Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban

Journal club:are vancomycin trough concentrations adequate for optimal dosing?Michael N. Neely, Gilmer Youn, Brenda Jones, Roger W. Jelliffe, George L. Drusano, Keith A. Rodvoid, Thomas P. Lodise Antimicrobial Agents and Chemotherapy. 2014;58:309-16.Presented by:Megan HandleyPharmD Candidate Class of 2015University of Arizona College of PharmacyClinica BiblicaJanuary 29, 2015

ObjectivesBackground and overviewMethodsResults Authors conclusionsStrengths and limitationsConclusions

-background and overview of vancomycin and how it is dosed currently and why. Also introduce two studies that are referenced in the journal club study being analyzed and how they relate-the methods of the trial including the design, subject selection, modeling and simulation methods, outcome measures, and statistical analyses used-results of the article-conclusions proposed by the authors based on the results-strengths and weaknesses that I found to be true of the trial-and my set of conclusions based on my analysis of the article2

Background: Current guidelines24hr area under the curve (AUC): minimum inhibitory concentration (MIC) ratio has been established as the most accurate parameter to measure the efficacy of vancomycin against Staphylococcus aureus infections Target value AUC:MIC 400Trough concentrations of are an adequate surrogate marker for AUC Most adults with normal renal function (creatinine clearance {CrCl} of 100mL/min) being treated for an infection by an organism with a MIC 1mg/LA trough concentration in steady-state of 15-20mg/L would correlate with an AUC:MIC ratio 400 The most accurate and practical method for monitoring efficacy

*******The vancomycin dosing guidelines published in 2009 by the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists suggest the following points

3

BackgroundMonitoring peak concentrations has been abandoned as a technique for dosingThere are no data connecting peak concentrations with nephrotoxicity or efficacyTherefore, the only rationale to support trough concentration monitoring is the suggestion that trough concentrations are an adequate surrogate for AUC.It is also suggested trough concentrations are simpler to obtain than AUCIf this rationale is incorrect, the current guidelines for dosing would not be justified.Recent data has emerged revealing increased rates of nephrotoxicity with adherence to the established guidelines

-nephrotoxicity is the primary adverse effect of vancomycin treatment

-this is the main goal of the study, to determine whether trough concentrations are an accurate surrogate marker for AUC4

Background: ToxicityExample: Lodise TP, et al. conducted a retrospective study among 166 patients in Albany Medical Center Hospital who were treated with vancomycin for over 48hrsExposure-toxicity response relationship existsTrough value was the index that best described this association

-the occurrence of nephrotoxicity significantly increased as the initial trough value increased-one study that supports the current guidelines5

Bivariate analysis of the relationship between the vancomycin exposure profile and nephrotoxicity.

-As you can see, initial vancomycin trough value was the only statistically significant variable associated with the occurrence of nephrotoxicity. P=0.001-76.2% of patients that experienced nephrotoxicity had a trough value greater than or equal to 9.9. in comparison, only 38.6% of patients without nephrotoxicity had a trough value greater than 9.9. Therefore, if 100 patients with a trough value greater than 9.9 were treated with vancomycin, the absolute risk of acquiring nephrotoxicity is 37.6%.-Nephrotoxicity was defined as an increase in SCr level of 0.5 mg/dL or 50%, whichever was greater.6

Background: toxicity Conversely, Cataldo et al. conduced a meta-analysis that associated continuous infusions of vancomycin are associated with a significantly lower risk of nephrotoxicity (RR 0.6, 95% CI 0.4-0.9, p=0.02) when compared with intermittent dosing.

-Here is an example of a study that showed continuous infusions of vanco are associated with a significantly lower risk of nephrotoxicity compared to intermittent dosing. -since the relative risks are all less than 1, the risk of nephrotoxicity is decreased with continuous infusion compared to intermittent dosing. The relative risk is 0.6, so the relative risk reduction of acquiring nephrotoxicity with a continuous infusion is 40%. -Mortality, however, did not differ significantly between the two groups.7

Study objectivesPrimary: to explore whether the assumption that trough concentration is a good surrogate for AUC is true, and whether or not it is simpler to obtain and measure than the AUC.

Secondary: to explore the relationships among trough concentrations, AUC, and the potential rate of nephrotoxicity.

Tertiary: to test the level of adherence to the guideline-recommended timing of blood sampling (just prior to the fourth dose in those with normal renal function) in routine inpatient settings

8

methods

Study design: data setsObtained 3 independent data sets of adults receiving vancomycin (n=47)15 records consisting of: dosing history, concentrations at frequent intervals, and patient covariates such as weight and CrClOutpatients: samples obtained 0.5hr, 1h, at two random times, and 24hrs after the start of the doseInpatients: samples just before and 1, 2, 3, 8, and 12hrs after a dose22 patient records, various levels of renal function. Purpose was to measure influences of age, protein binding, and renal function on pharmacokinetics (PK)Had 11-13 samples taken over a 12-24hr period. 10 adult volunteers with normal CrCl enrolled in a study to measure PK in various fluids in the body. Received 9 doses of 1000mg every 12 hours followed by 7 blood samplings up to 24hrs after the last dose.

The data sets were used to draw conclusions regarding the first objective: whether or not trough value is an adequate surrogate for AUC, and the second objective, to explore the relationships between trough, AUC, and nephrotoxicity.

-Jettliffe formula used in first data set, is similar to C-G-second data set used C-GThe collected data sets were intended to represent a wide variety of patients with various degrees of renal function, enabling a relevant model of vancomycin pharmacokinetics. 3. normal CrCl was not defined10

Subject selectionInclusion criteriaData set 1:Adults with prosthetic cardiac valves each receiving single dose prior to outpatient dental procedure (n=12) ORORAcutely ill adults in the cardiac ICU with suspected or proven staphylococcal infections (n=7)Data set 2: Adult patients (n=22)Data set 3: Healthy adult volunteers (n=10)Normal CrCl (unspecified)Exclusion criteria: none mentioned

-information on the cohort subjects was very limited in the article. -The goal was to obtain a diverse group of patients with varying renal function to build a relevent vancomycin PK model11

Study protocolUsed Pmetrics (the nonparametric population modeling and simulation package) to:Model the PK dataSimulate from the modelGenerate plotsPerform standard data summaries and statistical testsWithin Pmetrics, the nonparametric adaptive grid (NPAG) algorithm was used to build a population PK model for the pooled data sets (used two-compartment model)

-the authors relied heavily on this program to create a pharmacokinetic model to determine AUCs and draw conclusions.

-these parameters were estimated based on the data set in full and two subsets

Two compartment model: Linear elimination (Ke) from central compartmentVolume (Vc)Linear transfer to peripheral compartment (KCP)Linear transfer from peripheral compartment (KPC)

12

Modeling and simulation: trough vs. aucEstimated PK parameters in population by using full data set (ModelF) with two subsets: peak and trough concentrations (ModelPT) and trough concentrations only (ModelT)Created concentration-time profiles at 12-minute intervals using the median of the joint distribution (Bayesian approach)Compared AUCs from ModelPT and ModelT to the gold standard ModelF using a Wilcoxon signed-rank test and linear regression

-These modeling techniques were used to draw conclusions on objective one: trough vs. AUC

-the two subsets were data-depleted since they only contained peak and trough concentrations-Peak concentration is concentration closest to 1 hour after end of infusion-Trough concentration closest to 1 hour before subsequent dose

-these concentration-time profiles allowed the authors to calculate the AUC for the various subsets (peak-trough, trough) and the full data set-The Bayesian approach involved determining the posterior parameter distribution which is the probability distribution of an unknown quantity based on the already established evidence on vanco PK

- AUC estimated from the full data was considered the gold standard gold standard: sort of like the control, what the subset results will be compared to -Wilcoxon signed rank test is equivalent to a paired student t-test but for non-normally distributed data (not in a symmetrical bell-shaped graph) It determines whether two population mean ranks differ. Able to use in this case since the same data is being utilizedOf note, evaluated the utility of a Bayesian approach to estimate the AUC from the limited sampling strategyUsed ModelPT and ModelF data sets as Bayesian priors to estimate the Bayesian posterior AUCs in the ModelT data set and justified their use of a bayesian approach

covariate=has an effect on the outcome13

-The first row, dataset, includes FULL (all 47 patient), considered rich sampling because vancomycin concentration measurements are taken at all times. -The trough data set consists of the full data set, except all non-trough measurements were eliminated-the peak/trough data set contained only the concentrations that were peaks and troughs.

-in the second row, you can see each dataset was used to construct a population model that differed only in the parameter value distributions based on the data. (Pmetrics computer program)

-From each population model, all 47 subjects AUCs were calculated using Bayesian calculations.

-The full data set was what was used to simulate the population pharmacokinetic model 14

Modeling and simulation: nephrotoxicityCombined the data sets with available CrCl values to use CrCl as a linear covariate, reestimated the population parameter value distributionsUsed model-predicted vs. observed concentration values by linear regression to calculate slope, intercepts, and R2 valuesUsed values and Pmetrics to simulate 5000 concentration-time profiles each for 1000 and 1500mg doses administered over 1hr every 12hrs for 5 days Used previous studies to define trough concentration intervals of