + 3.66

• Both from the same study

Kinetidex® vs. MatzkePatient Kinetidex® Matzke method

CLcr

(ml/min)

Ke

(1/hr)

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 0.085 97.7 0.107

CR 96.9 0.109 143.2 0.097

JR 69.4 0.062 69.4 0.086

MJ 74.4 0.066 85.3 0.064

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 10 -60 mL/min; – V=0.9L/kg if CLcr is <10mL/min

Trough Level Comparison between Methods

Patient Dose Measured Trough

(mcg/mL)

Kinetidex®

(mcg/mL)

Matzke method

(mcg/mL)

Bauer method

(mcg/mL)

Practical Method(mcg/mL)

GF 1000mg q12h 7.9 9.9* 7.2* 9.8* 7.3*

FR 1000mg q12h 8.2 21.7 15.5 17.6 16.4

NK 900mg q12h 8.5 15.6 7.8* 9.6* 8.1*

ML 1000mg q12h 9 15.8 7.4* 8.8* 7.6*

MG 500mg q12h 8.2 9.3* 4.8 4.8 5

CR 1000mg q12h 6.5 7.8* 7.2* 8.3* 7.2*

JR 750mg q12h 10.2 24.1 11.6* 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 8 6 out of 8

*: estimated trough level within 30% of measured trough level

Kinetidex® vs. Matzke

• Kinetidex®– 4 out of 8 estimated troughs within 30% measured

troughs– The other 4 estimated trough: 175-260% 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.

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 10 -60 mL/min; – V=0.9L/kg if CLcr is <10mL/min

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.

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?

Reference1. Birt JK, Chandler MH. Using clinical data to determine vancomycin dosing

parameters. Ther Drug Monit. 1990; 12:206–9. 2. 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.

3. Burton ME, Gentle DL, Vasko MR. Evaluation of a Bayesian method for predicting vancomycin dosing. DICP. 1989; 23:294–300.

4. 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.

5. 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.

6. Ambrose PJ, Winter ME. Vancomycin. In: Winter ME. Basic clinical pharmacokinetics, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2004:451–76.

7. Bauer LA. Applied clinical pharmacokinetics. New York: McGraw Hill, Medical Publishing Division; 2001:180–261.

8. Murphy, J. et. Al. Predictability of Vancomycin Trough Concentrations Using Seven Approaches for Estimating Pharmacokinetic Parameter. American Journal of Health-System Pharmacy. 2006:63(23)2365-2370.