Improving Bioavailability: A New Isotretinoin Formulation
Improving Bioavailability: A New Isotretinoin Formulation
Current practice guidelines recommend administration of oral isotretinoin with high-fat meals, which may pose issues with patient compliance. Isotretinoin-Lidose (Epuris), approved by Health Canada in November 2012 and scheduled for commercial release June 2013, is based on novel lipid encapsulation technology (Lidose®) to enclose isotretinoin, thereby increasing drug absorption during fasted states. An open label, single dose randomized crossover study demonstrated pharmacokinetic bioequivalence of isotretinoin-Lidose to standard isotretinoin formulations during fed states, with significantly greater absorption during fasting. Isotretinoin-Lidose, may lead to more consistent plasma levels of isotretinoin during variable dietary conditions, providing the potential for enhanced patient outcomes.
Since US FDA approval of the oral isotretinoin agent Accutane in 1982, and its subsequent approval by Health Canada in 1983, it has been and continues to be the standard of treatment for severe nodular acne in the US and Canada. As this agent is a synthetic derivative of vitamin A, it is similar to the parent compound in being fat-soluble. As a result, ingestion of oral isotretinoin with food increases bioavailability. In the fasted state, ingestion of standard oral isotretinoin formulations leads to plasma levels that are approximately 60% lower compared to the fed state. Accordingly, standard practice recommendations promote ingestion with food, particularly a high-fat meal, to enhance absorption.
However, patient adherence and reliability in taking isotretinoin with high-fat meals may be problematic. Inconsistent eating habits during drug administration may result in irregular dosing and considerable variation in plasma levels of isotretinoin, within and between patients. Thus, a previous unmet need with oral isotretinoin has been a formulation less dependent on the fed state to reduce this potential for suboptimal absorption and subtherapeutic plasma levels. Hoffman-La Roche Pharmaceuticals Inc., the manufacturer of Accutane the incumbent branded oral isotretinoin formulation, addressed this issue through the development of Accutane-NF (new formulation). This microionized version of Accutane was developed to reduce particle size, thereby increasing bioavailability. Accutane-NF was projected to result in therapeutic levels of isotretinoin with once-daily dosing and without the need for administration with food. A randomized, double-blind clinical trial comparing these two formulations in 600 patients with severe recalcitrant nodular acne showed that the overall efficacy of Accutane-NF was statistically similar to standard Accutane. However, the new formulation trended towards lower efficacy as demonstrated in the proportion of subjects achieving >90% reduction in nodule counts, including percentage changes with respect to nodule counts, papules/pustules, and total inflammatory lesion counts, as well as global evaluations of excellent response/clearance. At the dosages tested, a lower risk of mucocutaneous adverse event and hypertriglyceridemia were noted. However, in the absence of clear advantages of the new formulation compared to standard Accutane when considering the balance of efficacy to adverse events (benefit:risk), there was no apparent public health benefit to marketing both formulations.
Recently, this ongoing inadequacy was addressed with an innovative technology that encapsulates lipophilic drugs, such as isotretinoin, with lipid agents - thereby providing a more optimal environment for absorption within the formulation. Originally developed by SMB Laboratories, the Lidose® drug delivery system consists of a hard gelatin capsule containing liquid or semi-liquid contents composed of an active drug melted together with lipid excipients, then cooled under specific conditions. This technology has already been successfully combined with a fenofibrate formulation (Lipofen Cipher Pharmaceuticals Inc.) to create a novel capsule used for treatment of hyperlipidemia.
Potential advantages of Lidose® over conventional capsule technology include greater tolerability with less gastric irritation, rapid absorption, and protection of drug against oxidation. An application of this delivery platform encompassing oral isotretinoin-Lidose was approved by the US FDA in May 2012 (Absorica Cipher Pharmaceuticals Inc.) with indications for treatment of severe nodular and or inflammatory acne, acne conglobate, and recalcitrant acne. Health Canada approved isotretinoin-Lidose for the same indication in November 2012 (Epuris Cipher Pharmaceuticals Inc.).
Abstract and Introduction
Abstract
Current practice guidelines recommend administration of oral isotretinoin with high-fat meals, which may pose issues with patient compliance. Isotretinoin-Lidose (Epuris), approved by Health Canada in November 2012 and scheduled for commercial release June 2013, is based on novel lipid encapsulation technology (Lidose®) to enclose isotretinoin, thereby increasing drug absorption during fasted states. An open label, single dose randomized crossover study demonstrated pharmacokinetic bioequivalence of isotretinoin-Lidose to standard isotretinoin formulations during fed states, with significantly greater absorption during fasting. Isotretinoin-Lidose, may lead to more consistent plasma levels of isotretinoin during variable dietary conditions, providing the potential for enhanced patient outcomes.
Introduction
Since US FDA approval of the oral isotretinoin agent Accutane in 1982, and its subsequent approval by Health Canada in 1983, it has been and continues to be the standard of treatment for severe nodular acne in the US and Canada. As this agent is a synthetic derivative of vitamin A, it is similar to the parent compound in being fat-soluble. As a result, ingestion of oral isotretinoin with food increases bioavailability. In the fasted state, ingestion of standard oral isotretinoin formulations leads to plasma levels that are approximately 60% lower compared to the fed state. Accordingly, standard practice recommendations promote ingestion with food, particularly a high-fat meal, to enhance absorption.
However, patient adherence and reliability in taking isotretinoin with high-fat meals may be problematic. Inconsistent eating habits during drug administration may result in irregular dosing and considerable variation in plasma levels of isotretinoin, within and between patients. Thus, a previous unmet need with oral isotretinoin has been a formulation less dependent on the fed state to reduce this potential for suboptimal absorption and subtherapeutic plasma levels. Hoffman-La Roche Pharmaceuticals Inc., the manufacturer of Accutane the incumbent branded oral isotretinoin formulation, addressed this issue through the development of Accutane-NF (new formulation). This microionized version of Accutane was developed to reduce particle size, thereby increasing bioavailability. Accutane-NF was projected to result in therapeutic levels of isotretinoin with once-daily dosing and without the need for administration with food. A randomized, double-blind clinical trial comparing these two formulations in 600 patients with severe recalcitrant nodular acne showed that the overall efficacy of Accutane-NF was statistically similar to standard Accutane. However, the new formulation trended towards lower efficacy as demonstrated in the proportion of subjects achieving >90% reduction in nodule counts, including percentage changes with respect to nodule counts, papules/pustules, and total inflammatory lesion counts, as well as global evaluations of excellent response/clearance. At the dosages tested, a lower risk of mucocutaneous adverse event and hypertriglyceridemia were noted. However, in the absence of clear advantages of the new formulation compared to standard Accutane when considering the balance of efficacy to adverse events (benefit:risk), there was no apparent public health benefit to marketing both formulations.
Recently, this ongoing inadequacy was addressed with an innovative technology that encapsulates lipophilic drugs, such as isotretinoin, with lipid agents - thereby providing a more optimal environment for absorption within the formulation. Originally developed by SMB Laboratories, the Lidose® drug delivery system consists of a hard gelatin capsule containing liquid or semi-liquid contents composed of an active drug melted together with lipid excipients, then cooled under specific conditions. This technology has already been successfully combined with a fenofibrate formulation (Lipofen Cipher Pharmaceuticals Inc.) to create a novel capsule used for treatment of hyperlipidemia.
Potential advantages of Lidose® over conventional capsule technology include greater tolerability with less gastric irritation, rapid absorption, and protection of drug against oxidation. An application of this delivery platform encompassing oral isotretinoin-Lidose was approved by the US FDA in May 2012 (Absorica Cipher Pharmaceuticals Inc.) with indications for treatment of severe nodular and or inflammatory acne, acne conglobate, and recalcitrant acne. Health Canada approved isotretinoin-Lidose for the same indication in November 2012 (Epuris Cipher Pharmaceuticals Inc.).
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