It is a matter of time

Time is a critical factor in both TDM and toxicology, and its importance and roles repeat throughout discussions of these services. Results, including both serum drug concentrations and urine toxicology screens, are best interpreted with respect to the time of dosing or exposure and the time at which the samples are acquired. In TDM, sample collection is not a random process, but one that must be carefully controlled with collection taking place within specific windows of time in conjunction with the dosing regimen. Unfortunately, the steps involved in sample collection are often out of the hands of the analyst, a situation that represents a continuous source of frustration. This can somewhat be minimized by maintaining open lines of communication with, and providing detailed guidelines and resources to, the staff involved in sample collection.

Most commonly, the best window of collection takes place during the 30-60 min preceding a dose when circulating concentrations necessary for the drug to be effective are lowest. Samples collected at this time are referred to as trough samples. When a drug is most effective over a very narrow concentration range and toxicity is a concern, monitoring may be most effective using peak concentrations when maximal concentrations are achieved. This type of collection is difficult to control as the time at which peak concentrations are achieved vary with the individual for each drug collected in this manner and may even vary with the formula, dosing route, and coingestion of food.

Samples are also collected at other points in the dosing cycle, for example, as with the once-daily dosing protocols used for aminoglycoside or vancomycin administration. In these protocols, samples are collected at defined points within the dosing cycle. Some laboratories call these "random" samples because they are neither peak nor trough and the time of collection may vary, but this is an inaccurate use of the term because for the result to be useful, the collection time must be controlled and known—not random. The once-daily protocols for aminoglycosides differ from other protocols in another manner. Usually, peak samples are used to assess toxicity, but in these protocols, trough concentrations are used because at this time the patient should have completely cleared the drug. The finding that the aminoglycoside remains in the circulation at this time indicates reduced clearance and hence the likelihood of toxicity.

Over the years, numerous studies and surveys have shown that samples for digoxin monitoring are among the most problematic to collect at the optimal time. Because digoxin exhibits a long distribution phase, there is a significant lag in the time between dosing and when the maximum pharmacological response is observed. As a result, samples for digoxin measurement should be collected no earlier than 6-8 h after dosing and preferably after 12 h. Samples collected before distribution is complete are often elevated. Although these elevated concentrations are not associated with toxicity, they are nevertheless confusing and lead to misinterpretation of the results. The problem of incorrect timing of sample collection is not new and has been described since digoxin testing began in earnest in the 1970s! In 1991 and in 2004, the College of American Pathologists conducted Q-probe surveys on the problem (1,2). The recent study focused on outpatients, included results from 59 institutions, and correlated the collection time with the concentration measured for 1571 outpatients. It showed that for every five specimens for which toxic concentrations were obtained, three were inappropriately collected with respect to the dosing interval (2). Unfortunately, this study shows no improvement in processes from the previous survey conducted in the early 1990s (1). Given the interest in patient safety and utilization of health care resources, this is one area that cries out for attention. One institution looked at the problem closely and implemented a nighttime dosing regimen for both their inpatients and outpatients. This has reportedly worked well for this facility and could serve as an effective solution for others (3).

In an effort to improve efficiency, prepare patients for discharge earlier in the day, and minimize the use of blood, many hospitals have consolidated phlebotomy collections and begin routine collection rounds often as early as 0400 h. This has led to some TDM samples being collected as part of these very early routine chemistry and hematology collections. Unfortunately, this means that the sample is often being collected prematurely if the drug is scheduled to be given mid-morning or later. Such samples do not represent true troughs, and although the results may fall within the therapeutic range, they pose the risk of toxicity if used for calculating subsequent doses.

An example of this is seen with a recent inquiry from one of our transplant coordinators regarding a patient who was receiving tacrolimus. Following admission, the patient was found to have an elevated concentration and the team contacted the laboratory to question whether the result could be falsely elevated as the patient's dose had not been altered. Although the team was certain that the sample had been appropriately collected as a trough, we were able to document that the sample had been collected 7.5 h early. With no change in the patient's dose, subsequent samples collected at the appropriate time were within the targeted range.

In contrast, samples for toxicology testing are typically random. For serum-based monitoring, i.e., in situations involving salicylate or acetaminophen ingestions, the patient may not be willing or able to recall and give an accurate time of ingestion (4). For this reason, it may be useful to obtain more than one sample. Repeat measurements can be used to assess whether absorption is continuing as might happen with extended release preparations or when bezoars form and to calculate the half-life of the compound. Urine drug-screening results pose interesting dilemmas in that some health care providers often wish to use the results to estimate when the ingestion may have taken place. As a random urine collection represents a snapshot of the individual's metabolic and excretion pattern, this is simply not possible. At best, one can apply average windows of detection reported for drugs with the caution that variations occur related to differences in pharmacokinetics and pharmacogenetics.

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