Where did drugs go in the Alabama 24?
Study looks at pharmacokinetics
Researchers at the University of Alabama at Birmingham are engrossed in a piece of detective work, a study that might be called The Case of the Missing Drugs.
The mystery is this: When patients were given a standard three-drug regimen, blood samples taken from some of the patients showed surprisingly low levels of two of the drugs or in some cases, levels so low they weren’t measurable at all. At the same time, a third drug was present in normal levels.
What became of the drugs that weren’t there? A study underway is trying to answer that question, among others.
The study, conducted by Nancy Dunlap, MD, PhD, medical adviser to Alabama’s TB control program, and Michael Kimerling, MD, MPH, assistant professor of public health at the University of Alabama at Birmingham, is looking for answers to other questions as well, the two researchers say.
First, how much do blood levels for the drugs vary across a population? If there is variability, how does it affect patients’ response to therapy? And finally, are there any epidemiological markers that can be identified and used to predict such a response?
To start with, 24 patients with problems
Like many tales of sleuthing, the story got off to a relatively ordinary beginning.
In accordance with standard procedure in Alabama, 24 patients were placed on a three-drug regimen containing rifampin (RIF), isoniazid (INH), and pyrazinamide (PZA). Over an 18-month period, the various physicians taking care of the patients requested blood samples, so they could check serum concentrations of the drugs.
In a retrospective analysis Kimerling performed, something that hadn’t been apparent when the patients were viewed one by one suddenly jumped into view. Although the patients’ PZA levels all fell within the anticipated range, their levels of INH and RIF were strikingly off-base. "About 70% had [serum concentrations] less than what’s stated to be the normal range," Kimerling says.
Also, in about a fourth of the patients, levels of either RIF, INH, or both drugs were so low they couldn’t be measured. All of the patients had been having some sort of problem by the time they’d had their blood levels checked, Kimerling says. (Eight had suffered delayed sputum conversions, five had failed treatment, four had relapsed, six had had a worsening of symptoms, and one patient had experienced what doctors thought might be an adverse reaction to drugs.) Yet as he looked back, Kimerling says, he couldn’t find an exact fit between the clinical picture and the blood levels.
AIDS, gastrointestinal troubles weren’t culprits
Nor did any of the 24 suffer from conditions that would have affected their ability to absorb the drugs properly AIDS, for example, or gastrointestinal problems. All of the patients had been getting directly observed therapy. The fact that all had PZA levels within normal ranges suggests that any malabsorption that occurred would have taken place on a selective basis, Kimerling says.
So what was happening to the rifampin and the isoniazid?
To find out, Kimerling and Dunlap decided to begin a new, more systematic study, this time with 50 newly diagnosed TB patients. The plan is to start the patients on a three-drug regimen and then see what happens to blood levels of the drugs over time. Initially, they’ll draw blood levels eight times: at baseline, after thirty minutes, on the hour, and five more times, up to six hours. Subjects fast after midnight the day before and eat the same standard meal an hour after the first dose of medication is given.
Because they believe blood levels may change over time, the researchers will recheck levels twice again after two months, when the PZA is dropped and the patients begin semi-weekly therapy; and a third time, at completion of therapy.
"We want to see whether there is a norm and some outliers, or whether nobody’s normal," Dunlap says. In addition, the two say they want to know whether they can correlate the patient’s response to therapy and any variations in serum concentrations. Such a connection might help explain why a small percentage of patients fail treatment or relapse, even in the best TB control programs, Dunlap says.
"In Alabama, we have a very good program," Dunlap says, with more than 95% completion rates and only about a 3% relapse. "But that 3% probably occupies about 25% of our efforts," she says. "These are the people who get unhappy, stop taking their meds, get acquired resistance. We need to find out why. We need to know what is the problem."
Some remain skeptical
The idea that somehow factors unrelated to the usual culprits (chiefly, gastrointestinal malabsorption) could be to blame does not sit easily with some. "I’ve simply never heard of someone clearing the drugs that fast," says Charles Peloquin, PharmD, director of the infectious disease pharmacokinetics laboratory at National Jewish Hospital in Denver. "My guess is that these patients aren’t absorbing the drug. Why that is, I don’t know, since I haven’t seen the data."
Various circumstances could account for someone’s not absorbing a drug properly, he says diabetes mellitus with resulting gastroparesis, cystic fibrosis, Crohn’s disease, or recent gut surgery, to name a few. People with AIDS are known for having trouble with absorption, he adds, so that the lower the CD4 count, the worse the absorption, Peloquin says. Patients who abuse alcohol don’t always seem to metabolize drugs in a normal fashion either. "In certain advanced stages of alcoholism, you can get malabsorption," Peloquin says.
Dunlap doesn’t disagree. She recalls an instance in which a patient picked up his meds, left the clinic, and embarked on a drinking spree. A few days later, he wandered back into the clinic, where a nurse drew blood levels; his serum concentration turned out to be five times higher than they should have been, Dunlap says. "Chronic alcohol abusers may chew up meds because their livers are revved up," she suggests; binge drinkers, on the other hand, may evidence a mix of high and low levels.
Then there’s nicotine, known to affect certain hepatic enzymes, says Peloquin. For example, patients suffering from Chronic Obstructive Pulmonary Disease (COPD) or asthma who should not be doing so in the first place are advised not to smoke if they’re taking theophylline, says Peloquin.
Such factors notwithstanding, surprisingly little is known for sure about the pharmacokinetics of TB drugs, says Dunlap. Many early studies of the drugs were conducted on populations that bore little resemblance to patients in low-prevalence countries like the United States, she says. "We went back and looked at the literature," she says. She found many early studies were done in Africa on populations that tended to be predominantly thin and male, she says. "But we also have patients who are female or obese, and who smoke and drink," or who otherwise don’t fit that description, she adds.
The same mixed bag of patients is what they’re starting to look at now, she says "your normal Alabama cohort," adds Kimerling. The study of these patients will probably raise issues rather than provide hard and fast answers, he adds. "As we get closer to TB elimination in this country, it becomes more and more difficult to get rid of that last batch," he says. "At the same time, we start noticing these interesting problems and patterns."
Whatever the findings, they won’t have much affect on the majority of TB patients, he says. "We’re talking about a minority of patients," he says. "After all, most people do get cured."
If the study does turn up markers for people who handle certain TB drugs in an unusual way, all the better, says Peloquin. "If you can identify a subgroup where you know a priori that you need to measure concentrations, that would be very useful." In the meantime, any TB patient who’s been on therapy but isn’t markedly better in about six weeks "is telling you something," says Peloquin. "They’re saying: Measure the serum concentrations."
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