Wide variability in drug levels casts doubt on the practicality of therapeutic drug monitoring

Levels of antiretroviral drugs vary considerably within HIV-positive patients, according to a small pharmacokinetic study from the United States published in the 15^th April edition of Clinical Infectious Diseases. This suggests that using single measurements of drug levels to guide modifications in drug doses may be misleading.

Measurements of antiretroviral drug levels in the blood can indicate whether the dose of the drug needs to be increased or decreased, to keep the drug's levels within its optimal range. Current guidelines for HIV treatment recommend that doctors use therapeutic drug monitoring when there is a risk of drug interactions, when there is a poor response to treatment or when a patient experiences side-effects that may be linked to high drug levels.

Despite these recommendations, there is still debate over the practicality of therapeutic drug monitoring. Since it is costly and inconvenient to take multiple measurements of drug levels from a patient, the usefulness of single measurements depends on drug levels being relatively stable within each patient. This uncertainty reflected in the results of clinical trials, with some studies showing that altering drug doses can improve treatment outcomes, while others have failed to show such a clear benefit.

To assess the stability of drug levels in patients taking antiretroviral therapy, investigators from Johns Hopkins University and Howard Hughes Medical Institute in Baltimore measured levels of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) in ten patients who had undetectable viral loads for at least eleven months. Blood samples were taken three times a week for up to four months.

The investigators found that the variability in drug levels was high. For protease inhibitors, the median intraindividual co-efficient of variation (ICV) was 44%, while it was 25% for NNRTIs. Higher ICVs indicate greater variability within each patient.

“Intraindividual variability in concentrations of antiretrovirals was surprisingly high in virologically suppressed patients,” the investigators conclude. “High intraindividual pharmacokinetic variability may limit the utility of single measurements in therapeutic drug monitoring for some antiretroviral agents.”

The four patients taking ritonavir-boosted lopinavir (Kaletra) had ICVs of 24, 33, 51 and 92% for lopinavir levels. The two taking nelfinavir (Viracept) had ICVs of 30 and 39% for nelfinavir and of 44 and 54% for nelfinavir’s active metabolite M8. ICVs for ritonavir (Norvir) were 34 and 43%, while for saquinavir (Invirase), they were 52 and 55%.

The degree of variability was lower for NNRTIs than for protease inhibitors. The four patients taking efavirenz (Sustiva) had values of 7, 13, 29 and 51%, while the one patient taking nevirapine (Viramune) had an ICV of 25%.

Therapeutic drug monitoring cannot easily be carried out for nucleoside or nucleotide reverse transcriptase inhibitors.

The investigators argue that the high degree of variability in the patients’ drug levels is unlikely to be due to poor adherence, as the patients reported 99.5% adherence, and all had good control of their HIV across the study.

The investigators also claim that the variation in drug levels was not due to variability in the timing of the blood sample relative to when the drug was taken. When they restricted their analysis to the blood measurements taken within 60 or 30 minutes of the average delay between dosing and blood sampling for each patient, the investigators saw the same degree of variability in drug levels.

“These results suggest that care providers should use caution when making clinical dosing decisions on the basis of limited drug concentration measurements for some antiretroviral agents,” they conclude. “Possible contributors to this variability include food effects, concomitant use of prescription and herbal medications, or medication timing, all of which were assessed by self-report.”

In an accompanying editorial commentary, David Haas of Vanderbilt University School of Medicine writes, “these findings [emphasise] that use of therapeutic drug monitoring in practice must be tempered with caution, particularly when considering a dose reduction on the basis of single assay determinations.

“In this situation, treatment modification in response to a transiently or spuriously elevated drug concentration may lead to suboptimal drug exposure, with emergence of drug-resistant virus,” he adds.

However, Dr Haas goes on to point out that therapeutic drug monitoring may still have a place in determining the effects of adding drugs that may interact with protease inhibitors or NNRTIs, in children, in patients suspected of having very high drug levels, and in assessments of adherence.