Development of the Dermal Absorption Model for the Ketoprofen Local and Systemic Exposure Prediction

Development of the dermal absorption model for the ketoprofen local and systemic exposure prediction

Sebastian Polak1,2, Nikunjkumar Patel1 1Simcyp (a Certara company), Sheffield, United Kingdom, 2Jagiellonian University Medical College, Kraków, Poland

Introduction Table 2. Partition and diffusion parameters for ketoprofen. Parameter Value [unit] Source The ketoprofen Ketoprofen is a nonsteroidal anti-inflammatory agent (NSAIA) with analgesic specific parition Kpsc_lip:vehicle 162.5451 predicted – Hansen 2013 and antipyretic properties. Topically applied drug is formulated in the form of and diffision Kp 6.9144 predicted – Kretsos 2008 patches, gels, or solutions. The main aim of the project was to develop sc:ve coefficients used physiologically-based pharmacokinetic (PBPK) model allowing for the Kpdermis:ve 1 assumed as the input quantitative assessment of the local (muscle) and systemic exposure after Kpsebum:vehicle 1643.341 predicted – Valiveti 2008 parameters are topical application of ketoprofen. Additionally the developed model have presented in Kpskin:blood 2.67544 predicted – Shatkin&Brown 1991 been verified against the literature derived clinical data. Table 2. Kpsebum:ve 0.0989 calculated – Kplip:vehicle/Kpsebum:vehicle 2 Materials and Methods Dsc_lip 3.392E-06 [cm /h] predicted – Mitragotri 2003 D 0.000311 [cm2/h] predicted – Bunge&Cleek 1995 Simcyp Simulator V17 with the MPML MechDermA model was used for the ve 2 ketoprofen dermal disposition [1]. Ddermis 0.000311 [cm /h] predicted – Kretsos 2008 D 0.000653 [cm2/h] predicted – Johnson 1996 Figure 1. MPML MechDermA Model Structure sebum The SC is modelled as fu sc 0.0934 predicted – Polak 2016 brick-and-mortar f 1 assumed Deff Formulation structure where bricks ni, corneocytes veh (Aqueous, Non-Aqueous solution; Gel; Paste; Patch) (corneocytes) are cuboid in shape Stratum Corneum (SC) DeffSC lipids (Thickness; Diffusivity; embedded within the The predicted and observed ketoprofen plasma concentration after single IV Permeability; Steady mortar of intercellular dose are presented in Figure 2A and after dermal application in Figure 2B state binding, Tortuosity) lipid matrix. The (circles + lines – observed average + SD). Deff corneocyte is SEB Viable Epidermis (VE) Figure 2. MPML MechDermA Model Structure DeffVE (Thickness; Diffusivity; composed of a water Mean Values of Systemic concentration in plasma of Mean Values of Systemic concentration in plasma of 12.00 Permeability; Blood flow) and protein core Ketoprofen over Time (Debruyne 1997, IV infusion) 18.00 Ketoprofen over Time (Debruyne 1997, IV bolus+infusion) encapsulated within a 10.00 16.00 14.00 lipid envelope. The 8.00 Dermis (D) 12.00 10.00 DeffD (Thickness; Diffusivity; model can simulate 6.00 Permeability; Non-Specific partitioning and 8.00 Clearance; Blood flow) 4.00 6.00 CLD absorption through a Blood flow 4.00

Systemic Concentration (mg/L) Concentration Systemic 2.00 Systemic Concentration (mg/L) Concentration Systemic (Local vasculature) hair follicular (HF) 2.00 Subcutis (S) pathway depending on 0.00 0.00 (Thickness; Diffusivity; 0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0 22.0 24.0 0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0 22.0 24.0 Time (h) Time (h) DeffS Permeability; Blood flow) the drug’s affinity to Mean Values of Systemic concentration in plasma of Mean Values of Systemic concentration in plasma of sebum and its 18.00 22.00 Ketoprofen over Time (Debruyne 1997, IV bolus) Ketoprofen over Time (Rosada 2016, IV bolus) Blood flow 16.00 (Local vasculature) molecular size. While 20.00 18.00 14.00 Muscle (M) the drug diffuses 16.00 12.00 (Thickness; Diffusivity; 14.00 DeffM through the 10.00 Permeability; Blood flow) 12.00 intercellular lipid matrix, 8.00 Blood flow 10.00 8.00 (Local vasculature) depending on the drug 6.00 6.00 1 4.00

4.00 (mg/L) Concentration Systemic

to cell affinity and the concentration gradient, it can permeate into or out of the (mg/L) Concentration Systemic 2.00 2.00 cells. Blood flow to dermis was modelled as a function of cardiac output, body 0.00 0.00 weight and body surface area as per the Simcyp PBPK model framework. 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 Time (h) Time (h) Simcyp simulator V17 was used in the study. ADME parameters utilized for the Individual Values of Systemic concentration in plasma of Individual Values of Systemic concentration in plasma of ketoprofen over Time (Shah 1996, dermal gel, back) compound file development were derived from the available sources and are 600 ketoprofen over Time (Shah 1996, dermal solution) 250 presented below (Table 1). 500 200

Table 1. ADME parameters for ketoprofen. 400 150 Group Parameter Value [unit] Source 300 Clinical study 100 200 MW 254.285 [2] settings (i.e. dose, 50

Systemic Concentration (ng/mL) Concentration Systemic 100 logP 3.12 [3] dosing, numer of (ng/mL) Concentration Systemic phys-chem individuals, 0 0 type monoprotic acid [2] 0 50 100 150 200 250 0 50 100 150 200 250 formulation, area Time (h) Time (h) pKa 4.45 [2] Individual Values of Systemic concentration in plasma of Individual Values of Systemic concentration in plasma of of application) 140 ketoprofen over Time (Shah 1996, dermal gel, knee) 200 ketoprofen over Time (Shah 1996, dermal gel, arm) B/P partition ratio 1.1 [4] 180 were closely 120 Binding 160 fuplasma 0.01 [3] mimicked during 100 140 Distribution Vss 0.132 [L/kg]; CV=17.2% [5] the simulation 80 120 100 60 Elimination CLIV 5.16 [L/h]; CV=17.4% [5] studies [5-8]. 80 40 60

40 Systemic Concentration (ng/mL) Concentration Systemic

20 (ng/mL) Concentration Systemic Discussion and Conclusions 20 0 0 0 50 100 150 200 250 0 50 100 150 200 250 The developed model was verified against the IV data and was able to recover Time (h)Individual Values of amount of ketoprofen in Muscle over Time Time (h) 450 (Sekiya 2010, dermal patch, arm)

the systemic and local concentration after dermal application. )

400

/ml g

n 350 300 250

in Muscle ( Muscle in 200 1) Martins F, et al. 2017 GRC - Barrier Function of Mammalian Skin, Waterville Valley, NH., 2) 150 https://pubchem.ncbi.nlm.nih.gov/compound/3825; 3) https://www.drugbank.ca/drugs/DB01009; 4) Fura A, et 100

al. Biopharm Drug Dispos. 2008;29(8):455-68.; 5) Debruyne D, et al. Clin Pharmacokinet. 1987;12(3):214-21.; 6) 50 Concentration Shah AK, et al. Pharm Res. 1996;13(1):168-72.; 7) Sekiya I, et al. AAPS PharmSciTech. 2010;11(1):154-8.; 8) Rosada 0 M, et al. JMS. 2016; 85(4):254-263. 0.0 4.0 8.0 12.0 16.0 20.0 24.0 Time (h) Acknowledgement Funding for the work presented here was made possible, in part, by the U.S. Food and Drug Administration through grant 1U01FD005225-01. Skin Forum Annual Meeting 2018, Tallin, Estonia