title: Use of minipig skin biopsy model as an innovative tool to design topical formulation to achieve desired pharmacokinetics in humans.
abstract: In vitro cadaver skin permeation studies are often conducted to characterize the permeation profile of compounds for dermal delivery. However, its utility could be limited in the case of topical products because of lack of reliable prediction of in vivo skin kinetics. In this paper, the use of in vivo skin biopsy data to guide topical formulation development is described. A formulation was developed by compounding MK-0873, a phosphodiesterase 4 (PDE4) inhibitor, into a commercially available cream base. The cream was characterized by skin pharmacokinetic studies in minipigs, which demonstrated that MK-0873 concentrations in the epidermis and dermis were substantially higher than the IC80 for human whole blood PDE4 inhibition of ∼200 nM, suggesting that cream should provide sufficient skin exposure to assess clinical efficacy. In toxicological studies, after 1 month repeat application in minipigs minor dermal irritation and minimal systemic exposure were observed. Based on these preclinical data, the cream formulation was chosen for single rising dose clinical studies, where plasma levels of MK-0873 were mostly below the LOQ, whereas skin biopsy concentrations ranged from 6.5 to 25.1 μM. These data suggested that minipig skin biopsy model can be a valuable tool to assess performance of topical formulations and guide formulation development.
authors.affiliation: Pharmaceutical Sciences and Clinical Supply, Merck & Co. Inc.
authors.forename: Amitava
authors.initials: A
authors.lastname: Mitra
authors.forename: Aquiles
authors.initials: A
authors.lastname: Leyes
authors.forename: Kimberly
authors.initials: K
authors.lastname: Manser
authors.forename: Brad
authors.initials: B
authors.lastname: Roadcap
authors.forename: Christine
authors.initials: C
authors.lastname: Mestre
authors.forename: Daniel
authors.initials: D
authors.lastname: Tatosian
authors.forename: Lan
authors.initials: L
authors.lastname: Jin
authors.forename: Naoto
authors.initials: N
authors.lastname: Uemura
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001706:Biopsy; D002626:Chemistry, Pharmaceutical; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D006801:Humans; D009287:Naphthyridines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D009924:Organ Culture Techniques; D012869:Skin Absorption / Q000187:drug effects* / Q000502:physiology; D063465:Skin Cream / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013552:Swine; D013556:Swine, Miniature
chemical_list: C532496:MK 0873; D009287:Naphthyridines
keywords: absorption; biopsy; clinical pharmacokinetics; disposition; human; minipig; pharmacokinetics; skin; skin penetration; topical