Practical application of PK/PD principles

Integrating the MIC with the PK parameters peak, trough and AUC results in three PD targets for antibiotics

The dose-response curve is an underlying principle of pharmacology and pharmacodynamics. Once the target is met, a plateau is reached. Higher doses will not result in more rapid killing. In fact, as we will see, larger doses often lead to adverse effects.

What was missed by many is the fact that the 2009 vancomycin consensus guidelines established the 24-hr AUC/MIC ratio as the therapeutic target. The trough goal of 15 to 20 mg/L was chosen as a surrogate marker for the true pharmacodynamic target, the AUC/MIC ratio.

There is a good deal of evidence that AUC/MIC ratio is the proper target for vancomycin dosing. The slide below is from a study of a mouse model of soft-tissue MRSA infection. Above the dotted line there is no inhibition. Below the dotted line there is increasing inhibition. Time Above MIC and Peak/MIC ratio are scatter plots. Looking at 24-hr AUC/MIC ratio a well defined pattern can be seen. At 100 or less there is no inhibition. At 200, most colonies are inhibited. At 400 or greater all colonies are inhibited. It is important to note that the higher ratio of 1000 did not result in more colonies inhibited. In other words, a response plateau was seen at 400.

Numerous clinical studies have also established the suitability of the AUC/MIC ratio in predicting therapeutic efficacy.

After the 2009 guidelines advocating higher trough levels came into widespread practice, the number of published reports of vancomycin associated nephrotoxicity skyrocketed.

On the other hand, it has been clearly shown that a continuous infusion of vancomcyin, targeting a constant 20 to 25 mg/L, is less nephrotoxic than intermittent dosing targeting troughs of 15 to 20 mg/L. This apparent contradiction can be explained if we attribute the risk of nephrotoxicity to AUC, just as we do for efficacy.

What is the AUC threshold for vancomycin associated AKI? The most often cited number in the literature is 600. In 2017 Chavada, et al. sought to answer this question. Theirs was a six year study of patients with bacteremia. They used a 1-compartment model, with AUC calculated from Bayesian analysis of a steady-state trough. They found that AKI risk more than doubled when the AUC exceeded 563.

The most widely used pharmacokinetic model for vancomycin is one-compartment. The equations for a one-compartment model are practical and time-tested. Because vancomycin exhibits a multi-compartment pharmacokinetic profile, the clinical application of the one-compartment model requires post-distribution serum samples. Also realize that the one-compartment model does not capture the distribution phase(s), and thus underestimates true peak by approximately 5 to 10 percent.

It is important to be cognizant of this AUC underestimation for two reasons. One, if the AUC calculated by our one-compartment model is 400, then you can be sure that you have hit the minimum AUC target. It follows that the maximum AUC should be less than 600. The study cited above by Chavada, which used a one-compartment model, found the AKI threshold to be 563, which is 6.1% less than 600.

Therefore, a safe and effective target AUC range for our one-compartment vancomycin model should be 400 to 550.

Recent evidence regarding vancomycin pharmacokinetics/pharmacodynamics has initiated a paradigm shift in vancomycin dosing from targeting trough concentrations to area under the concentration-time curve (AUC), specifically the 24-hr-AUC/MIC ratio.

Compelling clinical data suggests that targeting a vancomycin 24-hr-AUC/MIC ratio of at least 400 mg · h/liter will ensure efficacy. The 2009 consensus committee on vancomycin TDM made the assertion that the vancomycin trough level is a good surrogate for the AUC, because in most adult patients a steady-state trough concentration of 15 to 20 mg/liter correlates with a 24-hr-AUC/MIC ratio of at least 400 for an organism with an MIC of 1 mg/liter or less.

Since the implementation of the vancomycin consensus guidelines, several studies have documented a higher incidence of nephrotoxicity associated with the more aggressive trough goal. In contrast, a large meta-analysis suggested that a continuous infusion targeting a constant vancomycin concentration of 25 mg/liter is less nephrotoxic than standard intermittent dosing. This can be explained if we attribute the risk of vancomycin nephrotoxicity to the AUC, just as we do for efficacy.

To date the AUC threshold for vancomycin nephrotoxicity has not been clearly defined, 600 to 700 has been suggested. The goal of Chavada et al was to define the upper limit of the vancomycin AUC range. They found that a vancomycin 24hr-AUC of greater than 563 mg · h/liter was associated with significantly increased risk of AKI.

One of the features of APK that I am most proud of is the population analysis tool. Each time you save a consult based on serum level analysis, the pk parameters are saved. This data set is a goldmine of information about your patient population.

The data set presented below is from 1,671 adult general med-surg patients, with 1,078 in the subgroup of BMI less than 30. The vanocomyin pk model used for Bayesian analysis of this subgroup is similar to that used by Chavada.

The patient specific pk parameters from this data set were then used to determine a dosing regimen based on either a target trough goal of 15 to 20 or a target AUC goal of 400 to 563. Dosing intervals were based on half-life and converted to a more practical 6, 8, 12, 18, 24 or 48 hours. Doses required to achieve the therapeutic goal were rounded to nearest 250mg whenever possible.

Assuming an MIC of 1 or less, the minimum target AUC was determined to be 400. The upper limit of AUC was set to 563, as determined by Chavada. This target range is displayed within the shaded area in the figures below.

Targeted trough dosing
Doses required in this group ranged from 400 to 2000mg. As we often see in clinical practice, a significant number of regimens (91) did not achieve a trough of 15 within what is considered a safe dose range.

All dosage regimens in the targeted trough group achieved an AUC of at least 400, which confirms the goal of the 2009 guidelines. However, the majority of these doses, 597/1078 (55%), resulted in an AUC above the likely AKI risk threshold.

Targeted AUC dosing
Doses required to achieve the target AUC ranged from 400 to 1500mg.

All dosage regimens in the targeted AUC group also achieved an AUC of 400. No doses resulted in an AUC above the AKI risk threshold. This analysis also confirms previously reported studies which found that, in the majority of patients, an AUC of 400 can be achieved with a trough less than 15. In this analysis, 77% of dosing regimens (831/1078) achieved the AUC goal with a trough less than 15.

Although controversy remains regarding whether vancomycin has a direct toxic effect, vancomycin-associated nephrotoxicity has been linked to troughs greater than 15. Targeted AUC dosing of vancomycin would be expected to reduce unnecessarily high exposure and thus reduce nephrotoxicity.

Reference
Chavada R, Ghosh N, Sandaradura I, Maley M, Van H. Establishment of an AUC0–24 threshold for nephrotoxicity is a step towards individualized vancomycin dosing for methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 61 (5). 2017 Apr 24.

The 24-hr AUC/MIC ratio

The trough level is but a surrogate marker for the true pharmacodynamic parameter for vancomcyin, the 24-hr AUC/MIC ratio. The target vancomycin trough level of 15-20 mg/liter was chosen in the 2009 vancomycin TDM guidelines to maximize the likelihood of achieving a 24-hr AUC/MIC ratio of >400 mg·h/liter.

Targeting the trough level has been criticized as trough concentrations underestimate the true AUC by 25% on average. Recent pharmacokinetic data suggest that the majority of patients can achieve AUC values of >400 with trough concentrations less than 15.

Although controversy remains regarding whether vancomycin has a direct toxic effect, vancomycin-associated nephrotoxicity has been linked to troughs greater than 15. Monitoring vancomycin by AUC would be expected to reduce unnecessarily high exposure and thus reduce nephrotoxicity.

Although clinical data suggest that targeting the daily vancomycin AUC above 400 will ensure efficacy, the AUC range associated with nephrotoxicity has not been clearly defined. Based on current data, it appears prudent to maintain the AUC below 600 (and trough below 20).

PK software

Since 2004 all of RxKinetics PK software has performed PK/PD parameter calculations. Unfortunately this feature was hidden behind a button in APK and AbPK. It makes me wonder how many folks using the software have missed this feature.

With that in mind, I’ve moved the AUC calculation in APK up front. No longer hiding behind a button, AUC is displayed along with the predicted peak and trough levels.

In addition, a Targeted AUC dialog has been added. This new dialog is accessed via the Tools menu.

The Targeted AUC dosing dialog does precisely what the name implies. Enter a target AUC and an ideal dose is calculated. This isn’t rocket science. The ideal interval is the half-life plus infusion time (usually one hour), plus distribution time (one hour). Ideal dose is then calculated with the AUC equation rearranged to solve for dose. After entering a practical dose and interval, the predicted 24-hr AUC, peak, and trough are displayed.

The PK/PD dialog remains unchanged, and is (still) accessed by the PK/PD button (or via the Tools menu).

Click Save on this dialog to copy the appropriate pharmacodynamic parameter. As detailed above, the 24-hr AUC/MIC ratio is the most useful parameter for vancomycin. For aminoglycosides, the peak/MIC ratio is the best predictor of efficacy.

Recommended reading

1. Zasowski E, Murray K, Trinh T, Finch N, Pogue J, Mynatt R, Rybak M. Identification of Vancomycin Exposure-Toxicity Thresholds in Hospitalized Patients Receiving Intravenous Vancomycin. Antimicrob Agents Chemother. 2017 Dec 21;62(1).
2. Chavada R, Ghosh N, Sandaradura I, Maley M, Van H. Establishment of an AUC0–24 threshold for nephrotoxicity is a step towards individualized vancomycin dosing for methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 61 (5). 2017 Apr 24.
3. Pai M, Neely M, Rodvold K, Lodise T. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Adv Drug Deliv Rev. 2014 Nov 20;77:50-7.
4. Andrew DeRyke, C & P. Alexander, Donald. Optimizing Vancomycin Dosing Through Pharmacodynamic Assessment Targeting Area Under the Concentration-Time Curve/Minimum Inhibitory Concentration. Hospital Pharmacy. 2009 44. 751-765.

Users of rxkinetics.net have been contributing to a large data set for the past three years. The web app has been saving anonymous data from serum level analysis during this time. See this blog post: The BBVM project part II.

It is important to state up front that there is no quality control over this anonymous data. Some of it could have been entered incorrectly. Also there is no way to know how much is real patient data versus someone experimenting with the web app.

The other problem with this type of data collection is that many don’t “run the numbers” when the results are within target range. Therefore, outliers tend to become more prominent in the data set.

With those caveats in mind, let’s examine the data.

Let’s delve into the statistics from the two largest groups.

BMI 19-30

The raw Vd histogram follows a normal distribution (as a large sample should).

But the histogram for Vd L/kg total body weight (TBW) has a noticeable negative (left) skew.

Because Vancomycin does not distribute well into adipose tissue let’s look at Vd L/kg of adjusted body weight (ABW), where ABW = LBW + 40% of the difference between TBW and LBW (i.e., the weight we used to dose Vancomycin “back in the old days”).

The histogram of Vd L/kg ABW is noticeably more normal than TBW (but not ideal).

Regression of CL vs CrCl results in a higher r^2 value when we use Normalized CrCl vs LBW-based CrCl, 0.528 vs 0.524. (CrCl Methods explained)

BMI > 30

As with the previous group, in obese patients the histogram for Vd L/kg of ABW has a more normal distribution than TBW.

The r^2 improvement is even greater in obese patients when using normalized CrCl for the Kel regression, 0.533 vs 0.412.

Summary
Again, since the data is not verified this analysis is debatable. However it does pose a couple of questions:

• Should we use adjusted body weight when modeling Vancomycin volume of distribution?
• Should we use normalized creatinine clearance when modeling Vancomycin elimination rate?

This is a feature that I have wanted to add to my PK programs for quite sometime. In the real world doses don’t get hung on time and dosages get changed before levels are drawn.

Complex is the keyword. This was incredibly complex to code, both the logic of data entry and analysis. It has taken weeks of intense work to complete. Currently in the testing phase, I hope to bring it to production soon.

When you select “Complex non-steady-state analysis” the program displays two grids, one for entering doses and the other for serum levels.

You may enter up to five doses of various amounts, given at different rates and at different times. You may enter up to two serum levels. Of course there are limitations (which the data entry routines catch). For example, you cannot enter a date/time for a level that conflicts with a dose date/time.

If the first serum level is drawn before the first dose it will be considered a baseline level. This is also something that I have wanted to add for years. It will be most useful when performing a follow-up pk consult on a long-term patient.

Another feature added from my to-do list is the ability to select an infusion rate for your recommended dose.

You will still see Bayesian fails. This new data entry methodology will not prevent them from happening. That is the nature of Bayesian and the highly variable nature of Vancomycin kinetics.

Even people who have used my programs for years fail to comprehend what Bayesian analysis involves. The first thing to realize is that Bayesian analysis begins with your population model. It then attempts to fit your measured levels to incremental variations of your population model. In classic Bayesian, if the data cannot be fitted to the model within reasonable statistical limits, then the data is thrown out. I do not believe that rule should be applied to clinical pharmacokinetics. So I leave it up to you to decide how to proceed by showing the “Bayesian analysis failed” dialog.

Essentially this dialog is telling you that your measured level differs too much from the model predicted level. You can find out what level the population model predicted by visiting the prospective tab. If you measured 6 but the model predicted 24, then never the twain shall meet. Either (1) you have chosen the wrong model for your patient, or (2) the measured level is wrong. That is your decision, not one to be made by a computer program, period.