Some Unanswered Questions About Therapeutic Drug Monitoring

July 2000

1. Intrapatient variability.
   “A blood level collected on Monday . . . may be markedly different from one drawn on Friday.” In one AZT study in women, the mean area under the curve (AUC) varied as much as two-fold in some patients (Cordaro 1993); in an indinavir study in women, the mean AUC varied from 20.2 nM*h in the menstrual phase to 34.0 nM*h in the follicular phase (Adams 1998). What you eat and when can also affect many antiretroviral drug concentrations.
2. Effect of protein binding.
   Many protease inhibitors, such as amprenavir, bind to alpha-1 acid glycoprotein (AAG), “an acute phase reactant . . . whose concentrations can be increased by stress, injury, or infection.” So here you’d need to monitor amprenavir concentrations along with AAG.
3. Sample timing.
   Would you sample the peak, the trough, the area under the curve (AUC)?
4. What is the target concentration?
   Most studies assess this only in drug-naive patients. Target concentrations will vary by viral phenotype. So you have to do phenotypic resistance testing as well as therapeutic drug monitoring.
5. Logistics.
   To catch suspected treatment failure, you’d have to get to the clinic, give the specimen, have it sent to an outside lab, wait for the results, confer with your doctor, and act on them. By this time, drug resistance — especially if it is to 3TC or a non-nucleoside reverse transcriptase inhibitor (NNRTI) — may well have emerged and it will be necessary to change regimens in any case.
6. Interpretation.
   Who will interpret the results of therapeutic drug monitoring? With the nucleoside analogues, the concentration of interest is of the intracellular metabolite, not drug in the plasma. In the blood, ddI has a half-life of two hours, but in the cell, it is over 11 hours.
7. Assays.
   Certain labs will perform therapeutic drug monitoring, but there are no standardized, simple, and inexpensive methods, nor any quality assurance for labs carrying out therapeutic drug monitoring.

Source: “The Limited Value of Therapeutic Drug Monitoring,” Stephen C. Piscitelli, Medscape Inc., 1999