The question of the correct dosage of immunomodulatory drugs has often been discussed in the comments. Many patients do not understand why doctors usually use the full (approved) dose of a drug, even though a lower dosage might be more tolerable in individual cases. Others are concerned that they are generally being treated with too high doses, which “throw their immune system out of balance” because doctors and industry go “all out” uncontrolled. This latter concern is relatively unfounded and probably based on a rather “homeopathic” point of view. It is by no means the case that no thought is given to the dosage – on the contrary. The approval of a certain drug dose is fundamentally not without reason. Usually, the identification of a specific dosage is based on so-called dose-finding studies, which always stand at the beginning of drug development. Different dosages are tested here, and the aim is ultimately to find the lowest dose that has the best effect and the fewest side effects in the experiment. This dose is then used for the further development of an active substance. An example of this is Gilenya. Initially, experiments were conducted with a dosage of 5 mg, but later only 0.5 mg was approved. In the case of Tecfidera, 720 mg of dimethyl fumarate was also used in the studies, but when the same efficacy of 480 mg was demonstrated, the lower dose was ultimately approved.
Thus, the claim that “conventional medicine” always works at high doses is false. The first point of discussion – why it always has to be the full approved dosage in individual cases, even if patients have had better experiences with low dosages of a corresponding drug – is, however, a very interesting and important question that is based on a problem of clinical cohort studies and also puts us doctors in a certain dilemma.
The dilemma is that a drug – e.g. for the treatment of multiple sclerosis – is officially approved in a certain dosage. This means that only data exist for this dose that provide reliable information about the effect and side effects of an active ingredient. If I use a different dose than the approved dose, I am ultimately moving on unknown terrain and must justify my deviating behavior. A justification could be, for example, that I achieve better tolerability with a “different” dose individually in one of my patients, without noticing any relevant losses in efficacy. An example could be that I always fall below the recommended limit of lymphocyte values in a patient under a daily dose of 0.5 mg Gilenya and therefore have prescribed 0.5 mg only every 2nd day. As a result, the blood values remained stable and the effect on MS was still sufficient, as stable clinical findings and MRI recordings have proven. In this individual case, my deviation from the approved dose would then be justified, but I must not generalize this individual observation.
On the other hand, we examine cohorts of patients in studies that are the basis for drug approvals – i.e. defined groups with a varying number of individuals. Due to the heterogeneity of humans, these cohorts, despite a strict definition of inclusion and exclusion criteria, represent a collection of individuals with completely different equipment in terms of their metabolism, their physique, their muscle mass, etc. A positive result of a (dose-finding) study means that the mean values of two defined cohorts differ statistically significantly. However, a positive result in the mean value does not simultaneously mean that a thus defined “optimal” dosage is optimal for an individual. It may indeed be the case that an individual either needs less or more of an amount of an active ingredient to achieve an optimal effect with optimal tolerability. Of course, against this background it is a legitimate question whether it is sensible to treat every Tysabri patient with a dosage of 300 mg every four weeks, regardless of whether a 120 kg heavy bodybuilder or a 50 kg light high school graduate is sitting on the infusion chair.
But as long as there are no reliable data, one cannot simply deviate from the approval of a drug. And a good success in individual cases, e.g. with a dose reduction, must not lead to the “invention” of a new dose regimen that is advertised as universally valid – sometimes some people overshoot the mark here. The demand probably has to go in the direction that more importance is given to individualized studies, so-called “one-person-trials” (N of 1), in the future, and that the new approval of drugs possibly bases on a mix of different study methods. The time indeed seems ripe for a rethink.
