The Impact of Systemic Redistribution on Cutaneous Pharmacokinetic-Based Bioequivalence: An In vivo Dermal Open Flow Microperfusion Study for Lidocaine and Prilocaine.

BACKGROUND: Cutaneous pharmacokinetics (PK) can be assessed using dermal open flow microperfusion (dOFM) and dermal microdialysis (dMD). However, the dermal vasculature can clear and redistribute compounds to the skin, which may affect an assessment of bioequivalence (BE). OBJECTIVE: This study verified the BE of a topical cream product to itself under high-dose conditions, evaluated the impact of systemic redistribution on BE assessment, and compared the performance of dOFM and dMD. METHODS: In this open-label exploratory clinical study, 15 dOFM and 6 dMD probes were inserted in each of 20 healthy subjects at three treated sites on each thigh, and one untreated site on the arm. Systemic redistribution was assessed by comparing lidocaine and prilocaine AUC0to12h at untreated versus treated sites, which collectively received 60 g of EMLA cream (lidocaine/prilocaine 2.5%/2.5%) applied across 400 cm2 per subject. The performance of dOFM and dMD was compared using dermal PK parameters and data variability. Applying a reference-scaled approach, BE was assessed using dOFM-derived logAUC0to12h and logCmax, both, with and without correction for systemic redistribution. RESULTS: The BE of EMLA to itself was confirmed using dOFM and was unaffected by systemic redistribution; despite the high dose and large treatment surface area, dOFM AUC0to12h values of untreated sites were ≤ 0.52% of treated sites. Under the standardized conditions of this study, dOFM and dMD exhibited comparable dermal PK profile characteristics. CONCLUSIONS: Systemic redistribution was negligible and did not alter the BE assessment. Under standardized conditions, dOFM and dMD showed comparable PK profile characteristics, supporting the potential utility of both dOFM and dMD for characterizing the dermal PK of moderately lipophilic, protein-bound topical drugs under standardized study conditions. GOV REGISTRATION: NCT03813030.