Pharmacokinetics of ingenol mebutate gel under maximum use conditions in large treatment areas

Abstract

Purpose: Actinic keratoses (AKs) exist on a continuum with squamous cell carcinoma and can occur as sub-clinical and clinically visible lesions in cancerized fields on sun-damaged skin. Ingenol mebutate effectively treats AKs on areas up to 25 cm², but actinic keratosis can affect larger areas of skin. This trial evaluated systemic exposure and safety of ingenol mebutate gel on larger areas of skin under maximum use conditions.

Methods: Phase I, multicenter, open-label, uncontrolled, non-randomized trial. Patients received ingenol mebutate gel for three consecutive days on approximately 250 cm² of sun-damaged skin on the full face (0.027%), the scalp (0.027%), or arm (0.06%).

Results: Of 61 patients, 10 (face =8; arm =2) had ingenol mebutate in whole blood at subnanomolar levels (0.235–0.462 nM). The assayed metabolites were below the lower limit of quantification. Local skin responses increased during Days 1–4 and declined thereafter, approaching baseline by Day 16. Most adverse events were pain/pruritus of mild or moderate intensity.

Conclusions: Subnanomolar systemic exposure to ingenol mebutate was measured after application of the gel to approximately 250 cm² on the full face, scalp, or arm under maximum use conditions. No clinically relevant systemic adverse reactions were observed, and local skin responses were manageable.

Keywords:

• Actinic keratosis
• ingenol mebutate
• systemic exposure
• safety

Acknowledgements

LEO Pharma is sponsor of the trial (ClinicalTrials.gov: NCT02124239) and representatives from LEO Pharma were involved in the design and conduct of the trial; collection, management, analysis, and interpretation of data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. None of the authors received financial compensation for authoring the manuscript. Medical writing services were provided by Patrick Griffin, MSc, of iMed Comms, an Ashfield Company, part of UDG Healthcare plc.

Disclosure statement

Dr. Bucko has received funding for conducting clinical research in the area of actinic keratosis from LEO Pharma, GLK, Teva, Perrigo and Watson pharmaceutical companies. Dr Jarratt has served as a consultant for Allergan, Athenex, Dermira, and Valeant; and has been a principal investigator for Allergan, Amgen, Anacor Pharmaceuticals, Inc., Bayer Pharmaceutical/Intendis, Dermira, Galderma, Leo Pharma A/S, Lilly Research Laboratories, McNeil PPC (Johnson & Johnson), Maruho North America, Inc., Merck & Co, Merz Pharmaceuticals, Novartis, Perrigo, Pfizer, Photocure ASA, Tolmar, Inc., Topica Pharmaceuticals, Inc., Valeant Pharmaceuticals Inc. Dr Stough reports fees from LEO Pharma during the conduct of the study. Laerke Kyhl, Johan Villumsen and Anders Hall are employees of LEO Pharma.

Additional information

Funding

This work was supported by LEO Pharma Research Foundation is sponsor of the trial (ClinicalTrials.gov: NCT02124239).