When new drugs are being developed, research studies are conducted to find out the best doses to treat the disease and minimize side effects. Part of that process involves finding out how much of each dose of medicine is absorbed into the person’s blood stream and other tissues, and how long the medicine remains active in the body. Researchers also try to see if the amount and duration of active medicine in the body varies for specific groups of patients, such as between men and women, or among racial groups.
The study of how drugs are absorbed in the body and how long they remain active before being eliminated is called “pharmacokinetics.”
Mycophenolate mofetil (MMF), an immunosuppressive medicine being used to treat lupus, was originally developed to prevent rejection of organ transplants. When MMF is taken as a pill, the active ingredient mycophenolic acid (MPA) shows up in the blood stream. In studies of MMF in transplant patients, researchers have found different levels of MPA in patients who take the same dose of MMF. The levels of MPA also varied depending on the other immunosuppressive drugs that the patients were taking. These studies seemed to show that the level of MPA in the blood had an effect on how well the medicine worked in helping prevent transplant rejection, and on the amount of side effects, particularly low white blood cell counts, and stomach and intestinal disorders. For these reasons, many doctors, when using MMF for transplant patients, check the level of MPA in the patient’s blood to help predict if the MMF treatment will be successful; this is called “therapeutic drug monitoring” (TDM).
The researchers wanted to see if lupus patients taking the same dose of MMF had different levels of MPA in their blood, and if so, whether that affected how well MMF worked to treat their lupus.
Twenty adult lupus patients who had been treated with MMF at the University Hospital of Tours, France, were studied. Five of the patients were taking MMF as induction therapy (to treat recently active disease); 15 were taking MMF as maintenance therapy (to suppress lupus disease activity following induction treatment with another medication). On average, the patients had been taking MMF for approximately 2 ½ years (30.9 months); no patient had been taking MMF for less than four weeks. The individual doses varied among patients, with the average being 1600 mg/day. This is a relatively low dose of MMF in clinical practice, but not unusual if patients have relatively inactive symptoms and are on maintenance therapy.
All the patients had taken steroids for treatment at some time before the MMF study started, and 16 were still taking prednisone when the study was conducted. All the patients also had used a number of other immunosuppressive drugs or other medications to treat lupus: 12 had previously been treated with intravenous cyclophosphamide (IV CY), 15 with intravenous steroids, three with azathioprine (AZA), and six with hydroxychloroquine (HCL). Three of these patients were still taking HCL when the study was conducted.
After fasting for a total of 12 hours, including overnight, the patients in the study group took their regular dose of MMF the next morning. The researchers took blood samples from each of the patients just before they took their medicine, then again 30 minutes, one hour, two hours, three hours, and four hours afterward. Each of these blood samples was analyzed to determine the level of MPA at the time. The investigators also noted the level of special inflammatory proteins called complement proteins, and looked for autoantibodies, which can give some clues about lupus disease activity. The researchers recorded the highest level of MPA reached during this period (“maximum concentration”) for each patient and the time it took to reach the maximum, and calculated the total amount of MPA each patient was exposed to for the entire four hours. They compared these MPA levels to the levels of complement and autoantibodies to see whether patients with lower MPA levels in the body would be more likely to have these markers for lupus disease activity. In order to accurately compare the measurements, the researchers also factored in the differences in the patients’ MMF doses.
Even after accounting for the difference in doses of MMF, the researchers found considerable differences in the level of MPA in the blood of the patients at the times the blood samples were taken. Also seen were differences in the total MPA exposure for the four-hour period, in the maximum concentration of MPA in the patients, and in the time that maximum level was reached. However, no significant relationship was found between a patient’s weight and the concentration of MPA. Higher levels of MPA after one hour and higher maximum concentrations were predictive of higher overall exposure to MPA for the four-hour period. This suggests that elimination of the drug from the body is not as rapid as its accumulation in the body during this time.
Seven patients had low levels of complement C3 and five patients had low levels of complement C4 on the day of the study; complement levels fall when there is inflammation due to lupus, so lower levels of complement are taken to be a sign of lupus activity. Eleven patients had higher than normal levels of anti-doublestranded (ds) DNA antibodies, another sign of immune system activity. Patients who had lower C3, lower C4, and higher levels of anti-dsDNA antibodies tended to have lower total levels of MPA for the four-hour period than patients who did not have these markers.
This same relationship was seen in the blood samples taken before the patients took their morning MMF dose: those who had low C3 or C4 or high anti-dsDNA levels tended to have lower levels of MPA after the 12-hour fasting period. It also was found that patients were less likely to have a low level of the complement protein C4 if their overnight levels of MPA were
1 mg/L or greater.
These findings suggested that there may be a relationship between the level of MPA in the blood and the therapeutic effect of MMF on immune system disease activity. Because the MPA level varied considerably in the individual patients, the researchers felt it might be a good idea for doctors to do therapeutic drug monitoring of MMF for lupus patients as it is done for transplant patients, though they realized this may be difficult because it would require more blood samples. They suggested a target level for MPA of between 1 and 5 mg/L to provide good results.
One patient had diarrhea, which was the only side effect reported by any of the patients in the study. This patient did not have a high level of MPA.
There were only 20 patients in this study, but this was enough to strongly suggest that one dose does not fit all and that MMF levels might help optimize this dose for individual patients. Since all of these patients were from the same region in France, it is very likely that there will be even more differences in how this drug works in people of different genetic backgrounds. Further studies should be done to learn more about the extent to which MMF levels affect disease at the start of the treatment and when other medications are on board; studies in transplant patients have shown that other drugs affect MPA levels, as would be expected.
This was a prospective study, which means the researchers were able to take measurements and gather data going forward, rather than having to rely on past data from medical charts. Prospective studies are good because they enable the researchers to collect all of the information they need. However, for this study, the researchers did not give identical doses of MMF to the individual patients, but instead studied the doses the patients had been taking based on their doctors’ decisions, which varied from patient to patient. Although the researchers factored these differences in doses into their analysis, it is possible that the different doses had an effect on the data results. Also, the researchers stopped taking blood samples after four hours; there may have been important changes in the patients’ MPA levels and immune system markers occurring after the fourth hour and before the level that occurs in the early morning that would not have been picked up
Treating lupus always involves figuring out which medicines, when taken alone or in combination with other medicines, work for each individual patient. While many patients do well on MMF, some do not. This may, in part, depend on how much of the active ingredient actually makes it into a patient’s blood stream. This study provides a possible way for doctors to determine if it makes more sense to raise the dose or switch to another agent when their patients are responding to MMF, and even to help doctors tailor the initial MMF dose to get the best possible benefit for an individual patient.