Published online Feb 2, 2016. doi: 10.5314/wjd.v5.i1.57
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.
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.