Dermal disposition characterization and development of a retrospective level A in vitro–in vivo relationship for topical metronidazole products

Abstract

Dermal microdialysis involves the insertion of a probe into the dermis beneath an application site for a topical drug product (TDP). The probe measures local, unbound, active pharmaceutical ingredient (API or drug) concentrations in the dermis. The resulting dermal concentration-time profile is a combination of the simultaneous drug absorption and disposition (by distribution/elimination into surrounding tissues and into the dermal vasculature). For orally or subcutaneously administered drug products, the absorption process is estimated through deconvolution of plasma concentrations utilizing the unit impulse response (UIR) obtained from an intravenous administration. In this study, we implemented a retrodialysis/microdialysis (termed “dermal infusion”) approach to deliver metronidazole (MTZ) directly into the dermis allowing measurement of dermal disposition parameters (dermal clearance and dermal volume of distribution) and thus the calculation of MTZ’s dermal UIR (dUIR); The dUIR allowed for the estimation of the absorption process or in vivo dermal flux (input-rate) and cumulative amount (CA) permeated from MTZ TDP application. The in vivo (Yucatan mini-pig) CA permeated were compared with in vitro permeation testing data (human) to build a retrospective in vitro - in vivo relationship (IVIVR). The internal validation for C_max and AUC_0–48hr prediction errors indicated a reliable IVIVR. These results suggest that the dermal infusion approach can be used to study dermal API disposition, which can aid in the comprehension of in vivo cutaneous pharmacokinetic (cPK) data. Furthermore, a mechanistic cPK understanding is essential for the successful development of new topical therapeutics and assessment of bioequivalence of TDPs, alike.