Physiologically Based Biopharmaceutics Modeling (PBBM): Best Practices for Drug Product Quality, Regulatory and Industry Perspectives: 2023 Workshop Summary Report.

Physiologically based biopharmaceutics modeling (PBBM) is used to elevate drug product quality by providing a more accurate and holistic understanding of how drugs interact with the human body. These models are based on the integration of physiological, pharmacological, and pharmaceutical data to simulate and predict drug behavior in vivo. Effective utilization of PBBM requires a consistent approach to model development, verification, validation, and application. Currently, only one country has a draft guidance document for PBBM, whereas other major regulatory authorities have had limited experience with the review of PBBM. To address this gap, industry submitted confidential PBBM case studies to be reviewed by the regulatory agencies; software companies committed to training. PBBM cases were independently and collaboratively discussed by regulators, and academic colleagues participated in some of the discussions. Successful bioequivalence "safe space" industry case examples are also presented. Overall, six regulatory agencies were involved in the case study exercises, including ANVISA, FDA, Health Canada, MHRA, PMDA, and EMA (experts from Belgium, Germany, Norway, Portugal, Spain, and Sweden), and we believe this is the first time such a collaboration has taken place. The outcomes were presented at this workshop, together with a participant survey on the utility and experience with PBBM submissions, to discuss the best scientific practices for developing, validating, and applying PBBMs. The PBBM case studies enabled industry to receive constructive feedback from global regulators and highlighted clear direction for future PBBM submissions for regulatory consideration.

In Vitro In Vivo Extrapolation and Bioequivalence Prediction for Immediate-Release Capsules of Cefadroxil Based on a Physiologically-Based Pharmacokinetic ACAT Model.

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic concept, which helps to judge the effects of biopharmceutical properties of drug product such as in vitro dissolution on its pharmacokinetic and in vivo performance. With the application of virtual bioequivalence (VBE) study, the drug product development using model-based approach can help in evaluating the possibility of extending BCS-based biowaiver. Therefore, the current study was intended to develop PBPK model as well as in vitro in vivo extrapolation (IVIVE) for BCS class III drug i.e. cefadroxil. A PBPK model was created in GastroPlus™ 9.8.3 utilizing clinical data of immediate-release cefadroxil formulations. By the examination of simulated and observed plasma drug concentration profiles, the predictability of the proposed model was assessed for the prediction errors. Furthermore, mechanistic deconvolution was used to create IVIVE, and the plasma drug concentration profiles and pharmacokinetic parameters were predicted for different virtual formulations with variable cefadroxil in vitro release. Virtual bioequivalence study was also executed to assess the bioequivalence of the generic verses the reference drug product (Duricef®). The developed PBPK model satisfactorily predicted Cmax and AUC0-t after cefadroxil single and multiple oral dose administrations, with all individual prediction errors within the limits except in a few cases. Second order polynomial correlation function obtained accurately predict in vivo drug release and plasma concentration profile of cefadroxil test and reference (Duricef®) formulation. The VBE study also proved test formulation bioequivalent to reference formulation and the statistical analysis on pharmacokinetic parameters reported 90% confidence interval for Cmax and AUC0-t in the FDA acceptable limits. The analysis found that a validated and verified PBPK model with a mechanistic background is as a suitable approach to accelerate generic drug development.

A Semi-Mechanistic Physiologically Based Biopharmaceutics Model to Describe Complex and Saturable Absorption of Metformin: Justification of Dissolution Specifications for Extended Release Formulation.

Physiologically based pharmacokinetic (PBPK) or physiologically based biopharmaceutics models (PBBM) demonstrated plethora of applications in both new drugs and generic product development. Justification of dissolution specifications and establishment of dissolution safe space is an important application of such modeling approaches. In case of molecules exhibiting saturable absorption behavior, justification of dissolution specifications requires development of a model that incorporates effects of transporters is critical to simulate in vivo scenario. In the present case, we have developed a semi-mechanistic PBBM to describe the non-linearity of BCS class III molecule metformin for justification of dissolution specifications of extended release formulation at strengths 500 mg and 1000 mg. Semi-mechanistic PBBM was built using physicochemical properties, dissolution and non-linearity was accounted through incorporation of multiple transporter kinetics at absorption level. The model was extensively validated using literature reported intravenous, oral (immediate & extended release) formulations and further validated using in-house bioequivalence data in fasting and fed conditions. Virtual dissolution profiles at lower and upper specifications were generated to justify the dissolution specifications. The model predicted literature as well as in-house clinical study data with acceptable prediction errors. Further, virtual bioequivalence trials predicted the bioequivalence outcome that matched with clinical study data. The model predicted bioequivalence when lower and upper specifications were compared against pivotal test formulations thereby justifying dissolution specifications. Overall, complex and saturable absorption pathway of metformin was successfully simulated and this work resulted in regulatory acceptance of dissolution specifications which has ability to reduce multiple dissolution testing.

Integration of artificial neural network and physiologically based biopharmaceutic models in the development of sustained-release formulations.

Model-informed drug development is an important area recognized by regulatory authorities and is gaining increasing interest from the generic drug industry. Physiologically based biopharmaceutics modeling (PBBM) is a valuable tool to support drug development and bioequivalence assessments. This study aimed to utilize an artificial neural network (ANN) with a multilayer perceptron (MLP) model to develop a sustained-release matrix tablet of metformin HCl 500 mg, and to test the likelihood of the prototype formulation being bioequivalent to Glucophage® XR, using PBBM modeling and virtual bioequivalence (vBE). The ANN with MLP model was used to simultaneously optimize 735 formulations to determine the optimal formulation for Glucophage® XR release. The optimized formulation was evaluated and compared to Glucophage® XR using PBBM modeling and vBE. The optimized formulation consisted of 228 mg of hydroxypropyl methylcellulose (HPMC) and 151 mg of PVP, and exhibited an observed release rate of 42% at 1 h, 47% at 2 h, 55% at 4 h, and 58% at 8 h. The PBBM modeling was effective in assessing the bioequivalence of two formulations of metformin, and the vBE evaluation demonstrated the utility and relevance of translational modeling for bioequivalence assessments. The study demonstrated the effectiveness of using PBBM modeling and model-informed drug development methodologies, such as ANN and MLP, to optimize drug formulations and evaluate bioequivalence. These tools can be utilized by the generic drug industry to support drug development and biopharmaceutics assessments.

Advancing Virtual Bioequivalence for Orally Administered Drug Products: Methodology, Real-World Applications and Future Outlook.

Bioequivalence studies are pivotal in generic drug development wherein therapeutic equivalence is provided with an innovator product. However, bioequivalence studies represent significant complexities due to the interplay of multiple factors related to drug, formulation, physiology, and pharmacokinetics. Approaches such as physiologically based biopharmaceutics modeling (PBBM) can enable virtual bioequivalence (VBE) assessment through appropriately developed and validated models. Such models are now being extensively used for bioequivalence risk assessment, internal decision-making, and the evaluation of drug and formulation factors related to bioequivalence. Depiction of the above-mentioned factors through the incorporation of variability and development of a virtual population for bioequivalence assessment is of paramount importance in utilizing such models. In this manuscript, we have portrayed our current understanding of VBE. A detailed explanation was provided with respect to study designs, in vivo variability, and the impact of physiological, drug, and formulation factors on the development of the population for VBE. Furthermore, strategies are suggested to incorporate variability in GastroPlus with an emphasis on intra-subject and inter-occasion variability. Two industrial case studies pertaining to immediate and modified release formulation were portrayed wherein VBE was utilized for decision-making and regulatory justification. Finally, regulatory understanding in the area of VBE, along with future perspectives, was detailed.

Using Mechanistic Modeling Approaches to Support Bioequivalence Assessments for Oral Products.

This report summarizes the proceedings for Day 1 Session 3 of the 2-day public workshop entitled "Best Practices for Utilizing Modeling Approaches to Support Generic Product Development," a jointly sponsored workshop by the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) in the year 2022. The aims of this workshop were to discuss how to modernize approaches for efficiently demonstrating bioequivalence (BE), to establish their role in modern paradigms of generic drug development, and to explore and develop best practices for the use of modeling and simulation approaches in regulatory submissions and approval. The theme of this session is mechanistic modeling approaches supporting BE assessments for oral drug products. As a summary, with more successful cases of PBPK absorption modeling being developed and shared, the general strategies/frameworks on using PBPK for oral products are being formed; this will help further evolvement of this area. In addition, the early communications between the industry and the agency through appropriate pathways (e.g., pre-abbreviated new drug applications (pre-ANDA) meetings) are encouraged, and this will speed up the successful development and utility of PBPK modeling for oral products.

Can 3D Printed Tablets Be Bioequivalent and How to Test It: A PBPK Model Based Virtual Bioequivalence Study for Ropinirole Modified Release Tablets.

As the field of personalized dosing develops, the pharmaceutical manufacturing industry needs to offer flexibility in terms of tailoring the drug release and strength to the individual patient's needs. One of the promising tools which have such capacity is 3D printing technology. However, manufacturing small batches of drugs for each patient might lead to huge test burden, including the need to conduct bioequivalence trials of formulations to support the change of equipment or strength. In this paper we demonstrate how to use 3D printing in conjunction with virtual bioequivalence trials based on physiologically based pharmacokinetic (PBPK) modeling. For this purpose, we developed 3D printed ropinirole formulations and tested their bioequivalence with the reference product Polpix. The Simcyp simulator and previously developed ropinirole PBPK model were used for the clinical trial simulations. The Weibull-fitted dissolution profiles of test and reference formulations were used as inputs for the model. The virtual bioequivalence trials were run using parallel design. The study power of 80% was reached using 125 individuals. The study demonstrated how to use PBPK modeling in conjunction with 3D printing to test the virtual bioequivalence of newly developed formulations. This virtual experiment demonstrated the bioequivalence of one of the newly developed formulations with a reference product available on a market.

A Bayesian framework for virtual comparative trials and bioequivalence assessments.

Introduction: In virtual bioequivalence (VBE) assessments, pharmacokinetic models informed with in vitro data and verified with small clinical trials' data are used to simulate otherwise unfeasibly large trials. Simulated VBE trials are assessed in a frequentist framework as if they were real despite the unlimited number of virtual subjects they can use. This may adequately control consumer risk but imposes unnecessary risks on producers. We propose a fully Bayesian model-integrated VBE assessment framework that circumvents these limitations. Methods: We illustrate our approach with a case study on a hypothetical paliperidone palmitate (PP) generic long-acting injectable suspension formulation using a validated population pharmacokinetic model published for the reference formulation. BE testing, study power, type I and type II error analyses or their Bayesian equivalents, and safe-space analyses are demonstrated. Results: The fully Bayesian workflow is more precise than the frequentist workflow. Decisions about bioequivalence and safe space analyses in the two workflows can differ markedly because the Bayesian analyses are more accurate. Discussion: A Bayesian framework can adequately control consumer risk and minimize producer risk . It rewards data gathering and model integration to make the best use of prior information. The frequentist approach is less precise but faster to compute, and it can still be used as a first step to narrow down the parameter space to explore in safe-space analyses.

Virtual Bioequivalence Assessment of Ritlecitinib Capsules with Incorporation of Observed Clinical Variability Using a Physiologically Based Pharmacokinetic Model.

Ritlecitinib, an orally available Janus kinase 3 and tyrosine kinase inhibitor being developed for the treatment of alopecia areata (AA), is highly soluble across the physiological pH range at the therapeutic dose. As such, it is expected to dissolve rapidly in any in vitro dissolution conditions. However, in vitro dissolution data showed slower dissolution for 100-mg capsules, used for the clinical bioequivalence (BE) study, compared with proposed commercial 50-mg capsules. Hence, a biowaiver for the lower 50-mg strength using comparable multimedia dissolution based on the f2 similarity factor was not possible. The in vivo relevance of this observed in vitro dissolution profile was evaluated with a physiologically based pharmacokinetic (PBPK) model. This report describes the development, verification, and application of the ritlecitinib PBPK model to translate observed in vitro dissolution data to an in vivo PK profile for ritlecitinib capsule formulations. Virtual BE (VBE) trials were conducted using the Simcyp VBE module, including the model-predicted within-subject variability or intra-subject coefficient of variation (ICV). The results showed the predicted ICV was predicted to be smaller than observed clinical ICV, resulting in a more optimistic BE risk assessment. Additional VBE assessment was conducted by incorporating clinically observed ICV. The VBE trial results including clinically observed ICV demonstrated that proposed commercial 50-mg capsules vs clinical 100-mg capsules were bioequivalent, with > 90% probability of success. This study demonstrates a PBPK model-based biowaiver for a clinical BE study while introducing a novel method to integrate clinically observed ICV into VBE trials with PBPK models. Trial registration: NCT02309827, NCT02684760, NCT04004663, NCT04390776, NCT05040295, NCT05128058.

Modelling Based Approaches to Support Generic Drug Regulatory Submissions-Practical Considerations and Case Studies.

Model informed drug development (MiDD) is useful to predict in vivo exposure of drugs during various stages of the drug development process. This approach employs a variety of quantitative tools to assess the risks during the drug development process. One important tool in the MiDD tool kit is the Physiologically Based Pharmacokinetic Modelling (PBPK). This tool is extensively used to reduce the development cost and to accelerate the access of medicines to the patients. In this work, we provide an overview of PBPK modelling approaches in the generic drug development process, with a special emphasis on the bio-waiver applications. We describe herein approaches and common pitfalls while submitting model based justifications as a response to the regulatory deficiencies during the generic drug development process. With some in-house case studies, we have attempted to provide a clear path for PBPK model based justifications for bio-waivers. With this review, the gap between theoretical knowledge and practical application of modelling and simulation tools for generic drug product development could be potentially reduced.

Virtual Bioequivalence Assessment of Elagolix Formulations Using Physiologically Based Pharmacokinetic Modeling.

In lieu of large bioequivalence studies and exposing healthy postmenopausal women to additional drug exposure for elagolix coadministered with hormonal add-back therapy, physiologically based pharmacokinetic (PBPK) modeling was used with in vitro dissolution data to test for virtual bioequivalence. For endometriosis, elagolix is approved at doses of 150 mg once daily and 200 mg twice daily as a tablet. As a combination therapy, two individual tablets, consisting of an elagolix tablet and an estradiol/norethindrone acetate 1/0.5 mg (E2/NETA) tablet, were utilized in Phase 3 endometriosis trials. However, the commercial combination drug products consist of a morning capsule (containing an elagolix tablet and E2/NETA tablet as a fixed-dose combination capsule, AM capsule) and an evening capsule (consisting of an elagolix tablet, PM capsule). In vitro dissolution profiles were dissimilar for the tablet and capsule formulations; thus, in vivo bioequivalence studies or a bioequivalence waiver would have been required. To simulate virtual cross-over, bioequivalence trials, in vitro dissolution data was incorporated into a previously verified PBPK model. The updated PBPK model was externally validated using relevant bioequivalence study data. Based on results of the virtual bioequivalence simulations, the commercial drug product capsules met the bioequivalence criteria of 0.80-1.25 when compared to the reference tablets. This was a novel example where PBPK modeling was utilized along with in vitro dissolution data to demonstrate virtual bioequivalence in support of a regulatory bioequivalence waiver.

Integration of Biorelevant Pediatric Dissolution Methodology into PBPK Modeling to Predict In Vivo Performance and Bioequivalence of Generic Drugs in Pediatric Populations: a Carbamazepine Case Study.

This study investigated the impact of gastro-intestinal fluid volume and bile salt (BS) concentration on the dissolution of carbamazepine (CBZ) immediate release (IR) 100 mg tablets and to integrate these in vitro biorelevant dissolution profiles into physiologically based pharmacokinetic modelling (PBPK) in pediatric and adult populations to determine the biopredictive dissolution profile. Dissolution profiles of CBZ IR tablets (100 mg) were generated in 50-900 mL biorelevant adult fasted state simulated gastric and intestinal fluid (Ad-FaSSGF and Ad-FaSSIF), also in three alternative compositions of biorelevant pediatric FaSSGF and FaSSIF medias at 200 mL. This study found that CBZ dissolution was poorly sensitive to changes in the composition of the biorelevant media, where dissimilar dissolution (F2 = 46.2) was only observed when the BS concentration was changed from 3000 to 89 µM (Ad-FaSSIF vs Ped-FaSSIF 50% 14 BS). PBPK modeling demonstrated the most predictive dissolution volume and media composition to forecast the PK was 500 mL of Ad-FaSSGF/Ad-FaSSIF media for adults and 200 mL Ped-FaSSGF/FaSSIF media for pediatrics. A virtual bioequivalence simulation was conducted by using Ad-FaSSGF and/or Ad-FaSSIF 500 mL or Ped-FaSSGF and/or Ped-FaSSIF 200 mL dissolution data for CBZ 100 mg (reference and generic test) IR product. The CBZ PBPK models showed bioequivalence of the product. This study demonstrates that the integration of biorelevant dissolution data can predict the PK profile of a poorly soluble drug in both populations. Further work using more pediatric drug products is needed to verify biorelevant dissolution data to predict the in vivo performance in pediatrics.

Understanding Discordance between In Vitro Dissolution, Local Gut and Systemic Bioequivalence of Budesonide in Healthy and Crohn's Disease Patients through PBPK Modeling.

The most common method for establishing bioequivalence (BE) is to demonstrate similarity of concentration-time profiles in the systemic circulation, as a surrogate to the site of action. However, similarity of profiles from two formulations in the systemic circulation does not imply similarity in the gastrointestinal tract (GIT) nor local BE. We have explored the concordance of BE conclusions for a set of hypothetical formulations based on budesonide concentration profiles in various segments of gut vs. those in systemic circulation using virtual trials powered by physiologically based pharmacokinetic (PBPK) models. The impact of Crohn's disease on the BE conclusions was explored by changing physiological and biological GIT attributes. Substantial 'discordance' between local and systemic outcomes of VBE was observed. Upper GIT segments were much more sensitive to formulation changes than systemic circulation, where the latter led to false conclusions for BE. The ileum and colon showed a lower frequency of discordance. In the case of Crohn's disease, a product-specific similarity factor might be needed for products such as Entocort® EC to ensure local BE. Our results are specific to budesonide, but we demonstrate potential discordances between the local gut vs. systemic BE for the first time.

Model-Informed drug development of gastroretentive release systems for sildenafil citrate.

Gastroretentive drug delivery systems (GRDDS) are modified-release dosage forms designed to prolong their residence time in the upper gastrointestinal tract, where some drugs are preferentially absorbed, and increase the drug bioavailability. This work aimed the development of a novel GRDDS containing 60 mg of sildenafil citrate, and the evaluation of the feasibility of the proposed formulation for use in the treatment of pulmonary arterial hypertension (PAH), for once a day administration, by using in silico pharmacokinetic (PK) modeling and simulations using GastroPlusTM. The Model-Informed Drug Development (MIDD) approach was used in formulation design and pharmacokinetic exposure prospecting. A 22 factorial design with a central point was used for optimization of the formulation, which was produced by direct compression and characterized by some tests, including buoyancy test, assay, impurities, and in vitro dissolution. A compartmental PK model was built using the GatroPlusTM software for virtual bioequivalence of the proposed formulations in comparison with the defined target release profile provided by an immediate release (IR) tablet formulation containing 20 mg of sildenafil administered three times a day (TID). The results of the factorial design showed a direct correlation between the dissolution rate and the amount of hydroxypropyl methyl cellulose (HPMC) in the formulations. By comparing the PK parameters predicted by the virtual bioequivalence, the formulations F1, F2, F3 and F5 failed on bioequivalence. The F4 showed bioequivalence to the reference and was considered the viable formulation to substitute the IR. Thus, GRDDS could be a promising alternative for controlling the release of drugs with a pH-dependent solubility and narrow absorption window, specifically in the gastric environment, and an interesting way to reduce dose frequency and increase the drug bioavailability. The MIDD approach increases the level of information about the pharmaceutical product and guide the drug development for more assertive ways.

Proof of Concept in Assignment of Within-Subject Variability During Virtual Bioequivalence Studies: Propagation of Intra-Subject Variation in Gastrointestinal Physiology Using Physiologically Based Pharmacokinetic Modeling.

While the concept of 'Virtual Bioequivalence' (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as 'not plausible'. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. Graphical Abstract.

Prediction of pharmacokinetic parameters of inhaled indacaterol formulation in healthy volunteers using physiologically-based pharmacokinetic (PBPK) model.

BACKGROUND: Inhaled formulations are the first choices for treating asthma and chronic obstructive pulmonary disease (COPD), attracting the increasing investment and development in the pharmaceutical industry. Both the equivalence of local and systemic exposures need to be considered when assessing the equivalence of generic inhaled drugs, which has become a dilemma in the development of generic inhaled drugs. There is an urgent need for reliable methods such as physiologically-based pharmacokinetic (PBPK) model to assist in the development of inhaled drugs. METHOD: To test the strategy that in silico simulation is an effective tool in developing inhaled products and further assessing their clinically feasibility, a long-acting beta2-adrenergic agonists indacaterol, which was referred as the first-line therapy for patient with COPD, was selected as a tool drug. The PBPK model was established and the predicted plasma concentration curve was obtained by inputting the physicochemical properties of indacaterol and adjusting model parameters. The accuracy of simulation was verified by an alignment with the actual data. The main factor affecting PK in vivo was investigated by parameter sensitivity analysis. The biological equivalent size of indacaterol was investigated by virtual bioequivalence analysis. RESULTS: The models of indacaterol after intravenous and oral administration were established and confirmed, and used as a background for PBPK model of inhaled administration. All those models showed favorable stability and applicability. Appropriate lung deposition was generated in the PBPK model, and the predicted plasma profile of indacaterol was consistent with the clinical actual observation values. Particle size is the most important factor affecting the PK of indacaterol in vivo. Furthermore, virtual bioequivalence simulation exhibited statistically comparable results between the particle size fluctuates in the range of 3.5-6.5 µm and baseline levels (D90 = 5 µm). CONCLUSIONS: The PBPK model can simulate the pharmacokinetics and lung deposition of indacaterol, which will be a powerful tool to assist the development of inhaled drugs.

Development of Extended-Release Mini-Tablets Containing Metoprolol Supported by Design of Experiments and Physiologically Based Biopharmaceutics Modeling.

The development of extended-release dosage forms with adequate drug release is a challenge for pharmaceutical companies, mainly when the drug presents high solubility, as in Biopharmaceutics Classification System (BCS) class I. This study aimed to develop extended-release mini-tablets containing metoprolol succinate (MS), while integrating design of experiments (DOE) and physiologically based biopharmaceutics modeling (PBBM), to predict its absorption and to run virtual bioequivalence (VBE) studies in both fasted and fed states. Core mini-tablet formulations (F1, F2, and F3) were prepared by direct compression and coated using nine coating formulations planned using DOE, while varying the percentages of the controlled-release and the pore-forming polymers. The coated mini-tablets were submitted to a dissolution test; additional formulations were prepared that were optimized by simulating the dissolution profiles, and the best one was submitted to VBE studies using GastroPlus® software. An optimized formulation (FO) containing a mixture of immediate and extended-release mini-tablets showed to be bioequivalent to the reference drug product containing MS when running VBE studies in both fasted and fed states. The integration of DOE and PBBM showed to be an interesting approach in the development of extended-release mini-tablet formulation containing MS, and can be used to rationalize the development of dosage forms.

A mechanistic physiologically based model to assess the effect of study design and modified physiology on formulation safe space for virtual bioequivalence of dermatological drug products.

Physiologically based pharmacokinetic (PBPK) models are widely accepted tools utilised to describe and predict drug pharmacokinetics (PK). This includes the use of dermal PBPK models at the regulatory level including virtual bioequivalence (VBE) studies. The current work considers the Topicort® Spray formulation, which contains 0.25% desoximetasone (DSM), as an example formulation. Quantitative formulation composition and in vitro permeation testing (IVPT) data were obtained from the public literature to develop a mechanistic model using the multi-phase, multi-layer (MPML) MechDermA IVPT module in the Simcyp Simulator. In vitro-in vivo extrapolation functionality was used to simulate in vivo PK for various scenarios and predict a 'safe space' for formulation bioequivalence using the VBE module. The potential effect of vasoconstriction, impaired barrier function, and various dosing scenarios on the formulation safe space was also assessed. The model predicted 'safe space' for formulation solubility suggesting that a 50% change in solubility may cause bio-in-equivalence, whereas viscosity could deviate by orders of magnitude and the formulation may still remain bioequivalent. Evaporation rate and fraction of volatile components showed some sensitivity, suggesting that large changes in the volume or composition of the volatile fraction could cause bio-in-equivalence. The tested dosing scenarios showed decreased sensitivity for all formulation parameters with a decreased dose. The relative formulation bioequivalence was insensitive to vasoconstriction, but the safe space became wider with decreased barrier function for all parameters, except viscosity that was unaffected.

Modelling and simulation approaches to support formulation optimization, clinical development and regulatory assessment of the topically applied formulations - Nimesulide solution gel case study.

The objective of the study was to show how mechanistic modelling can be used to characterize the skin absorption of Nimesulide (NIM) in both in vitro systems and in vivo subjects. A basic PBPK model for oral absorption to characterize the systemic disposition of NIM and MPML MechDermATM models for in vitro permeation and in vivo, topical absorption was developed and verified using published data. The developed models utilize drug physicochemical properties, formulation attributes and physiology information either collected from literature and/or from Simcyp databases (systems' data). Following the verification of the PBPK models virtual bioequivalence (VBE) trials were performed both at systemic and local exposure levels (dermis concentrations) to compare these formulations. A parameter sensitivity analysis was conducted to understand the impact of vehicle-related attributes on IVPT (in vitro permeation test) data. The vehicle-stratum corneum lipids partition coefficient in the formulation layer (Kpsc_lip:vehicle) was identified to be an appropriate parameter to take into account the differences in dermal absorption of marketed preparations based on the qualitative composition. Thus, this parameter was optimized for each marketed product based on the published in vitro data. After verification of the IVPT model, IVIVE was performed to assess the predictability of the model for studying the in vivo pharmacokinetics of NIM. The VBE analysis concluded that these formulations are bioequivalent at the level of systemic and local dermis exposure. To summarize, the study shows the use of modelling and simulation (M&S) tools to better understand the behaviour of formulations and their interaction with human physiology.

In silico prediction of bioequivalence of Isosorbide Mononitrate tablets with different dissolution profiles using PBPK modeling and simulation.

AIM: The waiver of bioequivalence (BE) studies is well accepted for Biopharmaceutics Classification System (BCS) class I drugs in form of immediate-release solid oral products. This study aimed to assess whether the rapid dissolution profiles (≥85% in 30 min) was crucial to guarantee bioequivalence of isosorbide mononitrate (ISMN) and then established a clinically relevant dissolution specification (CRDS) for screening BE or non-BE batches. METHOD: A physiologically based pharmacokinetic (PBPK) model was constructed by integrating clinical and non-clinical data by B2O simulator. The model was verified by an actual clinical study (NMPA registration number: CTR20191360) with 28 healthy Chinese subjects. Then a virtual BE study was simulated to evaluate the bioequivalence of 7 virtual batches of ISMN tablets with different dissolution profiles, and the CRDS was established by integrating the results. RESULT: The simulated PK behavior of ISMN was comparable to the observed. Even though the batches with slower dissolution were not equivalent to a rapid dissolution profile (≥85% in 30 min), it was demonstrated these batches would exhibit the similar in vivo performance. Meanwhile, the in vitro dissolution specification time point and the percentage of drug release (75% in 45 min) proved to have clinical relevance. CONCLUSION: The virtual BE simulation by integrating in vitro dissolution profiles into the PBPK model provided a powerful tool for screening formulations, contributing to gaining time and reducing costs in BE evaluations.