Monitoring drug levels a great idea, or voodoo? VA researchers wonder
In new study, it seems to work; but why?
Therapeutic drug monitoring appeared to be the key that opened the door to successful treatment for patients slow to respond to TB treatment, a recent study found. In a one-two-three sequence that sounds absolutely foolproof, clinicians at a Veterans Affairs hospital decided to check rifampin levels in patients who weren’t responding promptly to TB treatment.1 Sure enough, when the physicians looked, the slow-to-respond patients’ serum concentrations of the key drug were low. Just as surely, when clinicians hiked up the dosages to attain the target serum level, the patients all got better.
But is therapeutic blood monitoring indicated for every patient who’s slow to respond? Are low serum drug levels always at fault? Do serum drug levels even matter? According to some TB experts, therapeutic drug monitoring may not always be the panacea it seems. Back at that VA hospital (the Veterans Affairs Medical Center in Mountain Home, TN), physicians were speculating about why some patients inexplicably failed to respond promptly to therapy, even though they clearly were taking the right drugs at the recommended dosages and were observed to be taking them.
Picking a likely culprit
"We’d all noticed this phenomenon over our collective careers," explains Ryland Byrd, MD, chief of pulmonary medicine at the VA hospital and professor of medicine at the Quillen College of Medicine at East Tennessee State University in Johnson City. "We decided the problem must be drug-related. So we asked ourselves which drug was the most likely candidate." Of all the drugs, rifampin seemed most likely to be culpable, they thought. This was because when the frequency of dosing slows from daily to twice-weekly, the drug’s dosage isn’t increased (as common sense would seem to dictate), but instead stays the same as during daily treatment, Byrd says.
In a cohort of 124 new TB patients at the VA hospital, six patients proved slow to respond. When blood levels of rifampin were checked, levels in the six slow responders were not only low, "they were virtually undetectable" in three of the patients, says Byrd. (Though one of the six was HIV-infected, none of the patients reported problems that might have interfered with absorption, he adds.)
Dose hikes achieve target concentration
Proceeding with their hypothesis, the physicians raised the dosage of rifampin from 600 mg to 900 mg; that, in turn, enabled the patients to attain target levels in all but one case. That patient required another dose hike up to 1500 mg to get up to target concentration. At that point, Byrd says, all the patients began to respond, and completed treatment without incident.
The study could be limited by the fact that other drug levels — say, for isoniazid — weren’t checked, Byrd concedes. Even so, he’s convinced that he’s onto something. "Though drug levels aren’t indicated for everyone, in patients who are slow to respond, I think the message here is that perhaps you should consider checking [serum drug concentration] levels," he says. "I think we’ll probably adapt our protocols here [at the VA] accordingly, at least with rifampin," he adds.
At the Centers For Disease Control and Prevention’s Division of TB Elimination, Rick O’Brien, MD, chief of the division’s research and evaluation branch, agrees. "Though we don’t currently see a role for routine blood monitoring, in patients who are apparently adherent and who aren’t responding, it’s an appropriate thing to do," he says. Choosing to check levels for rifampin makes good sense, too, O’Brien adds: "It’s the key drug in short-course therapy, and the most important sterilizing drug," he notes. "So if levels of rifampin are suboptimal, it’s not surprising that the patient wouldn’t respond."
A skeptical response comes from William J. Burman, MD, infectious disease specialist at the Denver Medical Health Center and chairman of the Core Science Group of the CDC’s TB Trials Consortium. Under conditions of a controlled trial, Burman explains, it turns out that serum concentrations are all over the map. What’s more, there seems to be little correlation between patient response and serum level.
"It’s not that there’s no relation, because at some extremes, there clearly is," Burman goes on. In other words, it’s plainly no good when no drug at all is present, and equally bad when there’s so much drug present that toxicity results. "But in between those extremes, many of the details are completely unknown," he says. For example, in the consortium’s Study 22, when investigators checked serum concentrations of drugs, they found that in some patients the levels were indeed low, says Burman. The trouble is that some patients with low levels did quite well and others with apparently adequate levels did poorly.
To Burman, that suggests that other host factors often precipitate a failure to respond. "So I’d say the danger is when you use [monitoring blood levels] as a simplistic model, reasoning that if you measure the levels and approve them, then you’ve taken care of any problems," he concludes. In addition, there are fewer clinical data to validate the supposed target serum levels than Burman would like. "Current standards for judging what’s low and what’s therapeutic haven’t been validated clinically," he says. "When people say low,’ what they really ought to mean is lower than the 95% confidence level interval for serum concentrations in healthy individuals who enrolled in a study.’"
His reservations notwithstanding, Burman agrees with O’Brien that checking serum levels in a patient who’s not responding isn’t a bad thing to do. "I don’t doubt that there’s the occasional rare patient in whom truly abnormal pharmacokinetics are the reason for treatment failure," he concedes. "I have no problem with those who do this selectively. But if you do it, you need to have some caution — plus the knowledge that it’s not easy to interpret what you find."
Reference
1. JB Meyta, H Shantaveerapa, RP Byrd, et al. Utility of rifampin blood levels in the treatment and follow-up of active pulmonary tuberculosis in patients who were slow to respond to routine directly observed therapy. Chest 2001; 120:1520-1524.
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