Purpose: Estimation of systemic exposure after skin absorption of any xenobiotic is very important in development of dermal pharmaceutical products as well as assessing exposures due to cosmetic products or environmental and occupational compounds. The Multi-Phase Multi-Layer Mechanistic Dermal Absorption (MechDermA) model is amechanistic absorption model with 4 formulation types and 8 application sites including specific skin physiology for these sites. The developed model is incorporated into the Simcyp simulator which is a ‘bottom-up’ IVIVE platform and database for mechanistic modelling and simulation of the drug disposition process using full body physiologically based pharmacokinetic modelling. In this abstract, we describe scientific background to the Multi-Phase Multi-Layer (MPML) MechDermA Model implemented in Simcyp simulator V17 and one of the elements of its performance verification based on the clinical cases using nicotine as a model drug.
Methods: The model performance has been assessed using nicotine as a model drug. Input data included model and drug parameters such as MW=162.2, pKa1= 3.12, pKa2= 8.02, LogP = -0.87,fusc=0.42, fniskin surface=0.01,Cli.v. =71.6 L/h, steady state volume of distribution Vss= 3 L/kg, and the skin surface pH=5.5. Diffusion and partition coefficients were calculated using QSAR models (see Table 1).
Case 1: This study reported by (Benowitz, Keith et al. 1991) included results for fourteen male heavy smokers aged 27 to 64 years (mean age 39). According to the study settings, each individual was given an i.v infusion of 0.87 mg/h of deuterium-labelled nicotine (nicotine-d2) for 24 hours (total dose 20.88 mg, at the same time the patch (TTS; Ciba-Geigy Corp., Ardsley, N nicotine-d0) was applied on the skin (lower abdomen). The patch was loaded with 52.5 mg (declared release rate – 0.9 mg/h) of drug to provide continuous and controlled release of nicotine after its application to intact skin.
Case 2: 13 males, aged 26±3 years were treated single dose of nicotine patch (Nicotinell TTS 30, declared release rate of 0.87 mg/h). The biopsy of subcutis was taken using “biopsy needle device” in 5 different sampling times (Schrolnberger, Brunner et al. 2001).
Results: Figure 1 and 2 present the superposition of a predicted nicotine in plasma and subcutis observed by Benowitz et al 1991 and (Schrolnberger, Brunner et al. 2001). Table 2 compares predicted and observed PK parameters, the observed pharmacokinetic parameters for nicotine infused and transdermal delivered were similar to those predicted. The difference between the model prediction and clinical data is well within the variability of such clinical studies. Benowitz et al 1991 observed that after the patch removal, the systemic absorption of nicotine was not suddenly interrupted, suggesting that some amount of drug remains in the skin, as it can be observed in Figure 1 with a slow plasma clearance after 24 hours. The subcutis concentration has a lag time of ~1 h compatible with lag time in plasma. The variability of skin physiology, biopsy technique and drug effect on skin blood flow could explain the over prediction of nicotine on subcutis.
Conclusion: The results demonstrate that the MPML MechDermA model prediction is in a good agreement with the reported clinical data. Furthermore, after verification with plasma concentration, such bottom-up model can predict the kinetic and bioavailability information in various skin layers and other organs, which may not be easily measured in clinical studies but are of particular importance for intended topical delivery. The impact of excipients on skin physiology was not directly accounted in this study, it is known that patch has multiple combinations of permeants to improve and control the drug release, but those were not reported in the papers. Once the excipients in formulation are known, a systematic modification of the skin physiology and drug parameters properties can be done to mimic more realistic scenario.