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

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Outline Meet MJ Vancomycin background The relationship between CL vanco & CL cr Comparison between methods of estimating CL vanco based on CL cr Kinetidex ® vs. Matzke method

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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 1998 o History of benign prostate hypertrophy o History of inguinal hernia repair o History of appendectomy o History of osteonecrosis with bilateral hip replacement

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Meet MJ Since 3/12 Pt on Ancef & Fortaz since 4/12 3/22: Day +1 Spiking temp: Tmax = 39.4 o C 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?

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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 o 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

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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

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Poll Time How do you estimate CL vanco based on CL cr ? CL vanco = _________ CL cr a.100% b.80% - 99% c.70% - 89% d.60 – 69% e.59% or less f.Other

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What is the relationship between the CL vanco & CL cr ?

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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: CL vanco = 0.79 x CL cr

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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 CL vanco and CL cr Results: –CL vanco = x CL cr

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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

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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 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 CL s and Vd calculated based on k e and C max Result: o No significant relationship between the steady-state volume of distribution and CL CR o Observed relationship between k e and CL CR o Ke = x CL CR o Observed relationship between CL S (serum clearance) and CL CR : o CL S = x CL CR

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Matzke, et. al.

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

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Text books Ambrose. Basic clinical pharmacokinetics. –CL vanco (mL/min) = CL cr Bauer, L. Applied Clinical Pharmacokinetics –CL vanco (mL/min/kg) = (0.695 x CL cr [mL/min/kg]

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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

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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. CL vanco (mL/min) = (CL cr x 0.689) –V=0.72L/kg if CL cr is >60mL/min; V=0.89L/kg if CL cr is mL/min; V=0.9L/kg if CL cr is <10mL/min

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

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

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Practical Population Pharmacokinetic Parameters Vd = 0.7L/kg CL vanco = 0.7 x CL cr –Closed to Bauer and Matzke method –Used to quickly estimate CL vanco

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Pharmacokinetic Parameters Comparison Among Models 1.Estimate CL vanco based on the CL cr 2.Estimate Vd 3.Estimate Ke based 4.Estimate the trough level based on The dose given to patients Above Ke Bolus model

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

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Back to MJ Vancomycin 1200mg IV dailyTrough (mcg/mL) Measured level6.7 Kinetidex6.8 Matzke method5.6 Bauer method6.7 Using Vd=0.7L/kg and CL vanco = 0.7 x CL cr 6

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Additional Patients PatientGenderAgeHeightWeight (kg) SCr (mg/dL) CrCL (ml/min) GFM4967” FRM4766” NKF4663” MLF3863” MGF4464” CRM3172” JRM3466” MJM6269”

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Trough Level Comparison between Methods PatientDoseMeasured Trough (mcg/mL) Kinetidex (mcg/mL) Matzke method (mcg/mL) Bauer method (mcg/mL) Practical Method (mcg/mL) GF1000mg q12h7.99.9*7.2*9.8*7.3* FR1000mg q12h NK900mg q12h *9.6*8.1* ML1000mg q12h *8.8*7.6* MG500mg q12h8.29.3*4.8 5 CR1000mg q12h6.57.8*7.2*8.3*7.2* JR750mg q12h * 12.4* MJ1200mg q24h6.76.8*5.6*6.7*6* Total *4 out of 86 out 8 6 out of 8 *: estimated trough level within 30% of measured trough level

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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)

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

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Kinetidex ® vs. Matzke Patient Kinetidex ® Matzke method CL cr (ml/min) K e (1/hr) CL cr (ml/min) K e (1/hr) GF FR NK ML MG CR JR MJ

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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 CL cr is >60mL/min; –V=0.89L/kg if CL cr is mL/min; –V=0.9L/kg if CL cr is <10mL/min

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Trough Level Comparison between Methods PatientDoseMeasured Trough (mcg/mL) Kinetidex ® (mcg/mL) Matzke method (mcg/mL) Bauer method (mcg/mL) Practical Method (mcg/mL) GF1000mg q12h7.99.9*7.2*9.8*7.3* FR1000mg q12h NK900mg q12h *9.6*8.1* ML1000mg q12h *8.8*7.6* MG500mg q12h8.29.3*4.8 5 CR1000mg q12h6.57.8*7.2*8.3*7.2* JR750mg q12h * 12.4* MJ1200mg q24h6.76.8*5.6*6.7*6* Total *4 out of 86 out 8 6 out of 8 *: estimated trough level within 30% of measured trough level

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Kinetidex ® vs. Matzke Kinetidex ® –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.

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Matzke, et. al. study No height listed for patients’ demographic AdjBW or IBW not mentioned ABW assumed to be used in CL cr 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 CL cr is >60mL/min; –V=0.89L/kg if CL cr is mL/min; –V=0.9L/kg if CL cr is <10mL/min

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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.

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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?

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Reference 1.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– 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– Bauer LA. Applied clinical pharmacokinetics. New York: McGraw Hill, Medical Publishing Division; 2001:180– 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)

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