"Pressure is mounting on pharmaceutical industry from regulators, professional associations, and patient advocacy groups to introduce more diversity in the clinical drug trials. In November 2020 FDA published a new guidance for industry entitled “Enhancing the Diversity of Clinical Trial Populations” where the current eligibility criteria, enrolment practices, and trial designs were questioned and new recommendations made on removing exclusion criteria for patient recruitment when such criteria are not supported by any scientific rationale. Despite the statement calling for expanded eligibility criteria (e.g. in oncology trials to include patients with hepatic and renal dysfunction) a clear regulatory pathway was not defined. Such a path will be required and should be incentivized. One potential contributor to such a path would be translational modelling and simulation (M&S) integrating diverse pieces of information and giving practical advice on most like outcomes related to patient sub-groups. The first step of rationalisation is adjusting the level of systemic exposure such that sub-groups are not exposed to higher levels compared to a typical patient. This ensures patient safety in the absence of any additional pharmacodynamics-related sensitivities. This presentation summarises the recent advances made in the use oi physiologically-based pharmacokinetics (PBPK) and advocates the use of M&S in drug development. Although a priori use of these models is not common, apart from limited areas such as drug-drug interactions or paediatrics pharmacology and dose adjustments, they have the flexibility to evolve into companion model-informed precision dosing (MIPD) tools in many other areas associated with special populations (hepatic or renal impairment, diverse ethnic groups, pregnancy, frail elderly, etc). Although these models only address the precision dosing from the angle of decreased heterogeneity in drug response, similar approaches in the quantitative systems pharmacology are starting to emerge that address the diversity in response when the exposure are similar. Some of the new technologies such as quantitative liquid biopsy based on plasma measurements are able to determine liver content of key enzymes, transporters and drug targets. Integration of the technique with translational M&S should facilitate the efforts for expansion of recruitment criteria to trials without jeopardising any of the outcomes. The ultimate goal would be delivering precise and effective dosage regimens (precision dosing) under the umbrella of precision medicine without the need for dedicated clinical studies in patient sub-groups, with massive time and cost implications."

Achievements for modelling the impact of transporter in recent years are tremendous, which is also reflected in the impact in drug labels. However, some improvements are still required and the session will discuss:- (1) what is needed for further qualification of transporter in vitro-to-in vivo extrapolation models that are linked to physiologically-based pharmacokinetic (IVIVE-PBPK) models, (2) what are the gaps in our knowledge to advance the research field further, and (3) what matrix approach could be successful for a specific transporter. This symposium will focus on the current scientific and regulatory aspects of the use of mechanistic modeling such as PBPK modeling in the prediction and evaluation of transporter-mediated DDI and organ concentrations. It becomes more recognized that transporters may play a significant role in drugs disposition affecting their efficacy and safety. At the same time transporter expression and activities may change by age, sex, race, disease status, comorbidity, and polypharmacy. We aim to discuss the concept of in vitro modelling of transporter data, new induction models for transporters, abundance/activity relationships, known genotype/phenotype disconnects for transporters, and relevance of transporters also in herb-drug interactions. The session will be suitable for students as well as professors, for industry as well as regulators. Pharmaceutical scientists from the drug development to the clinical pharmacology arena will benefit from this session. The session will discuss the quality and quantity of model informing data available for estimating transporter-mediated clearance and DDIs and its impact on translational PBPK predictions. We not only want to give a view of recent (=last 2 years) developments in the transporter field, but also want to highlight future needs and give new suggestions for research in this area. Hence, attendees can gain insight on constraints towards development of well-informed PBPK(PD) models, the sensitivity of assumptions and extrapolations involved, and may obtain some new ideas of future research in the area of transporter IVIVE-PBPK/PD.

Session: Rapid Fire: Clinical Pharmacology and Immunogenicity Considerations of Novel Modalities: Modeling the Impact of Immunogenicity on PK of Therapeutic Protein

Session: Symposium: Clinical Pharmacology Challenges and Opportunities in Rare and Neglected Diseases and Special Populations: Opportunities and Challenges for Physiologically Based Pharmacokinetic Models of mAbs in Pregnancy and Pediatrics

Session: Symposium: Clinical Pharmacology Challenges and Opportunities in Rare and Neglected Diseases and Special Populations: Opportunities for Physiologically Based Pharmacokinetic Models in Perinatal Pharmacology

Session: Symposium: Model-Informed Preclinical and Translational Drug Development: Modeling in-vitro Assays to Improve the Robustness of Transporters' Ki

Glyburide (INN: Glibenclamide), a BCS Class II weak acid used in the treatment of Type 2 diabetes, is a substrate of CYP2C9, CYP3A4, OATP1B1, P-gp and OATP2B1 in vitro. It is available as micronized and non-micronized glyburide in non-bioequivalent formulations. Published PBPK models for glyburide have focussed either on predicting drug-drug interactions1 or oral formulation performance2-4. Here we develop a PBPK model for glyburide predictive of both drug/food-drug interactions and oral formulation performance.

The purpose of this work is to describe skin absorption of eutectic mixture formulations using the Multi-Phase Multi-Layer Mechanistic Dermal Absorption (MPML MechDermA) in vitro skin permeation testing (IVPT) module within Simcyp simulator (V20). An In VitroIn Vivo Extrapolation (IVIVE) approach was used to derive critical kinetic parameters by modelling IVPT results of EMLA® cream (eutectic mixtures of lidocaine 2.5% w/w and prilocaine 2.5% w/w) and later to extrapolate model parameters towards the development of a Physiologically-Based Pharmacokinetic (PBPK) model to predict the systemic exposure of both lidocaine and prilocaine following in vivo topical application of the cream.

BIO89-100 is a glycoPEGylated analog of fibroblast growth factor 21 (FGF21) under development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia (SHTG). FGF21 is an endogenous metabolic hormone that regulates lipid, carbohydrate and energy metabolism; it has a half-life of < 2 hours. The purpose of glycoPEGylation is to prolong half-life, enabling less frequent dosing regimens. Early-development data to support first-time-in-humans trial (FTIH) and FTIH data are reported here.

This presentation will provide an overview of R Speaks NLME (RsNLME), a new collection of R packages, and companion RShiny applications that enable scientists to run pharmacometric models using a NLME engine and PML (pharmacometric modeling language) from the R command line, or using Pirana, a workflow management tool for NONMEM and NLME.

FDA is actively encouraging the use of Model Informed Drug Development (MIDD) for new drug development and Model Integrated Evidence (MIE) for generic drugs when appropriate.[FY 2021 GDUFA Science and Research Initiative]. These methods have played a critical role in the modernization of bioequivalence (BE) assessment and supporting regulatory decision-making, especially for locally acting drug products, complex products of other types, and modified-release solid oral dosage forms. During this presentation, we will share a number of case studies that demonstrate how MIE has been used to optimize formulations, justify dissolution specifications, support SUPAC, waive clinical studies based on scientific evidence, and prove bioequivalence.

The rectal route of drug administration is of considerable interest to pharmaceutical companies given that under certain circumstances (lack of patient compliance with oral drugs, unstable drugs or drugs prone to high first-pass metabolism), it can be more efficacious than oral intake. There is, however, no publicly available physiological mathematical model of rectal drug absorption. We present a novel minimal PBPK model addressing this gap. We verify the model by simulating published data pertaining to the uptake of paracetamol from laboratory-created suppositories and of promethazine from commercial suppositories.

Dissolution profile is one of the crucial input elements for the development of absorption models for the extended-release (ER) oral formulations. When using an in vitro dissolution profile as an input, an assumption about its in vivo relevance is made. The purpose of our study was to build a physiologically based pharmacokinetic model (PBPK) for the ropinirole 24-h ER formulation used in Parkinson's patients and check whether the dissolution profile obtained using the conventional USP methods will be predictive for the in vivo situation. Ropinirole belongs to the BCS Class 1 which suggests its consistent dissolution behavior in different media, however, it was hypothesized that the combination of formulation effect together with the potential Parkinson's disease-relevant modifications in the patients' gastro-intestinal tract, could affect the drug release.