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Biorelevant In Vitro Skin Permeation Testing and In Vivo Pharmacokinetic Characterization of Lidocaine from a Nonaqueous Drug-in-Matrix Topical System.

ABSTRACT: Recently, lidocaine topical systems utilizing nonaqueous matrices have been developed and provide efficient lidocaine delivery through the skin, such that lower concentrations of drug provide equivalent or greater drug delivery than drug-in-matrix hydrogel lidocaine patches. This study characterizes drug delivery from a nonaqueous lidocaine topical system with increasing drug load both in vitro and in vivo. Topical systems formulated with either 1.8% or 5.4% lidocaine were applied to healthy volunteers' backs (n = 15) for 12 h in a single-center, open-label, four-treatment, four-period crossover pharmacokinetic study. Subjects were dosed with either three 1.8% systems or one, two, or three 5.4% systems in each period. Blood was collected for up to 48 h, and plasma lidocaine levels were measured with a validated HPLC method. In parallel, human and mouse skin models characterized the in vitro skin permeation profile. The pharmacokinetic profile was linear between one, two, and three lidocaine 5.4% applications. Application of three lidocaine 1.8% systems (108 mg lidocaine) was bioequivalent to one lidocaine 5.4% system (108 mg lidocaine). Both topical systems remained well adhered to the skin and irritation was mild. The 5.4% system had approximately threefold higher skin permeability than the 1.8% system in the mouse and human skin models. The results indicate increasing the drug load by three times results in triple the drug delivery both in vivo and in vitro. The relationship between the in vitro permeation and in vivo absorption correlates and is nonlinear.

SUBMITTER: Greuber E

PROVIDER: S-EPMC8360843 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundStaphylococcal infection of the canine epidermis and hair follicle is amongst the commonest reasons for antimicrobial prescribing in small animal veterinary practice. Topical therapy with fusidic acid (FA) is an attractive alternative to systemic therapy based on low minimum inhibitory concentrations (MICs, commonly <0.03 mg/l) documented in canine pathogenic staphylococci, including strains of MRSA and MRSP (methicillin-resistant Staphylococcus aureus and S. pseudintermedius). However, permeation of canine skin by FA has not been evaluated in detail. This study aimed to define the degree and extent of FA permeation in canine skin in vitro from two sites with different hair follicle density following application of a licensed ophthalmic formulation that shares the same vehicle as an FA-betamethasone combination product approved for dermal application in dogs. Topical FA application was modelled using skin held in Franz-type diffusion cells. Concentrations of FA in surface swabs, receptor fluid, and transverse skin sections of defined anatomical depth were determined using high-performance liquid chromatography and ultraviolet (HPLC-UV) analysis.ResultsThe majority of FA was recovered by surface swabs after 24 h, as expected (mean ± SEM: 76.0 ± 17.0%). FA was detected within 424/470 (90%) groups of serial sections of transversely cryotomed skin containing follicular infundibula, but never in 48/48 (100%) groups of sections containing only deeper follicular structures, nor in receptor fluid, suggesting that FA does not permeate beyond the infundibulum. The FA concentration (mean ± SEM) in the most superficial 240 μm of skin was 2000 ± 815 μg/g.ConclusionsTopically applied FA can greatly exceed MICs for canine pathogenic staphylococci at the most common sites of infection. Topical FA therapy should now be evaluated using available formulations in vivo as an alternative to systemic therapy for canine superficial bacterial folliculitis.

Project description:PurposeThis study compares the pharmacokinetic (PK) profile, adhesion, and safety of lidocaine topical system 1.8%, a novel lidocaine topical system approved to treat postherpetic neuralgia, under conditions of heat and exercise vs normal conditions.Materials and methodsThis open-label, 3-period, 3-treatment crossover study randomized 12 healthy adults to receive three lidocaine topical systems 1.8% during each of three treatment periods, with 7-day washouts between treatments. The product was applied to the mid-lower back and was removed after 12 hours. During Treatment A, subjects exercised on a bicycle for 30 minutes at 0, 2.5, 5.5, and 8.5 hours. During Treatment B, heat (temperature set at 36.7-40.3°C) was applied at 0 and 8.5 hours. Treatment C was normal conditions. The PK profile of each subject under exercise and heat conditions was compared to normal conditions. Skin irritation, adhesion, and adverse events were assessed.ResultsTwelve subjects completed the study. Exposure to external heat resulted in increased peak plasma concentration of lidocaine with a mean Cmax of 160.3±100.1 ng/mL vs 97.6±36.9 ng/mL under normal conditions, with no effect on the extent of exposure (AUC). Concentrations returned to normal within 4 hours after the heat was removed. No clinically relevant differences in absorption were observed under exercise conditions with a mean Cmax of 90.5±25.4 ng/mL and no effect on the extent (AUC) of lidocaine exposure was observed relative to normal conditions. No systems detached during the study. Adverse events were mild, with none leading to discontinuation.ConclusionTransient heat exposure resulted in increased lidocaine plasma concentrations compared to normal conditions, whereas exercise had no effect. The effects of heat appear to be immediate, reversible, and below systemic therapeutic threshold in antiarrhythmic treatment (1000-1500 ng/mL), and well below the safe systemic threshold of 5000 ng/mL. Lidocaine topical system 1.8% remained adhered to the skin and was well tolerated under all conditions. ClinicalTrials.gov: NCT04150536.

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Biorelevant In Vitro Skin Permeation Testing and In Vivo Pharmacokinetic Characterization of Lidocaine from a Nonaqueous Drug-in-Matrix Topical System.

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