Presentation on theme: "Evaluation of Methods Used to Estimate Vancomycin Pharmacokinetic Parameters By Hanh Huynh, PSIII."— Presentation transcript:
1 Evaluation of Methods Used to Estimate Vancomycin Pharmacokinetic Parameters By Hanh Huynh, PSIII
2 Outline Meet MJ Vancomycin background The relationship between CLvanco & CLcrComparison between methods of estimating CLvanco based on CLcrKinetidex® 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 2006Currently admitted for a second allogeneic sibling-related transplantation from his brother (on 3/21)PMH:Nephrectomy d/t renal cell carcinoma in March 1998History of benign prostate hypertrophyHistory of inguinal hernia repairHistory of appendectomyHistory 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 = 39.4oCSCr: 1.03 mg/dLHemodynamically stableAncef and Fortaz D/CMeropenem was startedVancomycin 1,200mg IVPB Q24H was startedConcurrent nephrotoxic medications:Tacrolimus 1mg dailyWhat is the estimated trough for this patient?
5 Vancomycin Background Tricyclic glycopeptideUsed to treat gram-positive infectionsMOA: 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 functionCommon adverse reactions: hyptotension, flushing, erythematous rash, and chillsSerious adverse reactions: ototoxicity, nephrotoxicity
6 Vancomycin Pharmacokinetic Parameters Half life:Adult with normal renal function: 8 hoursAdult with renal failure: hoursBurns: 4 hoursObesity (>%30 over IBW): 3-4 hoursVolume of distribution: 0.5 – 1 L/kgCommonly used: 0.7L/kg
7 Poll TimeHow do you estimate CLvanco based on CLcr? CLvanco = _________ CLcr100%80% - 99%70% - 89%60 – 69%59% or lessOther
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 adultsAgeMethod: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 modelsResult:CLvanco = 0.79 x CLcr
10 Birt, JK. Using clinical data to determine vancomycin dosing parameter Patient population:22 patients,Unknown characteristicsMethod:Geometric regression analysis used to determine the correlation between CLvanco and CLcrResults:CLvanco = x CLcr
11 Burton, M.E. Evaluation of a Bayesian method for predicting vancomycin dosing. Purpose:Evaluate the performance of a vancomycin dosing programMethod: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 concentrationResults:Demonstrate the accuracy and lack of bias in individualized dosing predictions using the Bayesian dosing methodCLvanco (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 PurposeTo assess the relationship between renal function and vancomycin pharmacokineticsDevelop a nomogram for vancomycin dosage in patients with various degrees of renal functionPatient Population:56 patientsAge 17-85With different degrees of renal functionsMethod:Postinfusion log vancomycin concentration in serum-time profiles analyzed by linear least-squares regression techniqueElimination rate constant and the serum concentration at the end of infusion period estimatedCLs and Vd calculated based on ke and CmaxResult:No significant relationship between the steady-state volume of distribution and CLCRObserved relationship between ke and CLCRKe = x CLCRObserved relationship between CLS (serum clearance) and CLCR:CLS = x CLCR
15 Kinetidex®Comprehensive tool to optimize drug therapy for vancomycin, gentamicin, tobramycin, amikacin, theophylline, digoxin and valproic acidCalculate kinetic parameterDosing recommendationsGraphic representationsUse Matzke method to calculate keKe = x CLcrVd = 0.6L/kg
16 Text books Ambrose. Basic clinical pharmacokinetics. CLvanco (mL/min) = CLcrBauer, L. Applied Clinical PharmacokineticsCLvanco (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 ParameterPurpose:Seven methods for estimating vancomycin pharmacokinetic parameter were studiedDetermine 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 measuredMethods:Data reviewed retrospectivelyPatient information and data were entered into an Excel spreadsheet and steady state troughs were calculatedPrecision (root mean-squared error) – how close predicted concentration are to the measured concentrationBias (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 methodCLvanco (mL/min) = (CLcr x 0.689)Cockcroft-Gault method, ABWV=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/minABWRodvold methodCLvanco (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/kgBirt methodCLvanco (mL/min) = x CLcr ;V=0.54L/kgABW = Actual Body Weight, IBW = Ideal Body Weight
20 Murphy, J. et. Al. – Pharmacokinetic parameter prediction methods Ambrose methodCLvanco (mL/min) = CLcrCockcroft-Gault, ABWV(L) = (0.17 x [age in years]) + (0.22 x [ABW in kg]) +15ABWBurton methodCLvanco (mL/min/kg) =([CLcr (mL/min) x ] )V = 0.47 L/kg(*)Burton revised methodCLvanco (L/hr) = CLcr (mL/min) x 0.048V = L/kgBauer methodCLvanco (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/kgCLvanco = 0.7 x CLcrClosed to Bauer and Matzke methodUsed to quickly estimate CLvanco
22 Pharmacokinetic Parameters Comparison Among Models Estimate CLvanco based on the CLcrEstimate VdEstimate Ke basedEstimate the trough level based onThe dose given to patientsAbove KeBolus model
23 Methods Comparison Methods Equation Kinetidex ® (Ke = x CLcr )Matzke methodCLvanco (mL/min) = (CLcr x 0.689)Cockcroft-Gault method, ABWV=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/minABWBauer methodCLvanco (mL/min/kg) = (0.695 x CLcr [mL/min/kg](**)V = 0.7L/kgPractial methodUsing Vd=0.7L/kgCLvanco = 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 6.7Kinetidex6.8Matzke method5.6Bauer methodUsing Vd=0.7L/kg and CLvanco = 0.7 x CLcr6
26 Trough Level Comparison between Methods PatientDoseMeasured Trough (mcg/mL)Kinetidex(mcg/mL)Matzke methodBauer methodPractical MethodGF1000mg q12h7.99.9*7.2*9.8*7.3*FR8.221.715.517.616.4NK900mg q12h8.515.67.8*9.6*8.1*ML915.87.4*8.8*7.6*MG500mg q12h9.3*4.85CR6.58.3*JR750mg q12h10.224.111.6*12.4*MJ1200mg q24h6.76.8*5.6*6.7*6*Total *4 out of 86 out 86 out of 8*: estimated trough level within 30% of measured trough level
27 Difference between Vancomycin Pharmacokinetic models Vancomycin parameters vary among modelsMatzke, 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 1Ke = x CLcrMatzke method – Matzke equation 2CLvanco (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 methodCLcr(ml/min)Ke(1/hr)GF97.10.085152.30.087FR65.90.05981.60.063NK88.10.0781140.101ML106.90.0931150.123MG96.997.70.107CR0.109143.20.097JR69.40.0620.086MJ74.40.06685.30.064
30 Kinetidex® vs. Matzke Why are the ke values different? Kinetidex® IBW in CLcr calculationVd = 0.6L/kgMatzke (recommended by Murphy, et. al.)ABW in both Vd and CLcr calculationV=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 PatientDoseMeasured Trough (mcg/mL)Kinetidex®(mcg/mL)Matzke methodBauer methodPractical MethodGF1000mg q12h7.99.9*7.2*9.8*7.3*FR8.221.715.517.616.4NK900mg q12h8.515.67.8*9.6*8.1*ML915.87.4*8.8*7.6*MG500mg q12h9.3*4.85CR6.58.3*JR750mg q12h10.224.111.6*12.4*MJ1200mg q24h6.76.8*5.6*6.7*6*Total *4 out of 86 out 86 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 troughsThe other 4 estimated trough: % of measured troughsMatzke method6 out of 8 estimated troughs within 30% measured troughsThe 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 mentionedABW assumed to be used in CLcr calculationFuture investigation: clarification for which weight (ABW, IBW or AdjBW) being used in the studyAverage Vd reported in the studyV=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 ConclusionVariation in population pharmacokinetic parameters used to estimate trough levelReasonable 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 SCrRF: 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 ReferenceBirt 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)