Systematic Reviews
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Dermatol. Feb 2, 2016; 5(1): 57-64
Published online Feb 2, 2016. doi: 10.5314/wjd.v5.i1.57
Clinical pharmacokinetics profile of ivermectin 1% cream after dermal applications on the face
Khaled Benkali, François Rony, Michael Graeber, Jean Jacovella, Jean-Paul Chappuis, Marie-Helene Peirone, Michel Poncet, Stéphane Delage, Ronan Bouer, Nathalie Wagner
Khaled Benkali, François Rony, Jean Jacovella, Jean-Paul Chappuis, Marie-Helene Peirone, Michel Poncet, Stéphane Delage, Ronan Bouer, Nathalie Wagner, Galderma R and D, 06410 Biot, France
Michael Graeber, Galderma R and D, Princeton, NJ 08512, United States
Author contributions: Benkali K, Rony F and Wagner N were in charge of pharmacokinetics study designs and data analysis and interpretation; Graeber M and Jacovella J were in charge of the medical and safety aspects of the clinical studies; Benkali K wrote the Paper; Chappuis JP and Peirone MH were in charge of the project and clinical studies management; Poncet M was in charge of the statistical review and analysis; Delage S and Bouer R were in charge of the samples bioanalysis; all authors read and approved the final manuscript.
Conflict-of-interest statement: All authors declared that they are employees of Galderma R and D, SNC. Galderma R and D was the sponsor and funded all the clinical studies presented in this paper.
Data sharing statement: No raw or individual data will be shared.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Khaled Benkali PhD, Galderma R and D, Les Templiers, 2400, route des Colles, 06410 Biot, France.
Telephone: +33-4-92386865 Fax: +33-4-93957071
Received: July 2, 2015
Peer-review started: July 6, 2015
First decision: July 31, 2015
Revised: November 2, 2015
Accepted: November 23, 2015
Article in press: November 24, 2015
Published online: February 2, 2016

AIM: To investigate the pharmacokinetics profile of Ivermectin 1% cream after topical treatment in patients with papulopustular rosacea (PPR).

METHODS: Ivermectin 1% cream is a new, effective, and safe treatment for PPR. The human pharmacokinetic (PK) profile of ivermectin and its circulating metabolites were assessed following topical application of ivermectin 1% cream to the face. Clinical PK assessments were conducted after 4 wk of treatment using healthy volunteers and PPR subjects. Additionally, PK sampling was conducted up to 1 year of treatment in clinical phase 3 studies. Plasma concentrations of ivermectin and ivermectin metabolites were determined using high-performance liquid chromatography with fluorescence detection after a specific derivation to increase sensitivity.

RESULTS: Systemic exposure to ivermectin was quantifiable at low levels in healthy and moderate to severe PPR subjects following the first topical application of ivermectin 1% cream (mean Cmax of 0.5 ± 0.2 ng/mL and 0.7 ± 0.5 ng/mL in healthy volunteers and PPR subjects, respectively). Ivermectin plasma levels reached a plateau after 2 wk of repeated topical application, indicating that steady-state concentrations had been reached. No further ivermectin plasma accumulation was observed during the long-term clinical studies that investigated ivermectin treatment up to 1 year. Investigation of ivermectin metabolites indicated that 2 circulating metabolites represented more than 10% of parent drug systemic exposure at steady state. Repeated topical application of ivermectin 1% cream resulted in lower systemic exposure levels when compared with orally administered ivermectin, suggesting limited transdermal absorption of ivermectin. Topically applied ivermectin is cleared from the plasma slowly (with a prolonged plasma half-life when compared to the oral route).

CONCLUSION: Applications of ivermectin 1% cream result in low systemic exposure levels. Steady–state conditions are achieved by 2 wk without further accumulation under chronic treatment.

Keywords: Ivermectin, Pharmacokinetic maximal usage trial, Metabolites, Plasma and rosacea

Core tip: Papulopustular rosacea (PPR) is a chronic skin disease affecting patients face, with a dramatic impact on social and professional interactions. Ivermectin 1% cream is a new effective and safe treatment for PPR recently approved in many countries. This article presents the clinical pharmacokinetics (PK) assessments conducted during the drug development of Ivermectin 1% cream. Usually, for topical products, PK assessments are incomplete due to the low systemic exposure. For ivermectin cream, a comprehensive PK and metabolism program was conducted in healthy volunteers and PPR patients up to 1 year treatment. These provided valuable information to better assess ivermectin safety profile.