Physiologically‐based pharmacokinetic modeling to support bioequivalence and approval of generic products: A case for diclofenac sodium topical gel, 1%

Tsakalozou, Eleftheria; Babiskin, Andrew; Zhao, Liang

doi:10.1002/psp4.12600

Cited by 44 publications

(52 citation statements)

References 37 publications

(102 reference statements)

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“…On the other hand, the in silico methods are often supported by strong in vitro data and can provide timely results, bringing down costs and the need for extensive biological studies. The in vivo testing can be limited and a large proportion of the required criteria can be planned and met in silico [66,67].…”

Section: Discussionmentioning

confidence: 99%

Skin-on-a-Chip Technology for Testing Transdermal Drug Delivery—Starting Points and Recent Developments

et al. 2021

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During the last decades, several technologies were developed for testing drug delivery through the dermal barrier. Investigation of drug penetration across the skin can be important in topical pharmaceutical formulations and also in cosmeto-science. The state-of- the-art in the field of skin diffusion measurements, different devices, and diffusion platforms used, are summarized in the introductory part of this review. Then the methodologies applied at Pázmány Péter Catholic University are shown in detail. The main testing platforms (Franz diffusion cells, skin-on-a-chip devices) and the major scientific projects (P-glycoprotein interaction in the skin; new skin equivalents for diffusion purposes) are also presented in one section. The main achievements of our research are briefly summarized: (1) new skin-on-a-chip microfluidic devices were validated as tools for drug penetration studies for the skin; (2) P-glycoprotein transport has an absorptive orientation in the skin; (3) skin samples cannot be used for transporter interaction studies after freezing and thawing; (4) penetration of hydrophilic model drugs is lower in aged than in young skin; (5) mechanical sensitization is needed for excised rodent and pig skins for drug absorption measurements. Our validated skin-on-a-chip platform is available for other research groups to use for testing and for utilizing it for different purposes.

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Section: Discussionmentioning

confidence: 99%

Skin-on-a-Chip Technology for Testing Transdermal Drug Delivery—Starting Points and Recent Developments

et al. 2021

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“…Finally, it is interesting to note that recently FDA approved a generic diclofenac sodium topical gel (1%), based on the collective evidence including (i) Q1 and Q2 sameness and physical and structural similarity to the reference product, (ii) an in vivo bioequivalence study with pharmacokinetic endpoints, and (iii) a virtual bioequivalence assessment leveraging dermal physiologically-based pharmacokinetic (PBPK) modeling and simulation instead of a comparative clinical endpoint study in patients. The multiphase multi-layer (MPML) MechDermA model implemented within the Simcyp Simulator (Certara, Princeton, NJ., USA) was used for PBPK modeling [63,64]. To the best of our knowledge, this is the first ANDA approval utilizing the PBPK modeling to support the bioequivalence of topical semisolid drug products.…”

Section: Stratum Corneum (Sc) Samplingmentioning

confidence: 99%

The Implications of Regulatory Framework for Topical Semisolid Drug Products: From Critical Quality and Performance Attributes towards Establishing Bioequivalence

2021

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Due to complex interdependent relationships affecting their microstructure, topical semisolid drug formulations face unique obstacles to the development of generics compared to other drug products. Traditionally, establishing bioequivalence is based on comparative clinical trials, which are expensive and often associated with high degrees of variability and low sensitivity in detecting formulation differences. To address this issue, leading regulatory agencies have aimed to advance guidelines relevant to topical generics, ultimately accepting different non-clinical, in vitro/in vivo surrogate methods for topical bioequivalence assessment. Unfortunately, according to both industry and academia stakeholders, these efforts are far from flawless, and often upsurge the potential for result variability and a number of other failure modes. This paper offers a comprehensive review of the literature focused on amending regulatory positions concerning the demonstration of (i) extended pharmaceutical equivalence and (ii) equivalence with respect to the efficacy of topical semisolids. The proposed corrective measures are disclosed and critically discussed, as they span from mere demands to widen the acceptance range (e.g., from ±10% to ±20%/±25% for rheology and in vitro release parameters highly prone to batch-to-batch variability) or reassess the optimal number of samples required to reach the desired statistical power, but also rely on specific data modeling or novel statistical approaches.

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“…15,27,92 These efforts have resulted in an increase in literature reports highlighting the applicability of fully mechanistic dermal PBPK models. 57,66 The Office of Generic Drugs (OGD) within the FDA has noted an increase in the application of dermal PBPK modeling and simulation approaches supporting the development and approval of dermatological generic drug products, namely in pre-abbreviated new drug application meeting requests submitted for alternative BE approaches. Of note is the recent approval of a generic diclofenac sodium topical gel, 1% referencing Voltaren (diclofenac sodium) topical gel, 1%.…”

Section: Update On Dermal Pbpk Modeling and Simulation Approaches In ...mentioning

confidence: 99%

Physiologically‐Based Pharmacokinetic Modeling to Support Determination of Bioequivalence for Dermatological Drug Products: Scientific and Regulatory Considerations

Tsakalozou

Alam

Babiskin

et al. 2021

Clin Pharma and Therapeutics

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Physiologically‐based pharmacokinetic (PBPK) modeling and simulation provides mechanism‐based predictions of the pharmacokinetics of an active ingredient following its administration in humans. Dermal PBPK models describe the skin permeation and disposition of the active ingredient following the application of a dermatological product on the skin of virtual healthy and diseased human subjects. These models take into account information on product quality attributes, physicochemical properties of the active ingredient and skin (patho)physiology, and their interplay with each other. Regulatory and product development decision makers can leverage these quantitative tools to identify factors impacting local and systemic exposure. In the realm of generic drug products, the number of US Food and Drug Administratioin (FDA) interactions that use dermal PBPK modeling to support alternative bioequivalence (BE) approaches is increasing. In this report, we share scientific considerations on the development, verification and validation (V&V), and application of PBPK models within the context of a virtual BE assessment for dermatological drug products. We discuss the challenges associated with model V&V for these drug products stemming from the fact that target‐site active ingredient concentrations are typically not measurable. Additionally, there are no established relationships between local and systemic PK profiles, when the latter are quantifiable. To that end, we detail a multilevel model V&V approach involving validation for the model of the drug product of interest coupled with the overall assessment of the modeling platform in use while leveraging in vitro and in vivo data related to local and systemic bioavailability.

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Physiologically‐based pharmacokinetic modeling to support bioequivalence and approval of generic products: A case for diclofenac sodium topical gel, 1%

Cited by 44 publications

References 37 publications

Skin-on-a-Chip Technology for Testing Transdermal Drug Delivery—Starting Points and Recent Developments

Skin-on-a-Chip Technology for Testing Transdermal Drug Delivery—Starting Points and Recent Developments

The Implications of Regulatory Framework for Topical Semisolid Drug Products: From Critical Quality and Performance Attributes towards Establishing Bioequivalence

Physiologically‐Based Pharmacokinetic Modeling to Support Determination of Bioequivalence for Dermatological Drug Products: Scientific and Regulatory Considerations

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