Cutaneous pharmacokinetics-based bioequivalence: A clinical dermal open flow microperfusion verification study using lidocaine and prilocaine combination topical products.

Background: Using accurate, sensitive, reproducible and efficient in vivo cutaneous pharmacokinetics (PK)-based bioequivalence (BE) approaches can promote the development of topical generic drug products. A clinical dermal open flow microperfusion (dOFM) study has previously demonstrated the BE of topical drug products containing a hydrophilic drug. However, the utility of dOFM to evaluate the topical BE of drug products containing moderately lipophilic drugs, more representative of most topical drugs, has not yet been established.

Determining topical product bioequivalence with stimulated Raman scattering microscopy.

Generic drugs are essential for affordable medicine and improving accessibility to treatments. Bioequivalence (BE) is typically demonstrated by assessing a generic product's pharmacokinetics (PK) relative to a reference-listed drug (RLD). Accurately estimating cutaneous PK (cPK) at or near the site of action can be challenging for locally acting topical products.

Understanding the impact of formulation design on microstructure and drug release from porous microparticle-based tretinoin topical gels.

For proportionally formulated intermediate strengths of a topical product, the relationship of drug release across multiple strengths of a given product is not always well understood. The current study aims to assess the proportionality of tretinoin release rates across multiple strengths of tretinoin topical gels when manufactured using two different methods to understand the impact of formulation design on drug product microstructure and tretinoin release rate. Two groups of tretinoin gels of 0.

Bioequivalence Evaluation of Topical Metronidazole Products Using Dermal Microdialysis in New Zealand Rabbits.

Comparative assessment of cutaneous pharmacokinetics (cPK) by dermal microdialysis (dMD) appears to be suitable to evaluate the bioequivalence (BE) of topical dermatological drug products applied to the skin (TDDPs). Although dMD studies in the literature have reported inconclusive BE assessments, we have addressed several methodological deficiencies to improve dMD's capability to assess BE between reference (R) and approved generic (referred to as test (T)) gel and cream products of metronidazole (MTZ). The 90% confidence interval (CI) of the geometric mean ratios for the Ln(AUC) and Ln(C) endpoints was centered within the BE limits of 80-125%.

Regulatory utility of mechanistic modeling to support alternative bioequivalence approaches: A workshop overview.

On September 30 and October 1, 2021, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics cosponsored a live virtual workshop titled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches." The overall aims of the workshop included (i) engaging the generic drug industry and other involved stakeholders regarding how mechanistic modeling and simulation can support their product development and regulatory submissions; (ii) sharing the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (iii) establishing a consensus on best practices for using mechanistic modeling approaches, such as physiologically based pharmacokinetic modeling and computational fluid dynamics modeling, for BE assessment; and (iv) introducing the concept of a Model Master File to improve model sharing between model developers, industry, and the FDA. More than 1500 people registered for the workshop.

Mechanistic modeling of drug products applied to the skin: A workshop summary report.

The development of a generic drug product involves demonstrating that there is no significant difference in the rate and extent to which the active ingredient becomes available at the site of action, relative to the reference listed drug product. This remains challenging for many locally acting topical dermatological products because measuring the concentration of the active ingredient at the site of action in the skin may not be straightforward, and, in most instances, there are no established relationships between skin and plasma pharmacokinetic profiles. In recent years, the Office of Generic Drugs of the US Food and Drug Administration (FDA) established scientific research programs with the goal of enhancing patient access to high quality, affordable topical dermatological generics.

Cutaneous Pharmacokinetic Approaches to Compare Bioavailability and/or Bioequivalence for Topical Drug Products.

The evaluation of bioequivalence (BE) involves comparing the test product to its reference product in a study whose fundamental scientific principles allow inferring of the clinical performance of the products. Several test methods have been discussed and developed to evaluate topical bioavailability (BA) and BE. Pharmacokinetics-based approaches characterize the rate and extent to which an active ingredient becomes available at or near its site of action in the skin.

How Does the Food and Drug Administration Approve Topical Generic Drugs Applied to the Skin?

Approved generic drugs are therapeutically equivalent to a preidentified brand name product and are expected to have the same clinical effect and safety profile when administered to patients under conditions specified in the labeling. Availability of generic topical dermatologic drugs is expected to enhance patient access to such widely used drug products. Assessment of equivalence for a prospective generic product involves a systematic and rigorous comparative evaluation to ensure there is no significant difference in the rate and extent to which the active ingredients become available at the site of action for the prospective generic and corresponding brand name product.

Multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) model to predict local and systemic exposure of drug products applied on skin.

Physiologically-based pharmacokinetic models combine knowledge about physiology, drug product properties, such as physicochemical parameters, absorption, distribution, metabolism, excretion characteristics, formulation attributes, and trial design or dosing regimen to mechanistically simulate drug pharmacokinetics (PK). The current work describes the development of a multiphase, multilayer mechanistic dermal absorption (MPML MechDermA) model within the Simcyp Simulator capable of simulating uptake and permeation of drugs through human skin following application of drug products to the skin. The model was designed to account for formulation characteristics as well as body site- and sex- population variability to predict local and systemic bioavailability.

The dose-duration effect on cutaneous pharmacokinetics of metronidazole from topical dermatological formulations in Yucatan mini-pigs.

Dermal microdialysis (dMD) permits the investigation of cutaneous pharmacokinetics (cPK) for topical dermatological drug products (TDDP). dMD involves probe implantation into the dermis and a sample collection system that restricts subjects' movements for the experimental duration. A truncated dose-duration, by TDDP removal at predetermined time-points, may help to adequately characterize the cPK in a relatively short time.

Physicochemical and structural evaluation of microparticles in tretinoin topical gels.

Drug release from microparticle-based topical gels may affect their bioavailability, safety and efficacy. This work sought to elucidate spatial distribution of the drug within the microparticle matrix and how this impacts the product's critical performance attributes. The purpose of this research was to inform the development of in vitro characterization approaches to support a demonstration of bioequivalence.

Application of Confocal Raman Microscopy for the Characterization of Topical Semisolid Formulations and their Penetration into Human Skin Ex Vivo.

Purpose: The quality testing and approval procedure for most pharmaceutical products is a streamlined process with standardized procedures for the determination of critical quality attributes. However, the evaluation of semisolid dosage forms for topical drug delivery remains a challenging task. The work presented here highlights confocal Raman microscopy (CRM) as a valuable tool for the characterization of such products.

Research and Education Needs for Complex Generics.

Complex generics are generic versions of drug products that generally have complex active ingredients, complex formulations, complex routes of delivery, complex dosage forms, are complex drug-device combination products, or have other characteristics that can make it complex to demonstrate bioequivalence or to develop as generics. These complex products (i.e.

Evaluation of in vitro/in vivo correlations for three fentanyl transdermal delivery systems using in vitro skin permeation testing and human pharmacokinetic studies under the influence of transient heat application.

The value of developing an in vitro/in vivo correlation (IVIVC) is substantial in biopharmaceutical drug development because once the model is developed and validated, an in vitro method may be used to efficiently assess and predict drug product performance in vivo. In this study, three bioequivalent, matrix-type, fentanyl transdermal delivery systems (TDS) were evaluated in vitro using an in vitro permeation test (IVPT) and dermatomed human skin, and in vivo in human pharmacokinetic (PK) studies under harmonized study designs to evaluate IVIVC. The study designs included 1 h of transient heat application (42 ± 2°C) at either 11 h or 18 h after TDS application to concurrently investigate the influence of heat on drug bioavailability from TDS and the feasibility of IVPT to predict the effects of heat on TDS in vivo.

Comparative in vitro release testing (IVRT) of acyclovir products.

The aim was to evaluate whether an in vitro release test (IVRT) could differentiate the release rates from five pharmaceutically equivalent acyclovir cream products and one ointment compared to that from a reference product, Zovirax cream (USA), to identify a test product with an inequivalent drug release rate that could serve as negative control for bioequivalence (BE) in a separate in vivo study. The reference product showed equivalent drug release rates compared to itself. The six test products failed to show equivalent drug release rates compared to the reference product.

Relating transdermal delivery plasma pharmacokinetics with in vitro permeation test (IVPT) findings using diffusion and compartment-in-series models.

Increasing emphasis is being placed on using in vitro permeation test (IVPT) results for topical products as a surrogate for their in vivo behaviour. This study sought to relate in vivo plasma concentration - time pharmacokinetic (PK) profiles after topical application of drug products to IVPT findings with mechanistic diffusion and compartment models that are now widely used to describe permeation of solutes across the main skin transport barrier, the stratum corneum. Novel in vivo forms of the diffusion and compartment-in-series models were developed by combining their IVPT model forms with appropriate in vivo disposition functions.

Evaluation of local bioavailability of metronidazole from topical formulations using dermal microdialysis: Preliminary study in a Yucatan mini-pig model.

Dermal microdialysis (dMD) can measure the rate and extent to which a topically administered active pharmaceutical ingredient (API) becomes available in the dermis. Using multiple test-sites on the same subject, and replicate probes at each test-site, it is feasible to compare the cutaneous pharmacokinetics of an API from different topical dermatological drug products in parallel on the same subject with this technique. This study design would help to reduce variability.

Cutaneous Pharmacokinetics of Acyclovir Cream 5% Products: Evaluating Bioequivalence with an In Vitro Permeation Test and an Adaptation of Scaled Average Bioequivalence.

Purpose: The in vitro permeation test (IVPT) with a new statistical approach was investigated to evaluate the utility of an IVPT methodology as a sensitive tool to support a demonstration of bioequivalence (BE) for topical dermatological drug products.

Methods: IVPT experiments were performed utilizing ex vivo human skin. The initial screening tests involved four differently formulated acyclovir 5% creams: the U.

Variability of Skin Pharmacokinetic Data: Insights from a Topical Bioequivalence Study Using Dermal Open Flow Microperfusion.

Purpose: Dermal open flow microperfusion (dOFM) has previously demonstrated its utility to assess the bioequivalence (BE) of topical drug products in a clinical study. We aimed to characterize the sources of variability in the dermal pharmacokinetic data from that study.

Methods: Exploratory statistical analyses were performed with multivariate data from a clinical dOFM-study in 20 healthy adults evaluating the BE, or lack thereof, of Austrian test (T) and U.

Evaluation of Heat Effects on Fentanyl Transdermal Delivery Systems Using In Vitro Permeation and In Vitro Release Methods.

Experimental conditions that could impact the evaluation of heat effects on transdermal delivery systems (TDS) using an in vitro permeation test (IVPT) and in vitro release testing (IVRT) were examined. Fentanyl was the model TDS. IVPT was performed using Franz diffusion cell, heating lamp, and human skin with seven heat application regimens.

Evaluation of Heat Effects on Transdermal Nicotine Delivery In Vitro and In Silico Using Heat-Enhanced Transport Model Analysis.

A combined experimental and computational model approach was developed to assess heat effects on drug delivery from transdermal delivery systems (TDSs) in vitro and nicotine was the model drug. A Franz diffusion cell system was modified to allow close control of skin temperature when heat was applied from an infrared lamp in vitro. The effects of different heat application regimens on nicotine fluxes from two commercial TDSs across human cadaver skin were determined.

Modeling Temperature-Dependent Dermal Absorption and Clearance for Transdermal and Topical Drug Applications.

A computational model was developed to better understand the impact of elevated skin temperatures on transdermal drug delivery and dermal clearance. A simultaneous heat and mass transport model with emphasis on transdermal delivery system (TDS) applications was developed to address transient and steady-state temperature effects on dermal absorption. The model was tested using representative data from nicotine TDS applied to human skin either in vitro or in vivo.