This study challenges current guidelines for vancomycin dosing based on trough concentrations alone. The authors analyzed 3 datasets containing vancomycin concentration-time profiles in 47 adults. Pharmacokinetic modeling showed trough-only monitoring underestimated AUC by about 25% compared to using full concentration data. Simulation of 5000 dosing profiles found over 50% of patients with adequate AUC would not meet trough guidelines. The authors conclude trough is a poor surrogate for AUC and dosing based solely on trough risks underdosing and suboptimal treatment. A Bayesian approach using multiple concentrations like AUC is preferable for optimal vancomycin monitoring.
Antibiotics are prescribed in daily base to ICU critically ill patients
it needs understanding to PK, PD of these group of drugs to achieve a desirable outcome
Clinical Pharmacokinetics of Voriconazole Omar Negm
The presentation discusses the clinical pharmacokinetics of Voriconazole as anti fungal drug, in addition, it illustrates the drug pharmacology, side effects, indications, dose adjustment in special populations, and therapeutic drug monitoring.
Antibiotics are prescribed in daily base to ICU critically ill patients
it needs understanding to PK, PD of these group of drugs to achieve a desirable outcome
Clinical Pharmacokinetics of Voriconazole Omar Negm
The presentation discusses the clinical pharmacokinetics of Voriconazole as anti fungal drug, in addition, it illustrates the drug pharmacology, side effects, indications, dose adjustment in special populations, and therapeutic drug monitoring.
Laboratory offering TDM for Immunosuppressive Drugs needs to understands their pharmacodynamics & clinical applications so that the results value add in the patient care
Understand the rationale supporting the pharmacokinetic dosing model, discuss and interpret pharmacokinetic concepts that affect aminoglycoside dosing: volume of distribution and half-life / Elimination rate, utilize pharmacokinetics to properly dose aminoglycosides. Edited by Yazan Kherallah
conversion from INTRAVENOUS TO ORAL DOSING----- design of dosage regimenpavithra vinayak
conversion from INTRAVENOUS TO ORAL DOSING----- TYPES OF IV TO PO THERAPY CONVERSIONS: MEDICATIONS INCLUDED IN AN IV TO PO CONVERSION PROGRAM: SELECTION OF PATIENTS FOR IV TO PO THERAPY CONVERSION: design of dosage regimen--clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
Antibiotics in the ICU - when, what and how?scanFOAM
A presentation by Fredrik Sjövall at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Delivered in collaboration between scanFOAM, SSAI & SFAI.
Currently efficacy of therapy of patients with
MDR ТВ does not exceed 48.7% worldwide and in Russian
Federation. One of the reason is a frequent development of
adverse drug reactions during the use of combination of
antituberculosis drugs. Since 2013 after registration of
tioureidoiminomethylpyridinium perchlorate (Pecrhlozon®) in
Russian Federation, opportunities appeared for further study
of its efficacy and safety in treatment of tuberculosis with
multiple drug resistance (MDR). In the present study we
applied monitoring of adverse drug reactions during complex
therapy by Perchlozon in combination with five other drugs
with the use of international 5-grade scale. We used Common
Terminology Criteria for Adverse Events (version 3.0). In the
study only mild (grade 1) and moderate (grade 2) adverse drug
reactions were observed except single case when severe (grade
3) adverse drug reaction happened. Mild adverse reactions that
during receiving Perchlozon therapy in complex with other
drugs for MDR-TB did not require its cessation.
Pharmacokinetics of High-Dose Methotrexate in Egyptian Children with Acute Ly...iosrphr_editor
Aim:Since several factors have been shown to influence the clearance of methotrexate, the purpose of this study
was to identify potential relationships between patient covariates and the methotrexate clearance estimates and
deduce a pharmacokinetic model for the estimation of methotrexate clearance in Egyptian pediatric ALL
patients that may help dosage adjustment and achieve target steady-state plasma concentrations in a similar
sittings.
Patients and methods: A total of 94 pediatric patients with B-cell ALL, of whom 70 were the studied population
and 24 were the test population, were treated with four courses of HDMTX doses 2.5 gm/m2
(low-risk arm) or 5
gm/m2
(standard-/high-risk arm) given every other week by intermittent intravenous infusions over 24 hours as
a part of their treatment protocol. Patients were monitored for the 24 hour MTX concentration and the systemic
methotrexate clearance was calculated for each methotrexate dose
Laboratory offering TDM for Immunosuppressive Drugs needs to understands their pharmacodynamics & clinical applications so that the results value add in the patient care
Understand the rationale supporting the pharmacokinetic dosing model, discuss and interpret pharmacokinetic concepts that affect aminoglycoside dosing: volume of distribution and half-life / Elimination rate, utilize pharmacokinetics to properly dose aminoglycosides. Edited by Yazan Kherallah
conversion from INTRAVENOUS TO ORAL DOSING----- design of dosage regimenpavithra vinayak
conversion from INTRAVENOUS TO ORAL DOSING----- TYPES OF IV TO PO THERAPY CONVERSIONS: MEDICATIONS INCLUDED IN AN IV TO PO CONVERSION PROGRAM: SELECTION OF PATIENTS FOR IV TO PO THERAPY CONVERSION: design of dosage regimen--clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
Antibiotics in the ICU - when, what and how?scanFOAM
A presentation by Fredrik Sjövall at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Delivered in collaboration between scanFOAM, SSAI & SFAI.
Currently efficacy of therapy of patients with
MDR ТВ does not exceed 48.7% worldwide and in Russian
Federation. One of the reason is a frequent development of
adverse drug reactions during the use of combination of
antituberculosis drugs. Since 2013 after registration of
tioureidoiminomethylpyridinium perchlorate (Pecrhlozon®) in
Russian Federation, opportunities appeared for further study
of its efficacy and safety in treatment of tuberculosis with
multiple drug resistance (MDR). In the present study we
applied monitoring of adverse drug reactions during complex
therapy by Perchlozon in combination with five other drugs
with the use of international 5-grade scale. We used Common
Terminology Criteria for Adverse Events (version 3.0). In the
study only mild (grade 1) and moderate (grade 2) adverse drug
reactions were observed except single case when severe (grade
3) adverse drug reaction happened. Mild adverse reactions that
during receiving Perchlozon therapy in complex with other
drugs for MDR-TB did not require its cessation.
Pharmacokinetics of High-Dose Methotrexate in Egyptian Children with Acute Ly...iosrphr_editor
Aim:Since several factors have been shown to influence the clearance of methotrexate, the purpose of this study
was to identify potential relationships between patient covariates and the methotrexate clearance estimates and
deduce a pharmacokinetic model for the estimation of methotrexate clearance in Egyptian pediatric ALL
patients that may help dosage adjustment and achieve target steady-state plasma concentrations in a similar
sittings.
Patients and methods: A total of 94 pediatric patients with B-cell ALL, of whom 70 were the studied population
and 24 were the test population, were treated with four courses of HDMTX doses 2.5 gm/m2
(low-risk arm) or 5
gm/m2
(standard-/high-risk arm) given every other week by intermittent intravenous infusions over 24 hours as
a part of their treatment protocol. Patients were monitored for the 24 hour MTX concentration and the systemic
methotrexate clearance was calculated for each methotrexate dose
Population-Based Pharmacokinetic Modeling of Vancomycin in Children with Rena...Mawaya Tanaka
Background: Vancomycin dosing to achieve the area-under-the-curve to
minimum inhibitory concentration (AUC/MIC) target of ≥ 400 in children with
renal insufficiency is unknown. Our objectives were to compare vancomycin
clearance (CL) and initial dosing in children with normal and impaired renal
function.
Methods: Using a matched case-control study in subjects ≥ 3 months old
who received vancomycin ≥ 48 hr, we performed population-based modeling
with empiric Bayesian post-hoc individual parameter estimations and Monte
Carlo simulations. Cases, defined by baseline serum creatinine (SCr) ≥ 0.9 mg/
dL, were matched 1:1 to controls by age and weight.
Results: Analysis included 63 matched pairs with 319 serum
concentrations. Mean age (± SD) was 13 ± 6 yr and weight, 51 ± 25 kg. Mean
baseline SCr was 0.6 ± 0.2 mg/dL for controls, and 1.3 ± 0.5 for cases. Age,
SCr, and weight were independent covariates for CL. Final model parameters
and inter-subject variability (ISV) were: CL(L/hr) = 0.235*Weight0.75*(0.64/
SCr)0.497*(ln(DOL)/8.6)1.19 ISV=39%, where DOL is day of life. Target AUC/MIC
≥ 400 was achieved in 80% of cases at vancomycin 45 mg/kg/day, but required
60 mg/kg/day for controls. Drug CL improved in 87% of cases due to recovery
of renal function.
Conclusion: Due to reduced drug CL, a less frequent dosing at 15 mg/kg
every 8 hr (i.e., 45 mg/kg/day) is appropriate for children with renal impairment.
Close monitoring of renal function and drug concentrations is prudent to ensure
adequate drug exposure, especially in those with renal impairment since
recovery of renal function may occur during therapy.
Switch from Enfuvirtide to Raltegravir Lowers Plasma Concentrations
of Darunavir and Tipranavir: a Pharmacokinetic Substudy of the
EASIER-ANRS 138 Tria
Exposure rate measurements and radiation control in post therapy with I131IJRES Journal
During hyperthyroidism treatment, I131activities from 111MBqup to 296 MBq are used. In the aim to
determine if the I131uptake by the patient is a radiological risk to family members and public around the patient exposure
rate measurements were carried out, using a limit 1.8 mR/h. Measurements were carried out in the Nuclear Medicine
department of Almenara hospital in Lima, Peru. The exposure rate was measured to 0.3, 0.6, and 1.0 m from the patient
from 0 to 11 days after post-administrated dose (PDA). In this study measurements were carried out in 21 hyperthyroid
patients. Measurements to 1 meter, along 2-4(16/16), 5-7(15/15), and8-11(14/14) days after PDA, indicatethe
dose rate around 100% of patients is≤1.8mR/h. Measurements to 0.6 metersalong 2-4(16/16), 5 -7(15/15), and
8-11(14/14) days after PDA, indicatethat the dose rate around 44%(7/16), 93% (14/15),and100%(14/14) of
patientsis≤1.8mR h.On the other hand, dose rate measurements to 0.3 meters, along 2-4 (16/16), 5-7 (15/15),
and 8 -11 (14/14) days after PDA, indicate that de dose rate is 13% (2/16), 6% (1/15), and 43% (6/14) of
patients is ≤ 1.8 mR/h.Measured exposure rates are alike to values reported in the literature, and were used to
define radiation control recommendations.
Clinical Trial Simulation to Evaluate the Pharmacokinetics of an Abuse-Deterr...Loan Pham
A CTS was performed to estimate the sample size and optimal plasma sampling times that sufficiently characterize the PK parameters (CL, Vd) from a single dose of an abuse-deterrent (AD) opioid in pediatric subjects.
Methods For Assesment Of Bioavailability Anindya Jana
Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
Bioavailability studies are important in the Primary stages of development of a suitable dosage form for a new drug entity, determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption, development of new formulations of the existing drugs, control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption
1. 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 Handley
PharmD Candidate Class of 2015
University of Arizona College of Pharmacy
Clinica Biblica
January 29, 2015
2. OBJECTIVES
Background and overview
Methods
Results
Authors’ conclusions
Strengths and limitations
Conclusions
3. BACKGROUND: CURRENT GUIDELINES
24hr 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 ≥400
Trough 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/L
A 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”
4. BACKGROUND
Monitoring peak concentrations has been abandoned as a technique for
dosing
There are no data connecting peak concentrations with nephrotoxicity or
efficacy
Therefore, 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 AUC
If 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
5. BACKGROUND: TOXICITY
Example: Lodise TP, et al. conducted a retrospective study among 166
patients in Albany Medical Center Hospital who were treated with vancomycin
for over 48hrs
Exposure-toxicity response relationship exists
Trough value was the index that best described this association
6. Bivariate analysis of the relationship between the
vancomycin exposure profile and nephrotoxicity.
7. 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.
8. STUDY OBJECTIVES
• Primary: 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
10. STUDY DESIGN: DATA SETS
Obtained 3 independent data sets of adults receiving vancomycin (n=47)
1. 15 records consisting of: dosing history, concentrations at frequent
intervals, and patient covariates such as weight and CrCl
Outpatients: samples obtained 0.5hr, 1h, at two random times, and 24hrs after the
start of the dose
Inpatients: samples just before and 1, 2, 3, 8, and 12hrs after a dose
2. 22 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.
3. 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.
11. SUBJECT SELECTION
Inclusion criteria
Data set 1:
Adults with prosthetic cardiac valves each receiving single dose prior to
outpatient dental procedure (n=12) OR
OR
Acutely 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
12. STUDY PROTOCOL
Used Pmetrics (the nonparametric population
modeling and simulation package) to:
Model the PK data
Simulate from the model
Generate plots
Perform standard data summaries and statistical tests
Within Pmetrics, the nonparametric adaptive grid
(NPAG) algorithm was used to build a population
PK model for the pooled data sets (used two-
compartment model)
13. MODELING AND SIMULATION:
TROUGH VS. AUC
Estimated 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
14.
15. MODELING AND SIMULATION:
NEPHROTOXICITY
Combined the data sets with available CrCl values to use
CrCl as a linear covariate, reestimated the population
parameter value distributions
Used model-predicted vs. observed concentration values by linear
regression to calculate slope, intercepts, and R2 values
Used 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
<10, 10-<15, 15-<20, and ≥20mg/L and determined the proportion of
24-hr AUCs for each simulated dose that were:
≥1300mgh/L (breakpoint best associated with nephrotoxicity in Lodise et al.)
≥700mgh/L (more conservative breakpoint for increased risk defined in Suzuki et
al.)
Separately, estimated 24-hr AUC from a continuous infusion with a
concentration ≥30mg/L (typical target range to achieve AUC near
700mgh/L)
16. METHODS: ADHERENCE TO
MONITORING GUIDELINES
Analyzed adherence to the guidelines regarding trough collection
timing using data from an ongoing study at the University of
Southern California Medical Center:
Dosing was guided using BestDose software
Recorded all doses and measured concentrations
Subject demographic and clinical data were obtained
Prescribing and monitoring practices were followed
17. OUTCOME MEASURES
1. Compared the trough only and peak-trough data sets’ AUC values
to that of the full data set (AUCF) or “the gold standard” using:
Differences in AUC values from AUCF
Ratios of the depleted AUC values compared the the AUCF
2. Used the results of the 5000 simulated profiles for each of the two
varying doses (1000mg q12h, 1500mg q12h) to determine and
compare:
Median 24hr AUC
% of patients with 24hr AUC greater than various established nephrotoxicity levels
(400, 700, 1300mgh/L)
Median peak and trough ranges with those with 24hr AUC values >400 and
700mgh/L
% of patients with trough concentrations within the established ranges (<10, 10-
<15, 15-<20, ≥20) of those with 24hr AUC values >400mgh/L and 700mgh/L
3. Adherence to routine monitoring guidelines
Percentages of vancomycin-containing blood samples obtained within 1-2 hrs prior
to the following dose (trough)
Timing of the first trough sampling with respect to the dose number
Percentage of concentrations that were considered therapeutic according to the
guidelines
19. AUC VS. TROUGH
47 adults, 569 vancomycin concentrations
measured
By the Wilcoxon signed-rank test, the AUCs
estimated from both the peak-trough (AUCPT) and
trough (AUCT) data sets were significantly lower
than those from the full data set
Mean AUCPT/AUCF ratio was 0.86 (95% CI 0.81-0.93, p<0.0001)
AUCF-AUCPT difference was 159.3 (95% CI 63.9-284.6 p=0.0009)
Mean AUCT/AUCF ratio was 0.78 (95% CI 0.67-0.89, p=0.0002)
AUCF-AUCT difference was 341.9 (95% CI 189.8-553.4, p=0.0001)
23. ADHERENCE TO MONITORING
GUIDELINES
36 enrolled subjects with at least one available measured
vancomycin concentration in the first week
7/36 (19%) of the first samples were obtained within the hour
before the upcoming dose
5 of these were subtherapeutic (71%) according to the guidelines
14/36 (39%) of the first samples were obtained within two hours
before the upcoming dose
Median trough concentration was 8.0 (1.1-17.5) mg/L
2/36 (5%) were diagnosed with vancomycin-induced
nephrotoxicity
24. AUTHORS’ CONCLUSION
Vancomycin AUC, peak, and trough values can vary as much as
30-fold between patients, even if they have the same renal
function. This creates a strong justification for ongoing therapeutic
drug monitoring (TDM).
The traditional approach to TDM of using trough concentrations
and adjusting based on a predefined goal is a poor surrogate for
AUC and overall vancomycin efficacy and exposure. On average,
this technique will underestimate the true AUC by about 25%.
If vancomycin toxicity is most strongly correlated with AUC, then a
steady state 24-hour AUC of 700 mghr/L is a conservative upper
level of safe vancomycin exposure with a limited risk of
nephrotoxicity.
25. AUTHORS’ CONCLUSIONS
Trough concentrations differ greatly between patients, even
among adults with normal renal function receiving the same dose.
50-60% of adults who have an AUC of ≥400mghr/L, are not
expected to have a trough concentration >15mg/L.
Comparing trough concentrations to a predefined range is a poor
approach since many concentrations are not obtained at the
appropriate time. It is extremely difficult to obtain reliably timed
samples. Even among the appropriately timed samples, the
majority of the concentrations measured were below target range.
This would usually lead to dose adjustments and repeated
sampling at the new steady state, potentially leading to days of
suboptimal exposure, possibly inducing resistance.
27. LIMITATIONS
Small group of patients
Not optimal prospective, randomized, controlled trial design
No pediatric data included in data sets
Limited dosing regimens studied
The first data set included patients that received only a single dose of
vancomycin, which does not give sufficient information to determine whether
trough is an accurate surrogate marker for AUC, because there is no subsequent
dose, and the concentrations have not reached steady state.
Different data sets used different formulas to measure renal function, and the
third data set did not have renal function values available at all
Comorbidities, concurrent medications, age, etc. were not specified
Outcome measures were scattered and varied, organization of the article was
difficult to follow
Bias: one of the authors created the BestDose software recommended for use in
the discussion
28. STRENGTHS
Varying renal function in subjects
Samples were collected at intensively scheduled intervals, aiding the
simulation of a pharmacokinetic model that was reliable and served
as a model of comparison
Depth of investigation went beyond the scope of one study or
guideline
Well-described methods and rationale
All conclusions were reasonable based on not only results of the
study, but of results from studies in the past on similar topics
Used logical methods to draw statistically significant conclusions that
differed from the established guidelines, thereby creating a valid
argument and drawing attention to a discrepancy that must be
addressed
29. CONCLUSIONS
Neely, et al. successfully assembled vancomycin pharmacokinetic
data that challenges the logic behind the current trough
concentration-based monitoring guidelines.
Trough was found not to be an adequate surrogate marker for AUC,
and should not be used as the only basis for which to adjust
vancomycin dosing. Many adults will have adequate exposure with
lower trough values, lowering the risk of toxicity.
If vancomycin toxicity is most strongly correlated with AUC, then a
steady state 24-hour AUC of 700 mghr/L is a conservative upper
level of safe vancomycin exposure with a limited risk of
nephrotoxicity.
A tool that uses Bayesian statistics, such as BestDose, that reports
AUCs and can use levels other than troughs to aid in dosing, would
be a better tool to utilize when monitoring vancomycin therapy.
30. REFERENCES
Neely MN, Youn G, Jones B, et al. Are vancomycin trough concentrations
adequate for optimal dosing? Antimicrob Agents Chemother. 2014:58(1):309-16.
Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic montoring of
vancomycin in adult patients: a consensus review of the American Society of
Health-System Pharmacists, the Infectious Diseases Society of America, and the
Society of Infectious Diseases Pharmacists. Am. J. Health Syst. Pharm. 66:82-98.
Lodise TP, Patel N, Lomaestro BM, et al. Relationship between initial vancomycin
concentration-time profile and nephrotoxicity among hospitalized patients. Clin.
Infect. Dis. 2009;49:507-14.
Pritchard L, Baker C, Leggett J, et al. Increasing vancomycin serum trough
concentrations and incidence of nephrotoxicity. Am. J. Med. 2010;123:1143-9.
Cataldo MA, Tacconelli E, Grilli E, et al. Continious versus intermittent infusionn of
vancomycin for the treatment of gram-positive infections: systematic review and
meta-analysis. J. Antimicrob. Chemother. 2012;67:17-24.
Hurst AK, Yoshinaga MA, Mitani GH, et al. Application of a Bayesian method to
monitor and adjust vancomycin dosage regimens. Antimicrob Agents Chemother.
1990:34(6)1165-71.
-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 article
*******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
-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 AUC
-the occurrence of nephrotoxicity significantly increased as the initial trough value increased
-one study that supports the current guidelines
-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.
-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.
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-G
The 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 defined
-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 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 compartment
Volume (Vc)
Linear transfer to peripheral compartment (KCP)
Linear transfer from peripheral compartment (KPC)
-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 utilized
Of note, evaluated the utility of a Bayesian approach to estimate the AUC from the limited sampling strategy
Used 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 outcome
-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
-these modeling and simulations methods were used to draw conclusions regarding toxicity (objective 2)
-only data sets 1 and 2 had available CrCl
-linear covariate: means that the elimination constant was normalized to creatinine clearance
-the third outcome being analyzed was regarding timing of trough collection and the data was not included in the simulated models mentioned in the previous methods, however Bayesian statistics were utilized
-they analyzed preliminary data during the first year of a vanco study at USC medical center. Dosing in this hospital will be guided by Bayesian feedback and AUC targets using the BESTDOSE software
-this data did not contribute to the modeling and simulation described before
TROUGH VS AUC
NEPHROTOXICITY
Trough collection timing
-the mean AUCT/AUCF ratio shows that the AUC determined by the trough is about 22% lower than the actual AUC (using all data points), enforcing the point that trough only data are not an adequate surrogate for AUC, and by using trough only levels, you are increasing the risk of nephrotoxicity by overdosing
This figure shows the linear regression of AUCs predicted from the full data (AUCF) versus the depleted data (AUCT, triangles. and AUCPT, crosses). The solid line is the line of identity or perfect agreement. As you can see the AUC determined using only trough or only peak and trough values were in general less than the AUC determined using the full data set. This indicates the method of using trough concentrations as a surrogate of AUC results in an underestimation of the true AUC value, increasing the risk for toxicity.
AUC determined by peak and trough levels, indicated with crosses, predicted the AUC of the full data set with less variability, but still underestimated the actual AUC
-as in the last slide, the first column is with 1000mg q12h dosing, and the second column is with 1500mg q12h dosing
-81% were not actual trough concentrations
-this low percentage pf nephrotoxicity may be attributed to the low median trough concentration of 8, and the vast amount of subtherapeutic levels based on the guidelines.
2. Huge interpatient variability
3. They believe that above this threshold, the risk of nephrotox will increase substantially
-also, softwares such as BestDose to be implemented in an entire hospital are not affordable to all institutions
-used varying definitions of AUC goals and nephrotoxicity to create an overall objective conclusion
-AUC being the parameter most linked to vancomycin efficacy and toxicity. Trough is often an underestimation, risking nephrotoxicity
-400-700 would be the ideal range
