madman
Super Moderator
ABSTRACT
Since its approval in 1982, oral isotretinoin has revolutionized acne therapy. However, oral isotretinoin use has long been associated with challenges of variable bioavailability and food dependence. It is recommended to ingest oral isotretinoin with a high-fat meal in order to maximize absorption, but many patients fail to adhere to this recommendation. This may lead to inadequate isotretinoin absorption levels. Patients who fail to achieve isotretinoin target cumulative dose are more likely to experience symptom relapse. To address the challenge of traditional isotretinoin variable bioavailability, subsequent isotretinoin formulations have attempted to improve its absorption abilities. In 2014, an isotretinoin formulation utilizing Lidose technology, known as Absorica, showed significant improvements in absorption levels compared to traditional oral isotretinoin in the fasted state. In 2019, isotretinoin absorption levels were further advanced in a new formulation approved by the FDA known as Absorica LD. Utilizing advanced micronization technology that physically reduces the size of the drug molecule, Absorica LD exhibits twice the absorption levels of Absorica under fasting conditions. In the fed state, Absorica LD achieves similar plasma levels to Absorica with a 20 percent lower dose. Absorica LD also produces consistent serum isotretinoin levels irrespective of gastrointestinal contents. By eliminating the “food effect” seen in traditional oral isotretinoin, Absorica LD has the potential to improve patient adherence and long-term patient outcomes.
Introduction
Before isotretinoin, no other acne therapy targeted all four pathogenesis factors of acne (including hyper-keratinization, sebum production, Cutibacterium acnes proliferation, and inflammation).1,2 Rather, other non-isotretinoin treatments for acne are often used in combination to address multiple aspects of acne pathogenesis at once.3 Isotretinoin, available in the US for almost four decades, is an oral retinoid recommended as a first-line treatment option for treating severe nodular acne.3 In addition to severe nodular acne, oral isotretinoin is used for the treatment of moderate acne that is treatment-resistant or for the management of acne that causes physical scarring or psychosocial distress, or both.3 Over time, oral isotretinoin has revolutionized the management of severe and recalcitrant acne patients due to its ability to markedly induce acne clearance coupled with its ability to achieve prolonged remission.4,5Isotretinoin is the only treatment for which a single course of therapy has demonstrated complete or near-complete clearance of acne lesions and prolonged remission in the majority of patients with severe recalcitrant nodular acne.4,5
Although traditional oral isotretinoin has transformed acne management, its administration has faced several challenges. Notably, the bioavailability of traditional oral isotretinoin is variable and highly dependent on food administration. Isotretinoin, like other vitamin A derivatives, is a highly lipophilic molecule and its absorption is enhanced by a high-fat meal.6-8 Because of this, the maximal absorption of traditional isotretinoin depends on the consumption of a high-fat, high-calorie meal. Pharmacokinetics of traditional isotretinoin were performed with a standardized high-fat, high-calorie meal containing 50 grams of fat and 800 to 1000 calories.7,9 FDA guidance in 2002 recommended this test meal should derive approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and fat, respectively.9 When taking traditional isotretinoin without a high-fat meal, fasting isotretinoin plasma levels can be 60 percent lower than fed conditions.8 Furthermore, peak plasma concentrations of traditional oral isotretinoin between fed and fasted conditions can vary by a factor of nearly threefold, which may potentially affect both efficacy and safety.6
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.4,10,1
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 the 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 the 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
*Food Effects
*Safety Profile
Conclusions
While traditional oral isotretinoin has revolutionized acne management, its food-dependent nature and varying bioavailability represent critical challenges of its administration. Absorica LD, with its unique micronized technology, exhibits enhanced gastrointestinal absorption and bioavailability compared to Absorica and previous forms of oral isotretinoin.18Absorica LD produces consistent serum levels irrespective of gastrointestinal contents.18 By removing the “food effect” of previous formulations of oral isotretinoin, Absorica LD relieves patients from the requirement to ingest oral isotretinoin with a high-fat meal. Patients are able to administer Absorica LD on an empty stomach or with healthier meals (ie, low-fat, high-protein) without experiencing negative therapeutic consequences. With Absorica LD, we anticipate improved patient adherence and therefore improved long-term therapeutic outcomes.
Since its approval in 1982, oral isotretinoin has revolutionized acne therapy. However, oral isotretinoin use has long been associated with challenges of variable bioavailability and food dependence. It is recommended to ingest oral isotretinoin with a high-fat meal in order to maximize absorption, but many patients fail to adhere to this recommendation. This may lead to inadequate isotretinoin absorption levels. Patients who fail to achieve isotretinoin target cumulative dose are more likely to experience symptom relapse. To address the challenge of traditional isotretinoin variable bioavailability, subsequent isotretinoin formulations have attempted to improve its absorption abilities. In 2014, an isotretinoin formulation utilizing Lidose technology, known as Absorica, showed significant improvements in absorption levels compared to traditional oral isotretinoin in the fasted state. In 2019, isotretinoin absorption levels were further advanced in a new formulation approved by the FDA known as Absorica LD. Utilizing advanced micronization technology that physically reduces the size of the drug molecule, Absorica LD exhibits twice the absorption levels of Absorica under fasting conditions. In the fed state, Absorica LD achieves similar plasma levels to Absorica with a 20 percent lower dose. Absorica LD also produces consistent serum isotretinoin levels irrespective of gastrointestinal contents. By eliminating the “food effect” seen in traditional oral isotretinoin, Absorica LD has the potential to improve patient adherence and long-term patient outcomes.
Introduction
Before isotretinoin, no other acne therapy targeted all four pathogenesis factors of acne (including hyper-keratinization, sebum production, Cutibacterium acnes proliferation, and inflammation).1,2 Rather, other non-isotretinoin treatments for acne are often used in combination to address multiple aspects of acne pathogenesis at once.3 Isotretinoin, available in the US for almost four decades, is an oral retinoid recommended as a first-line treatment option for treating severe nodular acne.3 In addition to severe nodular acne, oral isotretinoin is used for the treatment of moderate acne that is treatment-resistant or for the management of acne that causes physical scarring or psychosocial distress, or both.3 Over time, oral isotretinoin has revolutionized the management of severe and recalcitrant acne patients due to its ability to markedly induce acne clearance coupled with its ability to achieve prolonged remission.4,5Isotretinoin is the only treatment for which a single course of therapy has demonstrated complete or near-complete clearance of acne lesions and prolonged remission in the majority of patients with severe recalcitrant nodular acne.4,5
Although traditional oral isotretinoin has transformed acne management, its administration has faced several challenges. Notably, the bioavailability of traditional oral isotretinoin is variable and highly dependent on food administration. Isotretinoin, like other vitamin A derivatives, is a highly lipophilic molecule and its absorption is enhanced by a high-fat meal.6-8 Because of this, the maximal absorption of traditional isotretinoin depends on the consumption of a high-fat, high-calorie meal. Pharmacokinetics of traditional isotretinoin were performed with a standardized high-fat, high-calorie meal containing 50 grams of fat and 800 to 1000 calories.7,9 FDA guidance in 2002 recommended this test meal should derive approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and fat, respectively.9 When taking traditional isotretinoin without a high-fat meal, fasting isotretinoin plasma levels can be 60 percent lower than fed conditions.8 Furthermore, peak plasma concentrations of traditional oral isotretinoin between fed and fasted conditions can vary by a factor of nearly threefold, which may potentially affect both efficacy and safety.6
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.4,10,1
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 the 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 the 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
*Food Effects
*Safety Profile
Conclusions
While traditional oral isotretinoin has revolutionized acne management, its food-dependent nature and varying bioavailability represent critical challenges of its administration. Absorica LD, with its unique micronized technology, exhibits enhanced gastrointestinal absorption and bioavailability compared to Absorica and previous forms of oral isotretinoin.18Absorica LD produces consistent serum levels irrespective of gastrointestinal contents.18 By removing the “food effect” of previous formulations of oral isotretinoin, Absorica LD relieves patients from the requirement to ingest oral isotretinoin with a high-fat meal. Patients are able to administer Absorica LD on an empty stomach or with healthier meals (ie, low-fat, high-protein) without experiencing negative therapeutic consequences. With Absorica LD, we anticipate improved patient adherence and therefore improved long-term therapeutic outcomes.
