Frontline Forum Part 4: A Discussion of the Pathophysiology of Acne and Available Treatment Strategies

Continued from part 3

Zeichner: What is the optimal dosing strategy for isotretinoin, including traditional dosing vs how we’re doing it in the real world in clinical practice?

Baldwin: The traditional dosing is 0.5 to 1 milligram per kilogram for 15 to 20 weeks.

Zeichner: Regardless of what it says in the package insert, how are you guys dosing your patients? I personally use this as a framework to start, but I’m adjusting the dose based on how I’m clinically evaluating the patients. If their skin and lips aren’t dry, then they’re either not taking the medication or they’re not absorbing it, and I’ll go up on the dose.

Farberg: The daily dosing is titrated based on symptomology that the patients are experiencing.

Baldwin: Where do you start?

Farberg: Start half dose of what I want to get them at or what I predict that they should be at.

Baldwin: I prefer half a mg per kg at start.

Zeichner: In terms of once vs twice daily dosing?

Baldwin: I’m a once a day.

Farberg: I’m a twice a day.

Baldwin: I’m a once a day with the food-dependent formulations because nobody eats breakfast and that morning pill falls on a deaf stomach. And we know that the absorption on an empty stomach is really quite dismal with the food-dependent formulations. If the insurance company is willing to let me go with the food-independent formulations, then I recommend bid.

Zeichner: So based on the metabolism of the drug, there is perhaps better absorption with twice-daily dosing. However, at the end of the day, we need to do what’s best for our patients in the real world. Traditional dosing has been, as Dr Baldwin mentioned, up to 20 weeks. However, there have been many clinical trials looking at longer dosing. And unlike clinical trials, in the real world, when we finish isotretinoin we want the patients to be 100% clear.

Kircik: So what’s a target cumulative dose?

Farberg: 120 to 150.

Baldwin: I’m still a 120 minimum. If I can get the food-independent formulations so that I’m pretty confident about how much medication has been absorbed as opposed to how many milligrams have been taken, then I’m comfortable stopping at 120.

Zeichner: I think you just hit the nail on the head. I think the 120 to 150 should really be based on absorption rather than what’s prescribed. And I think if you look at it that way, we can more effectively dose our patient.

Kircik: So if you have somebody clear 100%, do you continue to your target dose?

Baldwin: I do.

Kircik: Me too.

Baldwin: I want them clear for at least 2 months.

Farberg: That being said, I utilize the 120 to 150 as just a guardrail. But my typical length of treatment is outcomes-based. So understanding that I expect them to be clear for those 2 months prior. And if they’re having a breakout in that last month—they’ve already proceeded the treatment for 5, 6 months—will the patient go another 1 or 2 months? Absolutely, they will. And they should.

Zeichner: One month past the last pimple. That’s what I do.

Kircik: The next burning question, do you guys give them a topical or any maintenance treatment of isotretinoin?

Baldwin: Never know. We only have 1 study that I’m aware of that looked at that, which was a very small study utilizing isotretinoin. But it was a placebo-controlled, and it did show that there were 30%, if I’m not mistaken, fewer lesions in the 6 months following discontinuation of isotretinoin on the treatment group. So I am in favor if the patient is willing, but I do not force them.

Kircik: Right away?

Baldwin: Yeah. ActuallyI’d prefer a month before. And I prefer a combination of benzoyl peroxide in a retinoid, or retinoid alone. And in an adult female who has recurred before, if this is her second trial of isotretinoin, I start spironolactone a month before I discontinue.

Farberg: Which highlights a more important position for a topical version, Winlevi. Because oftentimes, even in an isotretinoin failure, the patient is still very pleased with their outcome and doesn’t want to proceed with another round of isotretinoin and oral spironolactone, Winlevi is an ideal choice in these patients.

Baldwin: I think that’s very true. And I haven’t had enough experience with Winlevi after isotretinoin yet to be able to comment on it. But I think you’re right. A patient would much prefer, I think, to switch from needing still to be on an oral medication to
a topical.

Kircik: Isotretinoin is a lipophilic molecule and requires not only food but fat for optimal absorption. So we always recommend taking isotretinoin with a fatty meal. The problem is that in the real world, patients are not necessarily eating as much fat as they need to, which is why newer medications have been developed to enhance absorption of isotretinoin in the absence of a fatty meal. And Lidose-based isotretinoin delivery meets that criteria.

Baldwin: And micronization even more so.

Kircik: So I always say vehicle matters in topical treatments and then delivery matters in systemic treatments. So it doesn’t matter how much of a drug you’re getting, if it’s not absorbed, it’s absolutely useless. And the biggest problem with isotretinoin, as we discussed, [is] the cumulative total dose and when it’s not absorbed, that…[is] not going to happen. So we do need Lidose-based delivery system for the drug. Lidose is sort of a eutectic mixture of the lipids. And it’s not only used in dermatology; it has been previously used in other medications, including fibroids. And so it does make sense to have this technology with isotretinoin, since most kids are not going to have [a] 1000-calorie high fatty meal.

Zeichner: We have even new medications that take it one step further where the isotretinoin is being micronized. Dr Baldwin, if you can just comment on the benefits of micronization?

Baldwin: So micronization, of course, makes extremely small particles. And those small particles have a larger surface area so that they dissolve more readily in the intestine, giving you an increase bioavailability of the drug. It’s been shown to give a plasma level of 50% higher than with the former Lidose formulation of isotretinoin, which in turn was shown to be absorbed 60% better than the generic formulations. So the newer micronized formulation is 2 levels of improvement beyond the generic food-dependent options that we have for…use. In the real world, the reason why it’s important to have the micronized formulation is because our patients are not consuming 50 grams of fat in their meal. Who in their right minds would actually do that?

Zeichner: Could you describe to us what a 1000-calorie, 50-gram meal would look like?

Baldwin: I can do that. My general summary is it’s like a Shake Shack meal. It’s a cheeseburger, French fries, and a Tim Hortons Dutchie donut.

Zeichner: So we know, according to the American Dietetic Association, that most people are not taking this type of meal. In fact, teenagers are skipping meals.

Baldwin: Sixty-six percent of teenage girls don’t eat breakfast, and everybody else in the world is on an intermittent fasting diet, and not having breakfast.

Zeichner: Plus there are people who genetically have a history of high cholesterol and triglycerides.

Kircik: The most ironic thing is how can we have a drug…[whose] major side effect is triglycerides and you advise them to eat [a] 1000-calorie high meal with the pill. It just doesn’t makes sense.

Zeichner: So the micronization not only enhances efficacy, but in many ways it’s better for the overall health of the patient?

Baldwin: That’s absolutely true. And then the last thing that we have to say is we’re all counting milligrams sort of generally. We’re not exactly down to the last milligram, but we’re counting milligrams in general to make sure we reach somewhere in the vicinity of 120 to 150. So if your patient is taking that morning pill on an empty stomach, they’ve had half as much, a quarter, because the evening pill is probably being taken with fat. They’re a quarter less than you thought they were. So here you are counting to 120, and they’ve reached nowhere near 120. So it increases the risk of recurrence and increases the risk of the need for an additional course of isotretinoin, which no one wants. And that’s the whole game here. Isotretinoin will make a patient better if you sprinkle isotretinoin dust over their heads. The question is, is it going to come back? And in my opinion, micronization gives us the best chance of it not coming back.

Zeichner: So in clinical trial settings, when patients are observed and specifically taking the caloric and fat intake that they need to, there really is no difference between the effectiveness of the generic vs the brand name medications. But in the real world, that doesn’t happen. Which is why it’s essential that we have access to
brand names

Kircik: And can they also say low dose also means less side effects?

Farberg: Potentially.

Kircik: Potentially, if you take less of something.

Baldwin: It’s a 50% better absorption and [a] 20% lower dose. And we have no data, there’s no clinical study on absorbed LD.

Zeichner: What are some strategies to reduce the risk of acne
flares initially?

Kircik: Especially patients with severe acne, we will start isotretinoin at very low doses or on a case-by-case scenario combined with various doses of oral prednisone.

Baldwin: Because you have 2 types of flares. You have that minor flare that many people experience, which can be helped by lowering your starting dose to half a mg per kg or lower. And then you have the people who are at risk for pseudo acne fulminans, which is what we’re really worried about. And those are generally teenage boys with very inflammatory lesions with a truncal preponderance. And those are the patients you have to be super careful with. I personally start with 10 milligrams a day and they go home with
a prescription.

Kircik: But you don’t know who it is to begin with.

Baldwin: Right, but the high risk are boys…[with] very inflammatory in truncal. So those patients in my practice go home with a bottle of prednisone. I don’t have them take it yet, but they have the bottle.

Zeichner: What dose of prednisone do you give?

Baldwin: Ultimately if you’re treating pseudo acne fulminans it’s 1 mg per kg, but in the beginningI’m giving them maybe 20 milligrams or so to try to suppress. How much do you guys use?

Kircik: I give them a bunch of 20s and tell them maybe 40, depending on what’s going on.

Baldwin: On how bad it goes. I just have them send me pictures.

Kircik: And I bring them in. I don’t see pictures, but I bring them in.

Zeichner: There have been many studies evaluating a questionable association with inflammatory bowel disease. Causation has not been established, but what are your thoughts?

Kircik: I think more evidence of patients who were on long-term antibiotics before they were started on isotretinoin, those who developed the IBD. There’s no causation that has been associated between isotretinoin and inflammatory bowel disease. The largest study that we have was a 2014 study and the GI literature showing no association between isotretinoin and ulcerative colitis. And, in fact, a protective effect of isotretinoin in Crohn’s disease.

Baldwin: There’s no evidence that it makes existing IBD worse.

Zeichner: And there are studies evaluating patients with IBD on isotretinoin for both acne and
other conditions.

Farberg: And those GI doctors don’t appear to be concerned about the risk.

Baldwin: They’re never concerned. I’ve never had a GI doctor turn me down when I ask permission to put a patient on isotretinoin.

Zeichner: What about the association between isotretinoin and depression?

Baldwin: Two meta-analyses indicate that it’s not of concern. However, for depression, in my opinion, we should keep a high index of suspicion, especially in this patient population because the background noise is immense. This is the group, the 18- to 25-year-olds are the group that’s most likely to commit suicide in general and has the least mental stability of all of the patients that we treat. So we need to keep a high index of suspicion in this group and just make sure that that individual patient isn’t developing suicidal ideations.

Farberg: The association with depression is with acne, not
with isotretinoin.

Baldwin: I agree. It’s not the drug, it’s the disease and the time of life.

Zeichner: Both the Scandinavian studies [Isotretinoin and Risk Factors for Suicide Attempt: A Population-Based Comprehensive Case Series and Nested Case-Control Study Using 2010-2014 French Health Insurance Data]³ have shown fewer suicide attempts in patients on isotretinoin.

Kircik: We also know something that is totally new from the psoriasis population, that in psoriasis we always assume that people are depressed because of their disease, the way they look, but they’re also depressed because of increased IL-17 levels in the brain. Which we know, there’s IL-17 levels in acne patients. So I’m making that correlation.

Zeichner: It’s an exciting time to be a dermatologist treating acne because we have innovation in both the topical and systemic space to give our patients novel treatments that are both safe and effective, ultimately improving quality of life.

Disclosure

This Frontline Forum is supported by Sun Pharmaceutical Industries Ltd.

[Edited for space and clarity]

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Reference

3. Droitcourt C, Poizeau F, Kerbrat S, et al. Isotretinoin and risk factors for suicide attempt: a population-based comprehensive case series and nested case-control study using 2010-2014 French Health Insurance Data. J EurAcad Dermatol Venereol. 2020;34(6):1293-1301. doi:10.1111/jdv.16005