Predicting diclofenac systemic and synovial fluid concentrations after dermal application using the Multi-Phase Multi-Layer MechDermA PBPK model
Sebastian Polak1,2, Nikunjkumar Patel1, Frederico Martins1, Farzaneh Salem1, Masoud Jamei1. Amin Rostami-Hodjegan1,3
1 Simcyp Ltd. (part of Certara), 2 Jagiellonian University Medical College, 3 University of Manchaster, School of Pharmacy
Objectives: To assess the prediction performance of the MPML MechDermA model. The ultimate goal is to develop a flexible simulation framework for the topically applied drugs. Diclofenac in various gel formulations was used as a model compound.
Methods: The physiologically based pharmacokinetics (PBPK) model is a dynamic, Multi-Phase and Multi-Layer (MPML) Mechanistic Dermal Absorption (MechDermA) model, where the stratum corneum (SC) is modelled as a brick-and-mortar structure [1]. The model determines the number of corneocytes that can be accommodated in the skin surface area where the formulation is applied, accounting for the tight packing mosaic arrangement of cells with intercellular lipid thickness. This structure allows simulation of complex diffusion through the SC for drugs with different physicochemical properties as well as different formulations: gels, emulsions, patches, suspensions, and pastes [2]. The tortuosity parameter was taken from the experimentally reported value for in vivo human skin [3]. Blood flow to the dermis was modeled as a function of body cardiac output, body weight and body surface area as per Simcyp Simulator (V16). The Simcyp default diclofenac compound file was used and the skin disposition parameters (partition, diffusion, and binding coefficients) were calculated using the built-in QSAR models. The Single Adjusting Compartment (SAC) was used to mimic the synovial fluid tissue. Clinical data from 6 different studies, 2 different formulations, namely emulsion gel and solution gel of diclofenac, 4 different locations (back, thigh, arm, and knee), a range of application areas (100-1200 cm2), multiple dosing scenarios (2-4 times a day), single and multiple dosing in various populations for different genders and age distribution were used [4-9]. Plasma and, whenever available, synovial fluid concentration were the endpoints of choice.
Results:
Results expressed in ng/ml are presented either as mean or median (*) values.
PLASMA
|
Clinical study |
OBSERVED |
SD or range |
PREDICTED |
SD or range |
|
[4] |
4.9* |
3.8 |
8.37 |
4.3 |
|
[5] (knee) |
9.7 |
5.3 |
9.35 |
3.5 |
|
[5] (knee+hand) |
33.6 |
19.9 |
32.5 |
10.5 |
|
[6] |
8.5 |
3.6 |
12.0 |
3.3 |
|
[7] |
12.9 |
8.1 |
15.1 |
7.6 |
|
[8] |
41.0 |
15.8 |
23.4 |
9.0 |
|
[9] b.i.d. |
3.9* |
1.3-302.2 |
4.5 |
3.1-8.8 |
|
[9] t.i.d. |
4.1* |
1.1-23.0 |
11.5 |
6.4-18.2 |
SYNOVIAL FLUID
|
Clinical study |
OBSERVED |
SD or range |
PREDICTED |
SD or range |
|
[8] |
23.7 |
8.9 |
15.2 |
6.5 |
|
[9] b.i.d. |
2.6 |
0.4-408.5 |
5.0 |
3.0-8.4 |
|
[9] t.i.d. |
2.8 |
0.2-47.1 |
12.1 |
6.1-17.5 |
Conclusions: The MPML-MechDermA model of the skin absorption accounts for the drug, formulation, physiology and environmental parameters with applications in drug development and regulatory assessment.
References:
[1] Patel N. et al. Towards development and validation of the Dermal PBPK model for virtual bioequivalence - model description and validation case studies. 2015 GRC Barrier Function of Mammalian Skin Conference, Waterville Valley, NH, USA.
[2] Polak S. et al. Towards mechanistic simulation and prediction of bioequivalence studies of topical formulations case study with two diclofenac formulations. 2015, GRC Barrier Function of Mammalian Skin Conference, Waterville Valley, NH, USA.
[3] Tarleja P. et al. Visualization of the lipid barrier and measurement of lipid pathlength in human stratum corneum. AAPS PharmSci. 2001 Jun; 3(2): 48–56.
[4] Brunner M. et al. Favourable dermal penetration of diclofenac after administration to the skin using a novel spray gel formulation. Br J Clin Pharmacol. 2005 Nov;60(5):573-7.
[5] Kienzler JL. et al. Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J Clin Pharmacol. 2010 Jan;50(1):50-61.
[6] Dehghanyar P. et al. Topical skin penetration of diclofenac after single- and multiple-dose application. Int J Clin Pharmacol Ther. 2004 Jul;42(7):353-9.
[7] Sioufi A. et al. Percutaneous absorption of diclofenac in healthy volunteers after single and repeated topical application of diclofenac Emulgel. Biopharm Drug Dispos. 1994 Aug;15(6):441-9.
[8] Radermacher J. et al. Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease. Br J Clin Pharmacol. 1991 May;31(5):537-41.
[9] Efe T. et al. Penetration of topical diclofenac sodium 4 % spray gel into the synovial tissue and synovial fluid of the knee: a randomised clinical trial. Knee Surg Sports Traumatol Arthrosc. 2014 Feb;22(2):345-50.
