What’s New In Vancomycin AUC and Best Practices For Other Therapeutic Areas
1.1 What is therapeutic drug monitoring?
Therapeutic Drug Monitoring (TDM) in simple terms is the measure of drug level within your system at a specific time to evaluate whether the drug concentration in a patient’s bloodstream is constant and within a desired therapeutic range.
The employment of TDM is particularly important for drugs with a narrow therapeutic index– meaning that for these drugs, the slightest deviation of blood concentration would lead to therapeutic failures or worse, such as acute kidney injury and other adverse drug reactions.
Vancomycin is amongst the most complex drugs to dose for patients, partially due to its nephrotoxic nature. Before 2020, guidelines instructed the intravenous dosing of vancomycin to be kept under a peak-to-trough relationship of 15-20mg/L ratio. Over the years, however, multiple studies have proven the ineffectiveness of this dosing method. The area-under-the-curve (AUC) attainment of dosage volume was proven to be a more accurate indicator of how much drug level is within the patient at any time.
The AUC, or area under the curve, provides a comprehensive measure of the drug's concentration in the blood over a specific time period, taking into account both peak and trough levels. By calculating the AUC, healthcare professionals can gain a more accurate understanding of the drug's effectiveness and potential risks, including toxicity. This approach offers a more holistic perspective on drug exposure compared to solely relying on peak-to-trough ratios.
1.2 Common Criteria to Determine If Drugs Need TDM and Why
A drug should satisfy certain criteria to be suitable for therapeutic drug monitoring. Examples include:¹
- Known adverse effects or drug toxicity: Drugs that are associated with known adverse effects or drug toxicity, such as vancomycin's nephrotoxicity, often require TDM.
- Narrow target range: Small differences in dose or blood concentration of narrow therapeutic index (NTI) drugs can lead to serious therapeutic failures and/or adverse drug reactions.²
- Significant pharmacokinetic variability: Interpatient variability in drug pharmacokinetics can impact how individuals metabolize and eliminate drugs, resulting in differences in drug absorption, distribution, metabolism, and elimination.
- A reasonable relationship between plasma concentrations and clinical effects: If drug concentration measurements are to be useful in modifying treatment, then they must relate closely to the effect of the drug or its toxicity (or both). This allows the definition of an effective therapeutic ‘window’ – the concentration range between the minimal effective concentration and the concentration at which toxic effects begin to emerge – and allows titration of the dose to achieve concentrations within that window.³
- Established target concentration range: An established target concentration range for a drug helps define the optimal therapeutic window. TDM is particularly relevant when there is a well-defined range within which the drug exhibits its maximum efficacy with minimal toxicity.
In summary, TDM is warranted when drugs have known adverse effects, a narrow target range, significant pharmacokinetic variability, a reasonable relationship between plasma concentrations and clinical effects, and an established target concentration range. Considering these factors, TDM helps personalize dosing based on individual patient characteristics and optimize therapeutic outcomes.
1.3 Drugs regularly monitored in clinical practice
According to the National Institutes of Health (NIH), below are some of the most common medicines that should be monitored.⁴
- Antibiotics: vancomycin, gentamicin, amikacin
- Heart drugs: digoxin, procainamide, lidocaine
- Anti-seizure drugs: phenytoin, phenobarbital
- Drugs treat autoimmune diseases: cyclosporine, tacrolimus
- Drugs that treat bipolar disorder: lithium, valproic acid
PrecisePK’s drug models encompassed most of the above medications and more, explore how we help you streamline the workflow here.
Vancomycin TDM Need-to-Know
2.1 What’s new since the 2020 vancomycin guideline release?
The 2020 guidelines thus proposed the new method of AUC-based dosing for vancomycin, a practice that is now synonymous with Vancomycin AUC dosing, Bayesian AUC, model-informed precision dosing, and so on. No matter the term to refer to this precision dosing technique, the basis is straightforward– with the predictive statistical power of Bayesian, vancomycin AUC dosing is modernized with much more accurate results and less time spent on traditional calculations.
The roadblocks to transitioning away from peak and trough dosing to AUC dosing are often not due to the lack of knowledge or a shortage of a good vancomycin AUC calculator. What hospital pharmacists struggle with is finding a comprehensive solution to their problem, a vancomycin AUC dosing tool that is accurate, easy to use, and reliable for the best clinical outcomes.
When pharmacists turn to a free online calculator for help, the results they get are likely to follow first-order kinetics and the area under the curve estimated by a two-part trapezoidal, hence not the most precise calculations. The peak and trough used for determining AUC24 are also assumed to be obtained under steady-state conditions⁵, while the Bayesian method can with one random draw. What is more concerning is that these online calculators bear the risk of patient data security concerns and it does not cater to patient’s specific characteristics, other than the basic parameters of height, weight, and age. In comparison, well-developed and robust software, like PrecisePK, can offer so much more.
Additionally, those who have yet to transition to AUC dosing with Bayesian methods might also have worries that the training and onboarding process will be overwhelming. The reality is quite the opposite. At PrecisePK, we offer unlimited 1-on-1 onboarding, where we will guide you through the use of our software. Within minutes, you will also find that the dashboards are intuitive to your clinical needs, and the workflow is streamlined and designed to minimize human errors.
Since the release of the 2020 guideline, more and more research came out supporting the positive associations of individualized pk/pd dosing with safer and more effective patient care. With United States healthcare systems leading the charge of evidence-based practice, PrecisePK has grown exponentially on a global level, positioning itself as a trusted provider of Bayesian precision dosing for vancomycin AUC and more.
Overall, what clinicians might previously believe about adopting new technology could be a daunting process, is proven to be not true, that the right technology would benefit clinical routine.
2.2 To recall what was stated in the 2020 vancomycin guideline:
“AUC/MIC-guided dosing with a target of 400-600 mg*h/L within the first 24-48 hours is suggested for vancomycin dosing in adults and children”-- As stated by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.⁶
What many pharmacy students and even clinical pharmacists missed from this statement is the rooted reason for vancomycin AUC dosing. Precision dosing at its core considers inter-patient variability and other extra factors for personalized dosing regimens, setting it apart from the outdated one-dose-fit-all belief. Therefore, one could also summarize that a Bayesian model-informed precision dosing for the therapeutic drug monitoring of vancomycin serves these key purposes:
- Ensure the minimum drug effects
- Calculate the right dose at the right time for the right person
- Deliver therapeutic solutions rapidly and accurately in clinical settings
- Provide clinical decision support tools to reinforce clinical judgment to deliver the highest quality of patient care
The guideline additionally mentioned that “Bayesian software programs (refer to Therapeutic Monitoring section) can be used to generate accurate and reliable estimates of the daily AUC values with trough-only PK sampling.”
So how can all of these key objectives be translated into feasible clinical strategies and what should clinical pharmacists be evaluating when trying out a Bayesian model-informed precision dosing (MIPD) software? What are some other parameters that need to be considered during any patient journey? Read on.
2.3 How does Bayesian dosing automate the model selection for vancomycin AUC/MIC:
PrecisePK conducts thorough selection and validation of well-established research models. Additional drug factors and special population inputs can be leveraged to treat complex patient cases. Dosing amongst adult populations should be differentiated from that of vulnerable groups, especially in pediatric and neonatal. Other cases where patients’ pharmacokinetics and pharmacodynamics are impacted by body weight such as amputation or obesity should also be further evaluated using Bayesian model-informed computations.
Auto-selection feature in PrecisePK is a practical mechanism to help clinical pharmacists quickly determine the appropriate patient-to-PK model match. Upon entering the patient’s data, such as weight, height, and date of birth, and selecting extra factors, users also have to option to override the auto-selected model based on their clinical judgment.
Moreover, for patients undergoing dialysis treatment or being treated in ICU, there will be additional options for the dosing recommendations. An acute kidney injury prediction tool is also available for further patient hospital stay surveillance, which acts as an extra guard to adverse drug event (ADE) prevention.
2.4 Commonly missed information by those new to the vancomycin AUC dosing
With the old dosing method of measuring peak and trough, a steady state is a required condition for nurses to conduct the blood serum level draw. If the lab order is placed in a non-steady state, the blood draw will be wasted and the same dosing regimen must be done to redraw the blood at the correct time. When making the switch to vancomycin AUC dosing with Bayesian software, the dosing becomes time-agnostic, meaning that:
- No steady-state is required to compute or predict the dosing recommendations
- One serum level draw is sufficient, especially when accompanied by the two-compartment level model.
With the time saved, clinical procedure reduced, and the proven systematic reliability of Bayesian precision dosing software, hospitals will significantly reduce costs previously attributed to the labor and material.
Other facts commonly unknown about the Bayesian method precision dosing can be found here. It is worth noting that MIPD can work seamlessly with existing practices to optimize clinical workflow. Common approaches that work with MIPD to optimize clinical processes include EHR integration, antimicrobial stewardship program, compliance preparedness, real-time alerts, and collaboration.
Other Therapeutic Areas to Benefit from TDM or Bayesian Model-Informed Precision Dosing
As a result of the 2020 vancomycin guidelines for Bayesian AUC dosing, vancomycin is one of the first few things pharmacists concern themselves with when asked about TDM. Many large institutions, such as UCSF Benioff Childrens Hospital, UCLA, and many more, have selected PrecisePK for their bedside vancomycin AUC dosing. Independent research has shown that PrecisePK is the most accurate and comprehensive vancomycin AUC dosing tool (Turner et al 2018).
The use of the Bayesian model-informed precision dosing, however, can be used in therapeutic drug monitoring for more than just antibiotics treatment. PrecisePK’s drug models currently offer vancomycin and 20+ other medication models, covering infectious diseases, aminoglycosides, oncology, pulmonology, cardiology, transplants, and neurology. Below is our overview of some examples of these therapeutic areas that can be optimized through proper TDM practices and the significance of adopting a precision dosing protocol for clinical dosing.
3.1 Transplant Drug | Tacrolimus
“As CNI have a narrow therapeutic index with wide inter- and intra-patient pharmacokinetic variability, therapeutic drug monitoring (TDM) is mandatory.”⁷
In the management of post solid organ transplantation, therapeutic drug monitoring (TDM) of immuno-suppressive medications is an important tool. Optimization of TDM can lead to avoidance of therapy with toxic or too-low doses leading to rejection of the transplanted organ.
Traditionally, TDM is frequently based on a time-specific single measure, often in the morning where the trough level is collected. Because immunosuppressant is dosed more than once a day, implications entail. With the same dose, that of the morning compared to the night observed lower whole blood and intracellular tacrolimus concentrations according to Fontova et al. Circadian fluctuations can cause variations in both the extent and rate of absorption of tacrolimus due to drug metabolizing within 24 hours.
“While few studies have assessed the clinical benefits of TDM in a prospective, randomized manner, several studies have demonstrated a correlation between low immunosuppressant exposure and risk of acute rejection and high immunosuppressant exposure and drug toxicity.”⁸
3.2 Oncology Drug
In Clinical Setting | Busulfan
Busulfan has high intra-individual variability and possible time-dependent changes in clearance, which complicates therapeutic drug monitoring (TDM), as first-dose sampling may not predict steady-state concentrations. Serious side effects such as veno-occlusive disease (VOD), neurotoxicity, acute graft vs. host disease, and even death have been linked to higher AUCs for this drug. On the other hand, lower AUCs are associated with disease relapse, unsuccessful engraftment, and poorer survival rates. Therefore, therapeutic drug monitoring (TDM) is often performed to optimize busulfan dosing. The suggested target ranges to maximize efficacy and minimize toxicity are cumulative AUC0–96 values of 59.2–88.8 mg.h/mL or, more recently, 78–101 mg.h/mL.⁹ (Alsultan et al., 2022)
In Drug Development | Project Optimus
In 2021, FDA announced Project Optimus, an initiative by the Oncology Centre of Excellence that gears the development of oncology drugs toward precision dosing. The reform and improve dose optimization and selection in oncology drug development will rely on information from PK/PD modeling thus eventually having a relationship with model-informed precision dosing.
“Project Optimus emphasizes the need for a more robust understanding of the impact of different doses on efficacy and toxicity and randomized dose comparisons are expected to be necessary early in development. As a minimum, a comparison of the minimal biologically active dose (likely estimated from pharmacokinetic-pharmacodynamic (PK-PD) modeling) to the highest tolerable dose will be required, to explore if there is a clear differential benefit with acceptable tolerability.”10
3.3 Cardiology | TDM for Cardiac Medications
Overdose of inotropics and antiarrhythmics can cause vomiting, diarrhea, confusion, visual disturbances, and cardiac arrhythmia. When overdosed, these medications show the same symptoms as what the drug is used to treat, complicating the decisions for the dosing regimen.
“For example, procainamide is used for arrhythmia, but an overdose of procainamide can produce an arrhythmia. Thus, without TDM the physician will not know whether to give more drug or less, since both states can lead to the same presentation.”11
Examples of cardiac medications needing TDM with a narrow therapeutic index:
When combined with TDM, Bayesian software for vancomycin AUC dosing is effective in preventing serious adverse drug events, helping clinicians simply workflow, and delivering cost-saving clinical outcomes. Therapeutic drug monitoring is additionally crucial in antibiotics management to fight resistance by effectively reaching therapeutic status. Other existing practices that should be considered with Bayesian dosing are EHR integration, clinical surveillance tools, reporting compliance, data security, etc.
With more and more hospitals around the world adopting Bayesian precision dosing, it is crucial for hospitals to adapt early and transition with technological advancement for better care quality. Academic research and early drug development will also find this tool exceptional as it may fast-track the way PK/PD modeling data are translated into bedside applications. We anticipate an increasing number of studies aimed at furthering the application of Bayesian precision dosing in various therapeutic areas, including the optimization of vancomycin therapy through the use of therapeutic drug monitoring (TDM) and the assessment of area under the curve (AUC) values.
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