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    Isotretinoin’s discovery and development

    Expert discusses pearls gleaned from initial clinical observations

     

    Dose ranging studies

    I think one of the things that may be worth discussing is that if you look back at the dose-ranging study, it was 0.1, 0.5, and 1 mg/kg/day; basically all three groups completely cleared up. There was a one-year follow-up in that study for safety reasons.[3] This was a molecule that nobody knew anything about its safety. That’s when the second miracle happened.

    READ: Should you wait after isotretinoin to treat acne with laser?

    The second miracle was not only that these people all cleared, but most of them stayed clear. Now, there was a dose relationship in terms of the percentage of the patients who stayed clear or relapsed depending on how you want to look at it. With 1 mg/kg, 90 percent of them were still clear one year later, but (with) the 0.1 mg/kg dosing, 60 percent of them were still clear one year later. I think people have lost sight of that, because ever since that first observation, the focus of a lot of people in our specialty has been to try to push the dose in some way to get everybody to get clear and stay clear with a single course of isotretinoin. Right from the start, I pretty much disagreed with that and I never started any patient on 1 mg/kg.

    The highest (dose) I ever started anybody was 0.5 mg/kg, because there were all kinds of side effects. For example, the third patient I ever treated in the protocol that I described as clinic research protocol, we were doing 1 mg/kg.  The patient’s meibomian glands shut down and they stayed shut down for three years. I’ve seen patients that have been referred to me who have had that problem. The triglycerides, the bone pain, muscle pain, nosebleeds, etc., which can be a real problem are clearly dose-influenced and are more severe at higher doses. There wasn’t any clear difference in the incidence of side effects in the early studies, but the intensity clearly is dose-related.

    For that reason, I have always believed in not starting at high dose and I am really very much opposed to the recent trend of pushing the dose. There’s this widespread use of trying to reach a certain total cumulative dose. I’ll tell you where that came from.

    READ: How to recognize sinus tracts, keratinous cysts

    This 120-150 mg/kg dosage came from a S.I.D.Tri Society Meeting in Belgium at some point in the ‘90s. A group of us got together prior to that meeting to discuss our collective experiences, with each of us bringing the results of at least 500 patients each in whom we had at least two- or three-year follow-up. We discussed many issues, one of which was dosing. At the end, the group concluded that it looked like the dose that was associated with least relapse was in the range of 150 mg/kg for most of us; Bill Cunliffe thought 120, so that is where 120-150 mg/kg came from.

    At that point, I felt there was a nuance with respect to age and recommended that we should look at relapse rates stratified by age.  At that time there was not much support for this idea. I think many  people have come to appreciate that the younger patients with severe acne have a different relapse rate.

    NEXT: More data, better understanding

    Elaine Siegfried, M.D.
    Elaine Siegfried, M.D., is professor of pediatrics and dermatology, Saint Louis University Health Sciences Center, St. Louis, Mo. She ...

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