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

Abstract

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.

In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part II

“…Due to the limitations of the mouse model in the current V21 version of Simcyp Animal software, estimation of inter-individual variability was not possible; therefore, models were fitted to the averaged values of PK and PD data at particular timepoints. PBPK model performance was evaluated based on the “2-fold” criterion for maximum concentration (C max ) and area under the concentration vs. time curve (AUC) and T max [ 41 , 42 ]. A graphical representation of PBPK model development is presented in Figures S20–S22 .…”

Increasing impact of quantitative methods and modeling in establishment of bioequivalence and characterization of drug delivery

“…Specifically, detailed MIE case studies representing the FDA's current thinking and expectations on MIE for regulatory applications, can be effectively disseminated through organizing workshops and other communication means, in addition to scientific publications. We note that the FDA is dedicated to actively publishing the progresses and case examples of MIE from the GDUFA research and there are several publications in the complex products including orally inhaled, long‐acting injectable/implant, and dermal products 5–8 . In addition, we believe that this special issue will provide a useful summary of the most recent development and discussion around the application of MIE to generic drug product development and assessment.…”

“…We note that the FDA is dedicated to actively publishing the progresses and case examples of MIE from the GDUFA research and there are several publications in the complex products including orally inhaled, long-acting injectable/implant, and dermal products. [5][6][7][8] In addition, we believe that this special issue will provide a useful summary of the most recent development and discussion around the application of MIE to generic drug product development and assessment. The annual GDUFA science and research reports are another resource to check out the progress in MIE, which include a summary of research activities, research highlights, comprehensive lists of new, ongoing, and completed grants and contracts, and outcomes generated from the GDUFA-funded science and research program in each fiscal year.…”

Regulatory Requirements for the Development of Second-Entry Semisolid Topical Products in the European Union

“…Cutaneous PBPK models include inter- and intra-subject variability by adding variability into skin physiology parameters, such as skin thickness, pH and blood flow, and virtual subjects of different sex, race, and age groups. Simulation can reflect the cutaneous kinetics of the active moiety after drug application at different anatomic sites, including arms, legs, head, abdomen, and back within the same virtual subject [ 157 ].…”