Use of the Same Model or Modeling Strategy Across Multiple Submissions: Focus on Complex Drug Products.

Evidence shows that there is an increasing use of modeling and simulation to support product development and approval for complex generic drug products in the USA, which includes the use of mechanistic modeling and model-integrated evidence (MIE). The potential for model reuse was the subject of a workshop session summarized in this review, where the session included presentations and a panel discussion from members of the U.S. Food and Drug Administration (FDA), academia, and the generic drug product industry. Concepts such as platform performance assessment and MIE standardization were introduced to provide potential frameworks for model reuse related to mechanistic models and MIE, respectively. The capability of models to capture formulation and product differences was explored, and challenges with model validation were addressed for drug product classes including topical, orally inhaled, ophthalmic, and long-acting injectable drug products. An emphasis was placed on the need for communication between FDA and the generic drug industry to continue to foster maturation of modeling and simulation that may support complex generic drug product development and approval, via meetings and published guidance from FDA. The workshop session provided a snapshot of the current state of modeling and simulation for complex generic drug products and offered opportunities to explore the use of such models across multiple drug products.

Use of physiologically-based pharmacokinetic modeling to understand the effect of omeprazole administration on the pharmacokinetics of oral extended-release nifedipine.

Proton pump inhibitors (PPIs) can affect the release of drugs from their dosage forms in vivo by elevating the gastric pH. Our recent clinical study has demonstrated that drug-drug interactions (DDIs) exist between a PPI, omeprazole, and nifedipine extended-release formulations, where systemic exposure of nifedipine was increased in subjects after multiple-dose pretreatment of omeprazole. However, the mechanism of the observed DDIs between omeprazole and nifedipine has not been well-understood, as the DDI may also be mediated through CYP3A4 enzyme inhibition in addition to the elevated gastric pH caused by omeprazole. This study used physiologically-based pharmacokinetic (PBPK) modeling and simulations to investigate the underlying mechanism of these complex DDIs. A formulation exhibiting differences in in vitro dissolution across physiological pH range and another formulation where pH does not impact dissolution appreciably (e.g., an osmotic pump) were chosen to characterize the potential impact of pH. The PBPK models incorporated two-stage in vitro release profiles via US Pharmacopeia 2 apparatus. PBPK simulations suggest that the elevated gastric pH following multiple-dose administration of omeprazole has a minimal effect on nifedipine pharmacokinetics (PKs), whereas CYP3A4-mediated DDI is likely the main driver to the observed change of nifedipine PKs in the presence of omeprazole. Compared to the osmotic formulation, the slightly increased exposure of nifedipine can be accounted for by the enhanced drug release in the pH-dependent formulation. The reported model-based approach may be useful in DDI risk assessments, product formulation designs, and bioequivalence evaluations.

Topical pharmacokinetics of brinzolamide suspensions in rabbits and variability analysis for sample size and design considerations.

Identifying critical attributes for complex locally acting ophthalmic formulations and establishing in vitro-in vivo correlations can facilitate selection of appropriate thresholds for formulation changes that reflect lack of impact on in vivo performance. In this study the marketed antiglaucoma product Azopt® (1% brinzolamide suspension) and five other brinzolamide formulations varying in particle size distributions and apparent viscosities were topically administered in rabbits, and their ocular pharmacokinetics was determined in multiple ocular tissues. Statistical evaluation with ANOVA showed no significant differences between the formulations in the peak drug concentration (Cmax) in the aqueous humor and iris-ciliary body. As a post-hoc analysis, the within animal and total variability was determined for Cmax in the aqueous humor and iris-ciliary body. Based on the observed variability, we investigated the sample size needed for two types of study designs to observe statistically significant differences in Cmax. For the sample size calculations, assuming both 25% and 50% true differences in Cmax between two formulations, two study designs were compared: paired-eye dosing design (one formulation in one eye and another formulation in the other eye of the same animal at the same time) versus parallel-group design. The number of rabbits needed in the paired-eye dosing design are much lower than in the parallel-group design. For example, when the true difference in aqueous humor Cmax is 25%, nine rabbits are required in the paired-eye design versus seventy rabbits (35 per treatment) in the parallel-group design to observe a statistically significant difference with a power of 80%. Therefore, the proposed paired-eye dosing design is a viable option for the design of pharmacokinetic studies comparing ophthalmic products to determine the impact of formulation differences.

Transport and deposition of beclomethasone dipropionate drug aerosols with varying ethanol concentration in severe asthmatic subjects.

This study aims to assess the effects of varying an ethanol co-solvent on the deposition of drug particles in severe asthmatic subjects with distinct airway structures and lung functions using computational fluid dynamics. The subjects were selected from two quantitative computed tomography imaging-based severe asthmatic clusters, differentiated by airway constriction in the left lower lobe. Drug aerosols were assumed to be generated from a pressurized metered-dose inhaler (MDI). The aerosolized droplet sizes were varied by increasing the ethanol co-solvent concentration in the MDI solution. The MDI formulation consists of 1,1,2,2-tetrafluoroethane (HFA-134a), ethanol, and beclomethasone dipropionate (BDP) as the active pharmaceutical ingredient. Since HFA-134a and ethanol are volatile, both substances evaporate rapidly under ambient conditions and trigger condensation of water vapor, increasing the size of aerosols that are predominantly composed of water and BDP. The average deposition fraction in intra-thoracic airways for severe asthmatic subjects with (or without) airway constriction increased from 37%±12 to 53.2%±9.4 (or from 20.7%± 4.6 to 34.7%±6.6) when the ethanol concentration was increased from 1 to 10%wt/wt. However, when the ethanol concentration was further increased from 10 to 20%wt/wt, the deposition fraction decreased. This indicates the importance of selecting appropriate co-solvent amounts during drug formulation development for the treatment of patients with narrowed airway disease. For severe asthmatic subjects with airway narrowing, the inhaled aerosol may benefit from a low hygroscopic effect by reducing ethanol concentration to penetrate the peripheral region effectively. These results could potentially inform the selection of co-solvent amounts for inhalation therapies in a cluster-specific manner.

Computational Model of In Vivo Corneal Pharmacokinetics and Pharmacodynamics of Topically Administered Ophthalmic Drug Products.

INTRODUCTION: Although the eye is directly accessible on the surface of the human body, drug delivery can be extremely challenging due to the presence of multiple protective barriers in eye tissues. Researchers have developed complex formulation strategies to overcome these barriers to ophthalmic drug delivery. Current development strategies rely heavily on in vitro experiments and animal testing to predict human pharmacokinetics (PK) and pharmacodynamics (PD). OBJECTIVE: The primary objective of the study was to develop a high-fidelity PK/PD model of the anterior eye for topical application of ophthalmic drug products. METHODS: Here, we present a physiologically-based in silico approach to predicting PK and PD in rabbits after topical administration of ophthalmic products. A first-principles based approach was used to describe timolol dissolution, transport, and distribution, including consideration of ionized transport, following topical instillation of a timolol suspension. RESULTS: Using literature transport and response parameters, the computational model described well the concentration-time and response-time profiles in rabbit. Comparison of validated rabbit model results and extrapolated human model results demonstrate observable differences in the distribution of timolol at multiple time points. CONCLUSION: This modeling framework provides a tool for model-based prediction of PK in eye tissues and PD after topical ophthalmic drug administration to the eyes.

Establishing quantitative relationships between changes in nasal spray in vitro metrics and drug delivery to the posterior nasal region.

Nasal sprays are typically characterized using in vitro spray metrics such as spray cone angle and droplet size distribution. It is currently not clear how these in vitro metrics correlate with regional nasal deposition, and these relationships could help explain the impact of product differences. In this study, the effects of changes in spray cone angle, spray velocity, spray ovality and droplet size distribution on regional nasal deposition were analyzed using a validated computational fluid dynamics model in recently developed adult characteristic nasal airway anatomies. The impact of the spray on the surrounding air phase was included. Results indicated that changes in spray cone angle largely influenced the nasal posterior deposition (PD) of the drug. Changes in the plume ovality and characteristic droplet size moderately influenced PD, but the results were dependent on the insertion conditions and nasal geometry. Changes in spray velocity and uniformity constant of the droplet size distribution had only minimal influence on PD. The rank order of metrics having the greatest to least impact on PD was cone angle ≫ plume ovality ≫ characteristic droplet size ≫ velocity ≫ size distribution uniformity constant. Overall, results from this study established quantitative relationships for predicting expected changes in PD.

Mechanistic modeling of ophthalmic, nasal, injectable, and implant generic drug products: A workshop summary report.

For approval, a proposed generic drug product must demonstrate it is bioequivalent (BE) to the reference listed drug product. For locally acting drug products, conventional BE approaches may not be feasible because measurements in local tissues at the sites of action are often impractical, unethical, or cost-prohibitive. Mechanistic modeling approaches, such as physiologically-based pharmacokinetic (PBPK) modeling, may integrate information from drug product properties and human physiology to predict drug concentrations in these local tissues. This may allow clinical relevance determination of critical drug product attributes for BE assessment during the development of generic drug products. In this regard, the Office of Generic Drugs of the US Food and Drug Administration has recently established scientific research programs to accelerate the development and assessment of generic products by utilizing model-integrated alternative BE approaches. This report summarizes the presentations and panel discussion from a public workshop that provided research updates and information on the current state of the use of PBPK modeling approaches to support generic product development for ophthalmic, injectable, nasal, and implant drug products.

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. Based on a postworkshop survey, the majority of participants reported that their fundamental scientific understanding of mechanistic models was enhanced, there was greater consensus on model validation and verification, and regulatory expectations for mechanistic modeling submitted in abbreviated new drug applications were clarified by the workshop.

Clinical Ocular Exposure Extrapolation for Ophthalmic Solutions Using PBPK Modeling and Simulation.

BACKGROUND: The development of generic ophthalmic drug products is challenging due to the complexity of the ocular system, and a lack of sensitive testing to evaluate the interplay of physiology with ophthalmic formulations. While measurements of drug concentration at the site of action in humans are typically sparse, these measurements are more easily obtained in rabbits. The purpose of this study is to demonstrate the utility of an ocular physiologically based pharmacokinetic (PBPK) model for translation of ocular exposure from rabbit to human. METHOD: The Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® v9.8.2 was used to build PBPK models for levofloxacin (Lev), moxifloxacin (Mox), and gatifloxacin (Gat) ophthalmic solutions. in the rabbit eye. The models were subsequently used to predict Lev, Mox, and Gat exposure after ocular solution administrations in humans. Drug-specific parameters were used as fitted and validated in the rabbit OCAT model. The physiological parameters were scaled to match human ocular physiology. RESULTS: OCAT model simulations for rabbit well described the observed concentrations in the eye compartments following Lev, Mox, and Gat solution administrations of different doses and various administration schedules. The clinical ocular exposure following ocular administration of Lev, Mox, and Gat solutions at different doses and various administration schedules was well predicted. CONCLUSION: Even though additional case studies for different types of active pharmaceutical ingredients (APIs) and formulations will be needed, the current study represents an important step in the validation of the extrapolation method to predict human ocular exposure for ophthalmic drug products using PBPK models.

Scientific and regulatory activities initiated by the U.S. Food and drug administration to foster approvals of generic dry powder inhalers: Bioequivalence perspective.

Regulatory science for generic dry powder inhalers (DPIs) in the United States (U.S.) has evolved over the last decade. In 2013, the U.S. Food and Drug Administration (FDA) published the draft product-specific guidance (PSG) for fluticasone propionate and salmeterol xinafoate inhalation powder. This was the first PSG for a DPI available in the U.S., which provided details on a weight-of-evidence approach for establishing bioequivalence (BE). A variety of research activities including in vivo and in vitro studies were used to support these recommendations, which have led to the first approval of a generic DPI in the U.S. for fluticasone propionate and salmeterol xinafoate inhalation powder in January of 2019. This review describes the scientific and regulatory activities that have been initiated by FDA to support the current BE recommendations for DPIs that led to the first generic DPI approvals, as well as research with novel in vitro and in silico methods that may potentially facilitate generic DPI development and approval.

Scientific and regulatory activities initiated by the U.S. food and drug administration to foster approvals of generic dry powder inhalers: Quality perspective.

Regulatory science for generic dry powder inhalation products worldwide has evolved over the last decade. The revised draft guidance Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products - Quality Considerations [1] (Revision 1, April 2018) that FDA issued summarizes product considerations and potential critical quality attributes (CQAs). This guidance emphasizes the need to apply the principles of quality by design (QbD) and elements of pharmaceutical development discussed in the International Conference for Harmonisation of (ICH) guidelines. Research studies related to quality were used to support guidance recommendations, which preceded the first approval of a generic DPI product in the U.S. This review outlines scientific and regulatory hurdles that need to be surmounted to successfully bring a generic DPI to the market. The goal of this review focuses on relevant issues and various challenges pertaining to CMC topics of the generic DPI quality attributes. Furthermore, this review provides recommendations to abbreviated new drug application (ANDA) applicants to expedite generic approvals.

Anatomically realistic nasal replicas capturing the range of nasal spray drug delivery in adults.

To improve the relationships between commonly conducted in vitro studies for locally-acting nasal spray drug products with in vivo regional deposition, this study developed a set of in vitro adult nasal geometries that captured the range of nasal drug delivery to the region posterior to internal nasal valve (INV), also known as posterior delivery (PD), and evaluated their performance with existing in vivo data. The PD of fluticasone propionate (FP) and fluticasone furoate (FF) in 40 nasal cavities was statistically analyzed to identify three airway models representing the low, mean, and high PD in adults. The models were also externally validated by comparing the in vitro nasal deposition from a different drug product (mometasone furoate (MF)) with the relevant in vivo data. The three selected geometries represented the low, mean, and high PD with multiple nasal sprays. They were verified in terms of reproducibility of in vitro data and validated by showing a reasonable agreement with preexisting in vivo MF PD despite differences in administration and defining the regions. The three models are envisioned to potentially facilitate the development of locally-acting nasal sprays and provide a better understanding of how in vitro metrics relate to in vivo regional nasal deposition.

Considerations for the Forced Expiratory Volume in 1 Second-Based Comparative Clinical Endpoint Bioequivalence Studies for Orally Inhaled Drug Products.

Herein, we present the US Food and Drug Administration (FDA) Office of Research and Standards' current thinking, challenges, and opportunities for comparative clinical endpoint bioequivalence (BE) studies of orally inhaled drug products (OIDPs). Given the product-associated complexities of OIDPs, the FDA currently uses an aggregate weight-of-evidence approach to demonstrate that a generic OIDP is bioequivalent to its reference listed drug. The approach utilizes comparative clinical endpoint BE or pharmacodynamic BE studies, pharmacokinetic BE studies, and in vitro BE studies to demonstrate equivalence, in addition to formulation sameness and device similarity. For the comparative clinical endpoint BE studies, metrics based on forced expiratory volume in the first second (FEV1 ) are often the recommended clinical endpoints. However, the use of FEV1 can pose a challenge due to its large variability and a relatively flat dose-response relationship for most OIDPs. The utility of applying dose-scale analysis was also investigated by the FDA but often not recommended, due to either flat dose-response relationships or insufficient clinical study data. As a potential way to reduce sample size, we found adapting covariate analysis only explained a limited portion of the variation based on further investigation. The FDA continues to develop alternative methods to make BE assessment of OIDPs more cost- and time-efficient. Prospective generic drug applicants and academia are encouraged to participate in this effort by proposing new approaches in pre-abbreviated new drug application meeting requests and collaborating in the form of grants and contracts under the Generic Drug User Fee Amendments (GDUFA) Regulatory Science and Research Program.

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

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.

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. complex generics) are an important element of the United States (U.S.) Food and Drug Administration's (FDA's) Generic Drug User Fee Amendments (GDUFA) II Commitment Letter. The Center for Research on Complex Generics (CRCG) was formed by a grant from the FDA to address challenges associated with the development of complex generics. To understand these challenges, the CRCG conducted a "Survey of Scientific Challenges in the Development of Complex Generics". The three main areas of questioning were directed toward which (types of) complex products, which methods of analysis to support a demonstration of bioequivalence, and which educational topics the CRCG should prioritize. The survey was open to the public on a website maintained by the CRCG. Regarding complex products, the top three selections were complex injectables, formulations, and nanomaterials; drug-device combination products; and inhalation and nasal products. Regarding methods of analysis, the top three selections were locally-acting physiologically-based pharmacokinetic modeling; oral absorption models and bioequivalence; and data analytics and machine learning. Regarding educational topics, the top three selections were complex injectables, formulations, and nanomaterials; drug-device combination products; and data analytics, including quantitative methods and modeling & simulation. These survey results will help prioritize the CRCG's initial research and educational initiatives.

A quasi-3D model of the whole lung: airway extension to the tracheobronchial limit using the constrained constructive optimization and alveolar modeling, using a sac-trumpet model.

Existing computational models used for simulating the flow and species transport in the human airways are zero-dimensional (0D) compartmental, three-dimensional (3D) computational fluid dynamics (CFD), or the recently developed quasi-3D (Q3D) models. Unlike compartmental models, the full CFD and Q3D models are physiologically and anatomically consistent in the mouth and the upper airways, since the starting point of these models is the mouth-lung surface geometry, typically created from computed tomography (CT) scans. However, the current resolution of CT scans limits the airway detection between the 3rd-4th and 7th-9th generations. Consequently, CFD and the Q3D models developed using these scans are generally limited to these generations. In this study, we developed a method to extend the conducting airways from the end of the truncated Q3D lung to the tracheobronchial (TB) limit. We grew the lung generations within the closed lung lobes using the modified constrained constructive optimization, creating an aerodynamically optimized network aiming to produce equal pressure at the distal ends of the terminal segments. This resulted in a TB volume and lateral area of ∼165 cc and ∼2000 cm2, respectively. We created a "sac-trumpet" model at each of the TB outlets to represent the alveoli. The volumes of the airways and the individual alveolar generations match the anatomical values by design: with the functional residual capacity at 2611 cc. Lateral surface areas were scaled to match the physiological values. These generated Q3D whole lung models can be efficiently used for conducting multiple breathing cycles of drug transport and deposition simulations.

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

Establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical end point studies can be costly and the studies may not be sufficiently sensitive to detect certain formulation differences. Quantitative methods and modeling, such as physiologically-based pharmacokinetic (PBPK) modeling, can support alternative BE approaches with reduced or no human testing. To enable PBPK modeling for regulatory decision making, models should be sufficiently verified and validated (V&V) for the intended purpose. This report illustrates the US Food and Drug Administration (FDA) approval of a generic diclofenac sodium topical gel that was based on a totality of evidence, including qualitative and quantitative sameness and physical and structural similarity to the reference product, an in vivo BE study with PK end points, and, more importantly, for the purposes of this report, a virtual BE assessment leveraging dermal PBPK modeling and simulation instead of a comparative clinical end point study in patients. The modeling approach characterized the relationship between systemic (plasma) and local (skin and synovial fluid) diclofenac exposure and demonstrated BE between the generic and reference products at the presumed site of action. Based on the fit-for-purpose modeling principle, the V&V process involved assessing observed data of diclofenac concentrations in skin tissues and plasma, and the overall performance of the modeling platform for relevant products. Using this case as an example, this report provides current scientific considerations on good practices for model V&V and the establishment of BE for dermatological drug products when leveraging PBPK modeling and simulation for regulatory decision making.

Physiologically Based Pharmacokinetic Modeling Approach to Identify the Drug-Drug Interaction Mechanism of Nifedipine and a Proton Pump Inhibitor, Omeprazole.

BACKGROUND AND OBJECTIVES: Proton pump inhibitors (PPIs) can affect the intragastric release of other drugs from their dosage forms by elevating the gastric pH. They may also influence drug absorption and metabolism by interacting with P-glycoprotein or with the cytochrome P450 (CYP) enzyme system. Nifedipine is a Biopharmaceutics Classification System (BCS) class II drug with low solubility across physiologic pH and high permeability. Previous studies have demonstrated that drug-drug interaction (DDI) existed between omeprazole and nifedipine with significantly increased systemic exposure of nifedipine in subjects after pre-treatment for 7 days with omeprazole compared to the subjects without omeprazole treatment. It was shown that omeprazole not only induced an increase in intragastric pH, but also inhibited the CYP3A4 activity, while CYP3A4-mediated oxidation is the main metabolic pathway of nifedipine. The purpose of this study is to apply a physiologically based pharmacokinetic (PBPK) modeling approach to investigate the DDI mechanism for an immediate release formulation of nifedipine with omeprazole. METHODS: A previously published model for omeprazole was modified to integrate metabolites and to update CYP inhibition based on the most updated published in vitro data. We simulated the nifedipine pharmacokinetics in healthy subjects with or without the multiple-dose pretreatment of omeprazole (20 mg) following oral administrations of immediate-release (IR) (10 mg) nifedipine. Nifedipine solubility at different pHs was used to simulate the nifedipine pharmacokinetics for both clinical arms. Multiple sensitivity analyses were performed to understand the impact of gastric pH and the CYP3A4-mediated gut and liver first pass metabolism on the overall nifedipine pharmacokinetics. RESULTS: The developed PBPK model properly described the pharmacokinetics of nifedipine and predicted the inhibitory effect of multiple-dose omeprazole on CYP3A4 activity. With the incorporation of the physiologic effect of omeprazole on both gastric pH and CYP3A4 to the PBPK model, the verified PBPK model allows evaluating the impact of the increase in gastric pH and/or CYP3A4 inhibition. The simulated results show that the nifedipine metabolic inhibition by omeprazole may play an important role in the DDI between nifedipine and omeprazole for IR nifedipine formulation. CONCLUSION: The developed full PBPK model with the capability to simulate DDI by considering gastric pH change and metabolic inhibition provides a mechanistic understanding of the observed DDI of nifedipine with a PPI, omeprazole.