TABLE 3.

Overview of the platform performance assessment conducted by the applicant in support of the dermal PBPK model for diclofenac sodium topical gel, 1%, developed in MPML MechDermA within the Simcyp Simulator, version 17

Active ingredient a
	1	2	3	4	5	6	7	8	9	10	11
Dosage form/products b	TDS	TDS	TDS	Solution	TDS	Cream	Gel ointment cream	TDS cream	Gel Solution Nanoparticles TDS	Gel	Solution
Verification matrix	Plasma	Plasma	Plasma	Plasma	Plasma	IVPT	Plasma	Plasma	Plasma Synovial fluid Subcutis Muscle Dermis Stratum corneum	Plasma Synovial fluid	Skin biopsy (stratum corneum, viable epidermis, dermis)
Number of literature sources for validation of the systemic disposition PBPK model	4	1	1	c	1	c	3	c	4	2	c
Number of literature sources for validation of the dermal PBPK model	8	2	1	1	1	1	1/1/1	1/1	6/1/1/1	2	1

Abbreviations: IVPT, in vitro permeation testing; MPML, multi‐phase multi‐layer; PBPK, physiologically‐based pharmacokinetic; TDS, transdermal delivery system.

^aThe selected active ingredients differed in terms of their physicochemical properties (lipophilicity and ionization potential) and pharmacokinetic characteristics (protein binding, extent of distribution in the human body, route of elimination, and blood‐to‐plasma partitioning among others). More specifically, the molecular weight, logP (lipophilicity), blood to plasma ratio, fraction unbound in plasma, volume of distribution at steady‐state and total systemic clearance of the selected active pharmaceutical ingredients ranged from 162 to 468 g/mol, from −1.6 to 6.4, from 0.55 to 1.107, from 0.003 to 0.95, from 0.123 L/Kg to 48.8 L/Kg and from 1.6 L/h to 71.5 L/h, respectively. The selected active ingredients were acids, bases, and ampholytes.

^bProduct‐specific dermal PBPK models were developed for each of these dosage forms.

^cNot provided in the submission or refers to a drug substance that is not given by other than the topical route.