ARTICLE: Advances in Oral Isotretinoin Therapy

May 2021 | Volume 20 | Issue 5 | Supplement Individual Articles | s5 | Copyright © May 2021

Published online April 23, 2021

Madison Jones BA,a April W. Armstrong MD MPH,a Hilary Baldwin MD,b Linda Stein Gold MD,c Leon H. Kircik MDd

aDepartment of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA
bDepartment of Dermatology, Rutgers Robert Wood Johnson Medical Center, New Brunswick, NJ; The Acne Treatment and Research Center, Brooklyn, NY
cDepartment of Dermatology, Detroit, MI; Division of Dermatology, West Bloomfield, MI
dIcahn School of Medicine at Mount Sinai, New York, NY; Indiana University Medical Center, Indianapolis, IN; Physicians Skin Care, PLLC; DermResearch, PLLC; Skin Sciences, PLLC, Louisville, KY

Taking isotretinoin without a high-fat meal can reduce the effectiveness of a course of therapy. Although patients are advised to take traditional oral isotretinoin with a meal, many patients skip meals.5,8 Adolescents and young adults, the predominant patient population receiving acne therapy, tend to exhibit inconsistent eating patterns. This inconsistent eating can introduce variability with gastrointestinal absorption after oral isotretinoin ingestion. Furthermore, very few patients consume a high-fat, high-calorie meal with each dose of isotretinoin twice a day throughout the 15- to 20-week course of therapy.5,8 Failure to ingest each dose of traditional isotretinoin with a high-fat meal can result in decreased absorption of the dose, fluctuations in drug plasma levels, and decreased cumulative exposure to isotretinoin therapy.5 If the target cumulative dose for isotretinoin is not achieved, patients are more likely to relapse and require subsequent courses of therapy.4,10,11

In order to improve the absorption and bioavailability of isotretinoin, advancements have been made with subsequent formulations. The initial brand formulation of oral isotretinoin, Accutane, was approved by the FDA in 1982. Accutane served as the reference comparator against which other subsequent formulations of oral isotretinoin were developed over time.12 Since Accutane’s patent expired in 2002, several branded generic formulations of oral isotretinoin have become available in the US. These formulations have all been officially rated as bioequivalent with Accutane. These branded generic formulations include Amnesteem (approved November 2002), Sotret (approved December 2002), Claravis (approved April 2003), Myorisan (approved January 2012), and Zenatane (approved April 2013).12 In 2009, the manufacturer of Accutane discontinued availability of the drug in the US.

In 2012, Absorica became the second non-generic formulation (after Accutane) to be approved by the FDA. Absorica was a new formulation that aimed to increase gastrointestinal absorption levels by utilizing Lidose technology. Lidose technology is a lipid encapsulation technology in which isotretinoin is partially pre-solubilized in a lipid matrix.13,14 This technology protects the active drug ingredient against air and moisture and increases the dissolution speed of the drug molecule, allowing for greater gastrointestinal absorption compared to other isotretinoin formulations when not administered by a high-fat, high-calorie meal.13-16 Absorica demonstrated bioequivalence to Accutane in the fed state, enabling its approval through the 505(b)(2) pathway. In addition, Absorica exhibited improved absorption in the fasted state when compared to Accutane. Compared to a 60 percent reduction in bioavailability of Accutane when taken on an empty stomach, Absorica bioavailability was reduced by only 33 percent when administered on an empty stomach compared with concomitant administration of high-fat, high-calorie meals.8,16 Despite this reduction in bioavailability and contrary to that for conventional isotretinoin, the Absorica package insert states that Absorica may be taken with or without meals.15 In 2019, Del Rosso and coworkers provided clinical evidence supporting this statement demonstrating that consumption of Absorica in the fasted state resulted in a low relapse in the 2-year period following completion of a 20-week course.17 In 2014, additional dosage strengths of Absorica were approved, which were unique and allow greater flexibility and precision in body weight-based dosing.

In an effort to further increase absorption, Absorica LD was developed using specific micronized technology and was approved by the FDA in 2019. Different from Absorica’s Lidose technology, Absorica LD’s micronization technology physically reduces the drug to micrometer size. Absorica LD is a micronized formulation of isotretinoin that delivers predictable absorption at a level two times greater than Absorica in a fasted state.18 Absorica LD is the only micronized isotretinoin and has no generic equivalent.

Benefits of Micronization
With its micronization technology, Absorica LD demonstrated improved absorption, allowing for a 20 percent decrease in dose across the board compared to generic isotretinoin. At a 20 percent lower dose, Absorica LD 32mg demonstrated bioequivalent drug levels to Absorica 40mg in the fed state and twice the bioavailabilty in the fasted state.18 Recommended daily dosage for Absorica LD should be individualized based on the patient’s body weight and is recommended at 0.4–0.8mg/ kg/day (20 percent less than the 0.5–1.0mg/kg/day for generic isotretinoin) in two divided doses with or without meals for a period of 15–20 weeks.15 The American Academy of Dermatology (AAD) recommended a cumulative dose for generic isotretinoin of 120–150 mg/kg and the recommendation for Absorica LD is 20 percent less: 100–120mg/kg.3 Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require Absorica LD dosage adjustments up to 1.6mg/kg/day (20 percent less than the 2.0mg/kg/day for generic isotretinoin) in divided doses as tolerated.15 The safety and efficacy of once daily dosing with Absorica LD has not been established.15

Traditional isotretinoin has poor aqueous solubility.19 Micronization is a strategy that was developed in an effort to improve and maximize the dissolution rate of drug molecules with limited aqueous solubility. Micronization involves the physical process of reducing drug particles to micrometer size.20 The micronization of isotretinoin substantially increases the surface area per particle compared to other isotretinoin formulations. 21,22 Through increased surface area, micronization increases the rate of isotretinoin drug dissolution.21,22 With its micronization technology, Absorica LD demonstrates twice the plasma levels of isotretinoin compared with Absorica in the fasted state.18 Thus, dose recommendations are different