Dermal Concentration Versus Systemic Bioavailability of Topical Lidocaine and Tetracaine: An Exploratory...

Background: Lidocaine, classified as an amide-type agent, and tetracaine, designated as an ester-type agent, are frequently co-formulated for dermatologic procedures. Despite the extensive literature on the pharmacokinetics (PK) of these substances, there is a paucity of head-to-head comparisons of intravenous (IV) and topical administration in the same preclinical model. Absolute bioavailability (F%) is imperative for optimizing formulation design and safety. Methods: A single-dose, single-sequence, three-period pilot study was performed in male Göttingen mini-pigs. The first period of the study involved the intravenous bolus administration of lidocaine HCl and tetracaine HCl, with a dosage of 1 mg/kg for each agent. In Period 2, the topical application of Pliaglis (a combination of 7% lidocaine and 7% tetracaine, with a concentration of 10 g/100 cm² and a duration of 60 min) was utilized. In Period 3, the pharmacokinetic profile of Z4T4L4 (a formulation comprising 4% lidocaine HCl and 4% tetracaine HCl) was assessed under the same experimental conditions. Blood samples were collected up to 24 h after the administration of the drug; skin biopsies were obtained 90 min after the application of the test substance. Plasma and skin concentrations were measured by means of validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK parameters were derived using a noncompartmental analysis approach, while F% was calculated through AUC comparison with IV dosing. Results: Subsequent to intravenous administration, the mean elimination half-lives of lidocaine and tetracaine were determined to be 1.62 h and 1.85 h, respectively. Pliaglis demonstrated higher skin concentrations of lidocaine (358 μg/g) and tetracaine (465 μg/g) compared to Z4T4L4 (33.6 μg/g and 46.1 μg/g, respectively). Despite lower skin levels, Z4T4L4 produced higher F% (lidocaine: 1.98% vs. 1.41%; tetracaine: 3.34% vs. 1.26%). The time to maximum plasma concentration (T_max) for lidocaine was found to be 2-4 h (Pliaglis) and 2-8 h (Z4T4L4), while for tetracaine, it was 1-8 h (Pliaglis) and 2-8 h (Z4T4L4). Conclusions: In this preliminary study, which included three subjects, Z4T4L4 exhibited a numerical tendency towards increased systemic bioavailability in comparison with Pliaglis. This observation was noted despite the fact that Z4T4L4 resulted in markedly lower skin concentrations. Due to the exploratory nature of the pilot study (n = 3), observed differences are reported as numerical trends. The data suggest that Z4T4L4 may enhance systemic absorption while reducing skin retention, highlighting a potential formulation-dependent dissociation between local concentration and systemic bioavailability. These preliminary findings provide in vivo evidence of a divergence between eutectic-based tissue retention and enhancer-driven systemic flux. This highlights that formulation design fundamentally dictates the safety profile of local anesthetics, necessitating a balance between local efficacy and systemic safety.