Therapeutic Drug Level Monitoring

Over the last few years there has been increasing interest in individualizing the dosing of antiretroviral therapy. Although careful dosing on the basis of weight or body surface area is standard practice in pediatrics, dosing in adults has tended to follow a "one size fits all" model. Doses generally are based on average pharmacokinetic profiles in volunteers, and dose ranging studies in HIV-infected subjects. Usually determining the best dose of a drug requires balancing antiviral activity and potential toxicities. However, there can be considerable inter-individual variation in drug absorption and elimination (76-78) Measuring plasma drug concentrations in patients could, in theory, identify patients receiving too little or too much of a drug, allowing patient-specific adjustments in dose to be made. Although the concept of therapeutic drug level monitoring (TDM) has gained in popularity over the last few years it remains controversial.

In the early years of antiretroviral therapy, little attention was paid to drug levels outside the pharmacology community because nucleosides have short plasma half-lives and because accurate measurement of active drug-intracellular nucleoside triphosphate (e.g., 3TC-triphosphate)-was available only in specialized laboratories. Nevertheless, one study did suggest that adjusting ZDV doses based on plasma drug levels resulted in optimum viral response to therapy (79). From practical purposes, however, TDM is best applied to drugs for which there is a clear dose-effect relationship, for which simple, precise, and reliable plasma assays exist, and for which there is a defined therapeutic range. The protease inhibitors and NNRTI's come closest to meeting these criteria. The relationship between trough plasma concentrations (Cmin) or area under the curve (AUC) and reduction in plasma HIV-1 RNA levels has been established for the PIs. Recent data regarding efavirenz (EFV) demonstrate a dose-relationship for antiviral activity and for central nervous system side-effects (80).

One misconception is that TDM can be a helpful adjunct to monitoring medication adherence. Because of the relatively short half-life of the NRTI's and PI's, random drug levels may provide some information regarding the most recent dose, but will not be helpful in determining longer-term adherence patterns. For example, a patient who frequently missed doses of a drug might be more likely to take his or her medication the day before a scheduled clinic visit, resulting in a plasma level that was "in range". Obviously, such results can produce a misleading picture of actual adherence.

A more appropriate use of TDM would be to ensure that adequate plasma drug levels are achieved in patients who are taking drugs with pharmacokinetic interactions (e.g., efavirenz and amprenavir), or to ensure that plasma trough levels exceed the drug concentration required to inhibit the patient's virus. As discussed in the section on drug resistance testing, the ratio between the plasma trough concentration (Cmin) and IC50 of the patient's isolate for a particular drug can be expressed as the inhibitory quotient (IQ). In one salvage therapy study, response rates to RTV/IDV were significantly higher among patients with an IQ>2 for IDV as compared to those with an IQ<2 (25). In the Viradapt study, optimal PI concentrations were an important determinant of outcome regardless of whether treatment was guided by the results of genotypic testing or not (see above) (19). Thus, TDM could play an important role in optimizing PI dosing in salvage therapy.

Despite these encouraging results, several important caveats must be kept in mind. First, drug levels need to be drawn at the appropriate time, preferably just prior to the next dose. For optimum interpretation, the time at which the last dose was taken needs to be recorded accurately. Second, the IQ should be based on IC50 values adjusted for drug binding to plasma proteins (see above), but there is considerable controversy over how such adjustments should be made. Third, there are limited data regarding the extent to which drug levels can be boosted safely. For certain highly resistant isolates, achieving an IQ >2 might require boosting a particular PI to levels that would not be safe, or for which safety data do not exist. Lastly, a randomized trial of TDM for management of salvage therapy, the Pharmadapt study, failed to show a benefit of TDM over standard of care (81). However, several aspects of the study design were flawed (for example, drug levels were related to the IC50 of control viruses, not the patient's own virus). Pharmadapt should be considered as a first attempt to study the role of TDM, not as the final word on this important topic.

In conclusion, although TDM offers potential promise, it is likely to be helpful only for a subset of drugs used in the treatment of HIV infection. A number of logistical hurdles need to be overcome and more data need to be gathered before TDM can be considered a part of the standard of care. As with virus load testing and drug resistance testing, moving TDM into the clinic will require carefully done retrospective and prospective studies to demonstrate the clinical utility of this potentially important tool.

4/15/01

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