TDM - (Therapeutic Drug Monitoring); PK (drug levels)
Jules Levin, NATAP
This article is informative regarding TDM & its utility, applications, and limits. However, recent research suggests PK studies are needed in special situations regarding special populations. This is particularly supported by recent studies finding PK concerns regarding EFV & African-Americans, NVP & women, and cirrhotics or HCV or HBV positive individuals. The FDA has recommended drug companies provide PK datafor their drugs related to the levels & affects on the liver. This is particularly important because the the emergence of hepatitis C & B coinfections and that many coinfected individuals have had hepatitis for many years and HIV can accelerate HCV & HBV. So drug levels of HAART medications may be significant for some individuals; levels may be higher in later stage hepatitis such as cirrhosis. Concern has been raised regarding patients with HIV drug resistabce who are also coinfected with HCV or HBV being excluded from studies of new drugs. These drug resistant patients may need timely access to new PIs, entry inhibitors & NNRTIs but may be excluded from studies and consequential timely access to these new drugs. It is important for industry now to consider special and separate phase III studies for these patients to provide access and this will also provide a nique opportunity to the companies and community to gather key data related to safety, drug levels, and provide a framework for the drug's use post-approval.
For several years the dosing of HAART medications and its relationship to weight and gender have been a hot topic for discussion and of considerable concern, particularly as it relates to side effects and toxicities. Women are both different biologically and weigh less. These factors may contribute to different and more concerning side effects and toxicity profiles. Drug companies ought to consider conducting PK studies to evaluate these concerns. A recent study at the 5th Pharmacology Workshop found that rash rates for NVP were higher in patients with lowest weight. There are similar concerns regarding ethnicity. At the 11th CROI researchers reported findings suggesting that genetic differences for African-Americans may slow clearance of efavirenz. This needs further examination. Other HAART drugs could also be examined in this light.
Therapeutic drug monitoring in HIV infection: current status and future directions
David Back et al.
TDM (Therapeutic Drug Monitoring)
Reported by Jules Levin
TDM is testing drug levels in blood to evaluate if a patient has too much or too little drug in blood or body. Too much drug can cause toxicity and too lttle can cause viral failure. Whether or not TDM can be useful is controversial and has not yet been established very well. TDM was the subject of a plenary oral discussion by David Burger at the 6th Intl Congress on Drug Therapy in HIV just completed in Glasgow. This is the annual European AIDS Conference. Several reports of his talk and this subject have been distributed on the internet. To truly understand TDM and why it has not caught on very widely, and to read the results from various studies that have been conducted so far I suggest reading this very comprehensive review of TDM on the NATAP website:
Here is a briefer review of the subject touching on key issues regarding the utility of TDM including excerpts from the much more detailed and comprehensive review linked to just above. For several years TDM in HIV has been the subject of much controversy and several studies. Pharmacology researchers in the USA for the most part feel TDM use has major flaws. They feel it is not realistic to consider it reliable for widespread clinical use. One reason is that you are testing blood levels at a given time point or at multiple time points if used more appropriately, but what about those other days on which you are not testing. Patients may not be taking their meds on those days; if the doctor tells the patient I'll be checking your drug blood levels on a particular day the patient may take their drugs for the few days before the test and then go back to poor adherence. Poor adherence could consist of not taking drugs at all, taking not all drugs at full dose at all times, or not eating properly according to the diet recommendations for achieving the best blood levels. So, dietary intake can vary from person to person and fron day to day for a given individual.
What if patient does not take drugs exactly on time so if therapy should be taken twice daily and at times they are taken 12 hours apart or at other times for example at 8am and 5pm? Will TDM drug blood levels give accurate readings that can be used to accurately evaluate a patient's situation?
One of the major confounders may be incomplete adherence. While patients who do not take their anti-HIV drugs on schedule or do not comply with dietary requirements would be expected to have low plasma levels and poor outcomes, these patients may have 'normal' plasma levels if they take their doses soon before a scheduled visit. Thus, patients who fail treatment because of low drug levels due to poor adherence may actually appear to have normal drug levels in outcome analyses. Hence, optimal design of trials aimed at the evaluation of concentration—response relationships should always include a thorough assessment of patient adherence to treatment. Monitoring of drug concentrations may be a reliable tool for assessing adherence, particularly if used in conjunction with other methods.
For drugs whose bioavailability is strongly influenced by the presence or absence of food, poor adherence to food requirements is likely to have the same effect on virological response as poor adherence to drug intake. Poor adherence to food requirements is difficult to monitor in many patients and may obscure proper interpretation of drug blood levels.
Researchers are not sure when drug blood levels should be tested although it appears testing at the time of the trough (the lowest point in drug levels nhear end of dosing period) is best to evaluate if patient has enough drug in blood is best. But we are not sure about that.
There is too much variability in the accuracy of doing TDM measurements by different laboratories requires that which might require assays to be optimized and validated and labs to be evaluated. This problem is one that is addressed by HIV viral load testing and resistance testinwhere test results appear more reliable, although interpreting resistance test results is not reliably performed and not consistent between doctors or experts in resistance testing.
You probably need to test blood levels at multiple times to truly gauge what levels a patient is getting. If you are evaluating whether a patient is getting adequate drug blood levels you will optimally need to draw several samples for initial evaluation, And after adjusting doses of drug you will need to again draw several samples of blood to see if adjusting dose was successful in altering drug blood levels. The exact timimg of when you draw blood samples is crucial. In France, the Netherlands, and Britain TDM is commonly used. In clinics in these countries patients commonly have TDM performed and assessed often by an in-house pharmacologist. In the US system this becomes much more cumbersome and difficult. The US has much more patients with HIV and a much larger care system that is already overwhelmed trying to provide adequate care to all the patients, particularly in large urban city hospitals. The USA population is much more diverse and in many instances it may be difficult, regardless of whether the care setting is private or a public institution, for getting patients to return for several visits on prescheduled days at specifictimes to perform TDM drug level testing in the blood. In the US system of care where HMOs and such systems predominate time and resources are more scarce than in the more public and government subsidzed systems of Western Europe.
If a patient is of a certain type and the doctor and care provider really want to use TDM in the proper way in the USA it's possible. You need a doctor who can and is willing to take the time to properly perform TDM which includes drawing blood and processing the blood properly. This means blood needs to be sent to TDM testing center or pharmacologist who knows what to do. You need a patient is reliably and consistently is properly and completely adherent; a patient who is honest with the doctor about taking their meds and a patient who will tell the doctor that over the past two days exactl their schedule for taking meds and dietary intake. What about patient weight? Are drug levels which may be good for a patient of 150 lbs the same for a person of 220 lbs. I don't think we know the ansswer to that. And what level of drug is appropriate for a 220 lb person? We don't have conclusive information on that. And of course whether a patient is treatment experienced or treatment naive and how much experience they have is crucial in interpreting TDM results and in adjusting proper dosing to achieve the drug levels you want. You must have a certain expertise in the doctor and pharmacologist performing the tests, in interpreting the results, and in selecting proper dose adjustments particularly for the treatment experienced patient. Then you need a very well qualified pharmacologist and doctor to evaluate the meaning and significance of the findings. They need to be familiar with the therapeutic ranges for drug levels targeted for each drug. One of the reasons TDM has not caught on very widely and has not caught on the USA is because these optimal circumstances are hard to put into place.
Another confounding factor may be the development of resistance. The concentrations required to inhibit the replication of a wild type virus may be lower than those necessary for a strain with decreased susceptibility. For this reason, measures of drug exposure normalized to measures of viral susceptibility may correlate better with treatment response
To test drug blood levels you will have to wait for drug levels to reach steady state after initiating a regimen and this takes about two weeks.
You can use TDM for protease inhibitors and NNRTIs but not yet for NRTIs because it is uncertain if blood levels reflect where perhaps NRTIs really work, in the cell. PIs represent the best candidates for TDM with current assay techniques, although NNRTIs should not be overlooked. Combination therapy also obscures the relationship between drug level and outcome: most first-line regimens contain three potent antiretrovirals, so a patient may still respond favourably to treatment, especially in the short term, even though one of the drugs is at suboptimal levels. Other covariables that may obscure a significant concentration—response relationship include protein binding and intracellular kinetics (see article linked to above for expansion on this in chapter 6).
At this point you must realize TDM testing is not very much of a science but can be of relative utilitity and of how much usefulness depends on the variations of the factors discussed above. This is why TDM has not caught on yet and it remains uncertain if it will catch on in a widespread way. Certainly there will be doctors who use it in their practice for certain situations but I think it's usefulness can be questionable, and just like resistance testing in the wrong hands it may not be helpful but might even be harmful.
What about intrpatient variability and interpatient variability. Plasma levels of antiretroviral agents vary greatly among patients receiving standard doses. HIV-1-infected patients constitute a highly heterogeneous population, in which covariables such as weight, gastrointestinal absorptive function, hepatic and renal function, adherence to drug intake schedule and food requirements, drug—drug interactions and many other factors may contribute to widen the range of plasma concentrations. The stage of HIV progression may play an important role in the interindividual variability in pharmacokinetics. Several studies have shown significant differences in pharmacokinetic values between HIV-negative and HIV-infected patients, as well as among HIV-infected patients at different stages of disease progression.
In study settings patient variabilities can be better controlled. In uncontrolled settings, a number of factors may contribute to increased intraindividual variability in plasma drug levels: these include patients not reporting the precise time of last dose intake, variable adherence to food requirements and lack of full adherence to the last doses (i.e. patient not at steady-state). Furthermore, drugs such as ritonavir and nelfinavir have been shown to exhibit a significant circadian effect, so that the concentrations after a morning dose are different from those after an evening dose, and indinavir and zidovudine pharmacokinetics may vary throughout the menstrual cycle This is discussed further in the study linked to above).
What the ability to assess proper drug blood levels when using ritonavir to boost levels of other protease inhibitors? Although perhaps researchers can evaluate and assess what are proper drug levels when using ritonavir as boosters do we have an adequate undertstanding of this now? Because ritonavir increases the plasma concentrations of other PIs, the future utility of TDM in HIV management has been questioned; with boosting, PI levels are less likely to fall below therapeutic ranges except in cases of poor adherence. This is addressed further in the article linked to.
Conceptually, the panel agrees that TDM may represent a practical tool to improve the outcome of patients receiving HAART. However, at present we cannot recommend its use in routine clinical practice for three reasons: (1) existing data are not adequate to confirm the utility of TDM in this setting; (2) current assays are not sufficiently reliable or standardized; and (3) interpretation of data is complex, and may require expert advice. To address these issues, we suggest that the following measures are necessary: (1) large randomized trials to assess the clinical utility of TDM in the management of HIV-1 infection; (2) assay standardization; and (3) education programmes for pharmacists, physicians and patients.
With the caveat that any application of TDM in HIV management should be validated in clinical trials before being incorporated into routine clinical practice, the panel has formulated the following list of position statements, which may help guide TDM trial objectives as well as provide points of reflection for centres in which TDM is already in use:
1. Levels of systemic exposure to PIs and NNRTIs correlate with their efficacy as well as some of their adverse effects — i.e. a concentration—effect relationship exists. Therefore, adjusting PI and NNRTI concentrations within a therapeutic window may be of benefit, especially in light of the high interindividual and relatively low intraindividual variability of plasma levels.
2. TDM has potential utility for patients who are initiating therapy with any PI or NNRTI or who are changing regimens — regardless of treatment history or pharmacoenhancement with ritonavir. TDM may help to ensure that appropriate plasma drug concentrations are achievedand to identify absorption or metabolic problems as well as unexpected interactions with over-the-counter or herbal medications that may lead to suboptimal drug levels.
3. TDM is more likely to be of benefit in specific situations that may occur at the beginning of a new treatment protocol or during ongoing treatment:
a. If a malabsorption syndrome is suspected
b. If drug interactions likely to cause clinically significant concentration changes are suspected
c. If more than two drugs with an influence on P450 activity are administered
d. In patients with hepatic impairment
e. In patients with particularly high or low body weight compared to the population average
f. During pregnancy
g. In children
h. If there is a change in clinical or physiological status that is suspected of causing abnormal drug levels
i. For evaluation of unsatisfactory virological response
j. For dose intensification of failing regimens
k. In once-daily regimens of PIs using ritonavir pharmacokinetic enhancement
l. In deep salvage therapy in order to expose patients to maximal tolerable levels while limiting the risk of toxicity (even in cases of ritonavir boosting) m.For preventing toxicity in patients with high plasma drug levels
n. In patients who develop adverse reactions while taking PIs, to adjust the dosage downward while still maintaining therapeutic levels.
4.Pharmacoenhancement with ritonavir does not necessarily mitigate the utility of TDM. Because of the high interindividual variability in plasma drug concentrations, and the possibility of higher than normal IC50 values in pretreated patients, individual patients may have sub-inhibitory trough/IC50 ratios, even though the average trough/wild-type IC50 ratios are high.
5.TDM may have a role in monitoring adherence. Adherence is probably best monitored with a combination of methods, including patient self-report, pill count, medication event monitoring systems and possibly TDM. On the other hand, the evaluation of patient adherence totreatment is important for a correct interpretation of TDM results
6.Possible interventions resulting from TDM include adjusting dosage or switching drugs if concentrations are excessive or inadequate — or, if possible, addressing the factor causing the unsatisfactory drug levels (e.g. patient education or discontinuation of an interacting drug).
7.The parameters of drug exposure that should be monitored, and their optimal target values, have not been adequately defined. These may differ depending on patient treatment history, concomitant antiretroviral drugs in the regimen and other factors. For example, PI-experienced patients may harbour virus populations with multi-fold increases in drug IC50 values compared with wild-type virus; thus, target concentrations may be higher in this clinical setting. TDM trials and available TDM services should focus on the definition of such targets by accruing data that integrate pharmacokinetics and resistance in diverse patient populations.
8.The future of TDM in HIV management may be an integration of pharmacokinetics and resistance. One of the major objectives of TDM studies should be to evaluate methods of integrating these data to optimize treatment. The innovative concept of the virtual inhibitory quotient should be investigated, since it has potential to be a cost-effective approach, and as such, adaptable to routine clinical practice.
9.Since the target drug level is usually defined as the ratio of a pharmacokinetic measure and a resistance measure, the variability of resistance testing assays, concentration determination and evaluations of the effect of protein binding on IC50 constitute a major obstacle. An effort should therefore be made towards assay standardization and quality control programmes.
10.The use of TDM to adjust dosages on the basis of plasma drug concentrations assumes that the free drug concentration at the site of action (the intracellular environment) correlates well with plasma concentrations. Potential confounding factors that may cause a lack of correlation, such as concentration-dependent protein binding, tissue penetration and intracellular accumulation, need to be thoroughly investigated.
11.Procedures for sampling and dose adjustment used to date include protocols based on peak and trough levels, concentration ratios and Bayesian methods. Further studies are needed to determine which method will yield the most useful results or whether alternative methods may be considered.