Advances in Acne Management and Patient Adherence

Jerry Tan, MD, FRCPC^1,2 and Sanja Knezevic, BSc¹

¹Department of Medicine, University of Western Ontario, London, ON, Canada
²Windsor Clinical Research Inc., Windsor, ON, Canada

Introduction

Acne vulgaris is a multifactorial disease characterized by different types of lesions at various stages of development. Treatment options must address a spectrum of disease from mild to severe; and encompasses topical to systemic agents, respectively. For all acne therapy however, adherence remains an issue. Advances in delivery mechanisms have been developed to improve patient compliance with both topical and systemic modalities. Most recently, the novel lipid technology (Lidose®) has been utilized in the administration of oral isotretinoin. CIP-Isotretinoin (Epuris™), approved by Health Canada in November 2012 and released commercially in June 2013, enhances drug absorption during fasted states and lessens the need for administration with a high-fat meal, thereby potentially improving bioavailability and patient adherence.

UVA and UVB Light-Induced Skin Reactions

• Acne treatment selection is generally based on the severity and type of lesions, with the goal of treatment being to reduce sebum production, infundibular occlusion, inflammation and Propionibacterium acnes proliferation.
• Conventional topical therapies were originally composed of single agent preparations.
• Improved knowledge of acne pathogenesis and topical formulation chemistry led to development and clinical application of combination products (Table 1).
• Recent studies have demonstrated greater efficacy and tolerability with combination therapy compared to monotherapy.
• As a result, current consensus guidelines recommend the use of combination treatment as first-line therapy for most patients with mild to moderate acne.
• Notwithstanding efficacy, issues such as irritation and the emergence of bacterial resistance to both topical and oral antibiotics remain significant barriers to improved treatment outcomes.
• It is estimated that 30-40% of patients using topical formulations do not adhere to their prescribed regimen.¹

Improving Patient Adherence to Topical Therapy

• Treatment efficacy, local tolerance and adherence have all been improved through recent advances in vehicle technology.²
• Additionally, delivery mechanisms such as pumps which provide convenience, are preferred by patients and may improve adherence.³
• In a Patient Preferences in Acne: A Point-of-Care Educational Initiative, a national survey of 1709 Canadian patients showed that pump delivery systems are the preferred format (42% of patients).³
• However, patient preferences have been shown to extend beyond treatment side-effects: variables such as vehicle composition, messiness, texture, aroma, difficulty of use, lack of early improvement, and staining, can all decrease compliance.⁴
• Many new topical acne formulations have aqueous-based gel vehicle delivery systems that do not contain alcohol and are suitable for use in all skin types as they are less drying.
• Topical acne agents can cause cutaneous irritation related in part to impaired epidermal barrier function.⁵ Therefore:
  • the use of gentle cleansers and moisturizers has been shown to reduce this cutaneous irritation;⁶
  • moisturizers containing ceramides can improve skin barrier function.
• Additionally, vehicle advances, such as microsphere technology and solubilized crystalline formulations, reduce the potential of irritation from tretinoin.
• Photodegradation is not increased with microsphere tretinoin, tazarotene and adapalene, allowing for morning application.
• Clindamycin/BPO formulations with humectants and emollients may reduce the dry skin associated with BPO use.
• Clindamycin/BPO formulations without preservatives may reduce the irritation associated with these agents.⁷
• The addition of BPO to topical antibiotic agents and the use of BPO with long-term oral antibiotics can reduce the risk of cutaneous bacterial resistance.

Systemic Treatment for Severe Acne

Oral Isotretinoin

• Since US FDA approval of the oral isotretinoin agent Accutane™ in 1982, and its subsequent approval by Health Canada in 1983, it has remained the standard of treatment for severe nodular acne in Canada.
• Oral isotretinoin is a synthetic derivative of vitamin A, and is similar to the parent compound in being highly fat-soluble.
• As a result, ingestion of oral isotretinoin with food increases its bioavailability.⁸
  • In the fasted state, ingestion of standard oral isotretinoin formulations leads to plasma levels that are approximately 60% lower compared to the fed state.⁸
  • 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 inconsistent.^9-11
• Irregular eating habits may result in irregular dosing and therefore variable drug absorption.

CIP-Isotretinoin (Epuris™)

• CIP-Isotretinoin (Epuris™) was approved by Health Canada in November 2012 and launched in June of 2013.
  • It utilizes Lidose® technology to imbed isotretinoin in a lipid matrix, thereby increasing drug absorption during fasted state.¹²
  • CIP-Isotretinoin may lead to more consistent plasma levels of isotretinoin during variable dietary conditions, providing the potential for enhanced patient outcomes.
• Particularly for those with irregular eating times, treatment adherence may be improved as the absorption of the drug is better than the standard formulation in the absence of a high fat meal.
• This technology has already been successfully combined with a fenofibrate formulation (Lipofen™) to create a novel capsule used for treatment of hyperlipidemia.
• An application of this delivery platform encompassing oral CIP-Isotretinoin was approved by the US FDA in May 2012 (Absorica™) with indications for treatment of severe nodular and or inflammatory acne, acne conglobate, and recalcitrant acne.

Efficacy & Safety

• An open label, single dose randomized crossover study demonstrated pharmacokinetic bioequivalence of CIPIsotretinoin to standard isotretinoin formulations during high fat fed states, with significantly greater absorption during fasting.¹³
  • In the fasted state, the absorption of CIP-Isotretinoin, was approximately 83% greater than that of conventional isotretinoin.
  • The products were bioequivalent when taken with a high fat meal.¹³
• In a double-blind, randomized, controlled trial comparing CIP-Isotretinoin under high fat fed conditions to a currently marketed formulation of oral isotretinoin (Accutane™), 925 subjects with severe recalcitrant nodular acne aged 12-54 years were recruited.⁸ Subjects had to have at least 10 acne nodules on the face and/or trunk.
  • The number of responders, defined as those with ≥90% reduction in nodules at end of study compared to baseline, was similar in both treatment groups with overlapping 95% confidence intervals in per protocol (79% CIPIsotretinoin versus 81% Accutane™) and intent-to-treat (70% versus 75%) analyses.
  • Furthermore, the mean reduction in nodules in both groups was similar for both analyses (-17 versus -16, -16 versus -16, respectively), demonstrating clinical noninferiority.
  • Almost all patients experienced at least one adverse event in both groups at a similar rate (92% with CIP-Isotretinoin to 90% with Accutane™).¹⁴
  • Reported adverse events were typical for oral isotretinoin use, with the majority related to dry skin and cheilitis.¹⁴
  • Rates of serious adverse events occurring with the use of both CIP-Isotretinoin and standard oral isotretinoin were low (5/464 or 1.1% and 7/464 or 1.5%, respectively).¹⁴
  • Adverse events leading to discontinuation of participation occurred in 4.1% (19/464) of patients with CIPIsotretinoin, compared to 3.3% (15/460) of patients with standard oral isotretinoin.

Dosage & Administration

• Capsules of CIP-Isotretinoin are available in 10 mg (yellow), 20 mg (red), 30 mg (brown), and 40 mg (brown and red) doses in packages of 30 capsules (3 x 10 blister cards), which provides for flexible, individualized dosing according to the patient’s weight and disease severity.
• Inactive ingredients in this formulation include: stearoyl macrogolglycerides, soybean oil, sorbitan monooleate, and propyl gallate.
• Accutane™ is currently available in Canada in 10 mg (pink), and 40 mg (orange) doses in blister packages of 30 capsules. Ingredients include beeswax, black iron oxide, gelatin, glycerol, soybean and peanut oils, parabens, shellac, and titanium dioxide.
• To prevent potential allergic reactions, Accutane™ should particularly be avoided in patients with sensitivities to peanut oil and parabens, in addition to the aforementioned contents.
• As with standard isotretinoin formulations, the starting dose of CIP-Isotretinoin should be administered according to the patient’s weight and severity of the disease.
• In general, patients should initially receive CIP-Isotretinoin 0.5 mg/kg body weight daily for 2-4 weeks while monitoring their responsiveness to the drug.¹⁴
• Maintenance dose should be adjusted between 0.1 mg and 1 mg/kg body weight daily, depending on response and tolerance.
• A complete course of therapy consists of 12-16 weeks of CIP-Isotretinoin administration.¹⁴
• In view of differences in bioavailability, CIP-Isotretinoin is not interchangeable with standard oral isotretinoin formulations.
• As with any oral retinoid treatment, the need for ongoing pregnancy prevention and safety monitoring is of paramount concern.
• Generally, the side effects of oral isotretinoin have been well characterized, with the most common ones being mucocutaneous and mild.
• It is recommended to initiate CIP-Isotretinoin treatment at a low dose of 0.5 mg/kg/day for 2-4 weeks to assess drug tolerance.

Conclusion

Advances in delivery technologies for mild, moderate and severe acne are improving treatment adherence. Additionally, in mild to moderate acne, a greater understanding of acne pathogenesis has led to the development of effective combination treatments. In severe nodular acne, the novel CIPIsotretinoin formulation has been designed to reduce variation in bioavailability during fed and fasted states. In the context of clinical use, where patients may be unable to consistently take oral isotretinoin with a high-fat meal, this product enhances bioavailability and has the potential of improving clinical outcomes.

References

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14. Epuris™ [Product monograph]. March 14, 2013. Cipher Pharmaceuticals Inc., Mississauga, ON.