(W1230-02-07) Investigation of the Relationship between Product-Dose and Dermal Exposure of Lidocaine and Prilocaine from a Topical Cream Product Using Dermal Microdialysis

Purpose: The purpose of this study is to investigate the relationship between the product-dose applied and the dermal exposure of lidocaine (LDC) and prilocaine (PLC) following topical application of the LDC and PLC topical cream, 2.5%;2.5% at four product doses (3, 10, 20, and 30 mg/cm²) using dermal microdialysis (dMD) in a New Zealand rabbit model.

Methods: Nine microdialysis probes were inserted into the dorsum of each tranquilized rabbit (N=4) using a predetermined scheme (Figure 1). Two dMD probes were inserted under each of the (4) test sites, whereas the ninth probe was inserted more than 3 cm away from application sites to evaluate the potential redistribution of LDC and PLC into to the dermis due to systemic absorption and recirculation. The LDC and PLC topical cream, 2.5/2.5% (manufactured by Actavis Pharma Inc.) was applied at doses of 3, 10, 20, and 30 mg/cm² at each test site. All probes were perfused with 1.0 μL/min of normal saline solution containing 5 ng/mL deuterated LDC as probe marker. Dialysate samples were collected at predetermined timepoints for up to 14 hours. Samples were analyzed for LDC, PLC, and their metabolites monoethylglycinexylidide (MEGX) and ortho-toluidine (OTE). Area under the curve (AUC_0-14) for dermal concentration vs. time profile, maximum dermal concentrations (Cmax), and terminal half-life (t _1/2) were estimated.  The relationship between the product-dose applied and the dermal exposure parameters were evaluated.

Results: The average dermal concentration (mean ± SEM, N=4) profiles for LDC, PLC and their respective metabolites MEGX and OTE are shown in Figure 2. Investigation of the relationship between the product-dose and the exposure parameter AUC_0-14, indicates that the exposure increased with the increase in product dose in the range of 3-20 mg/cm², yet no further enhancement was observed between the 20 mg/cm² and 30 mg/cm² dose. Investigation into the metabolites exposure and its relationship with product dose and LDC/PLC exposure showed that the dermal metabolites exposure increased with increase in the product dose from 3 to 10 mg/cm². The amounts of LDC/PLC or dermal metabolites observed in the redistribution probes were negligible, indicating that the amounts of LDC, PLC, MEGX, OTE observed in dialysate samples  resulted from absorption of drug from the cream product into the skin and dermal metabolism of LDC/PLC in epidermis and dermis.

Conclusion: The observed relationship between product-dose and cutaneous pharmacokinetics for the LDC/PLC topical cream in this study suggests that dermal exposure plateaus at doses higher than 20 mg/cm². A previous study [1] on the dermal disposition of LDC and PLC when delivered directly to the dermis (using dermal infusion) at similar or higher drug concentrations, demonstrated that the dermal clearance, dermal volume of distribution, and dermal elimination half-life of LDC and PLC are independent of the dose delivered. Thus, it can be concluded that the non-proportional relationship between product dose and dermal exposure of LDC and PLC and their metabolites observed in this study are due to potential saturation of the absorption process or drug permeation from the dosage form into the skin, and not attributed to lack of proportionality in the distribution/elimination process or technical performance issues of the dMD probes. Therefore, a dose of less than 20 mg/cm² may be appropriate for a prospective bioequivalence( BE) study with LDC and PLC topical cream product. Study designs similar to the one described in this abstract can be potentially utilized during the method development to identify appropriate dose (in the sensitive portion of the dose-permeation curve) for a BE study.

References: Senemar, S., et al., Dermal Clearance, Elimination Half-life, and Apparent Volume of Distribution of Lidocaine And Prilocaine Are Independent of the Dose Delivered Directly in Dermis Using a Dermal Infusion Technique, in ASCPT 2022: Online Annual Meeting

Acknowledgments: This project was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of an award (U01FD006930) totaling $750,000 with 100 percent funded by FDA/HHS. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government.

Mapping of the probes and corresponding product- dose applied on the rabbit’s dorsum for one experiment. The dose-product pattern was randomized for each rabbit.



Dermal concentration time course observed at each dose for lidocaine and prilocaine and their metabolites, MEGX and OTE respectively. Data are presented as mean ± SEM for 4 rabbits.