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Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling has been extensively applied to quantitatively translate invitro data, predict the invivo performance, and ultimately support waivers of invivo clinical studies. In the area of biopharmaceutics and within the context of model-informed drug discovery and development (MID3), there is a rapidly growing interest in applying verified and validated mechanistic PBPK models to waive invivo clinical studies. However, the regulatory acceptance of PBPK analyses for biopharmaceutics and oral drug absorption applications, which is also referred to variously as ""PBPK absorption modeling"" [Zhang et al. CPT: Pharmacometrics Syst. Pharmacol. 2017, 6, 492], ""physiologically based absorption modeling"", or ""physiologically based biopharmaceutics modeling"" (PBBM), remains rather low [Kesisoglou et al. J. Pharm. Sci. 2016, 105, 2723] [Heimbach et al. AAPS J. 2019, 21, 29]. Despite considerable progress in the understanding of gastrointestinal (GI) physiology, invitro biopharmaceutic and in silico tools, PBPK models for oral absorption often suffer from an incomplete understanding of the physiology, overparameterization, and insufficient model validation and/or platform verification, all of which can represent limitations to their translatability and predictive performance. The complex interactions of drug substances and (bioenabling) formulations with the highly dynamic and heterogeneous environment of the GI tract in different age, ethnic, and genetic groups as well as disease states have not been yet fully elucidated, and they deserve further research. Along with advancements in the understanding of GI physiology and refinement of current or development of fully mechanistic in silico tools, we strongly believe that harmonization, interdisciplinary interaction, and enhancement of the translational link between invitro, in silico, and invivo will determine the future of PBBM. This Perspective provides an overview of the current status of PBBM, reflects on challenges and knowledge gaps, and discusses future opportunities around PBPK/PD models for oral absorption of small and large molecules to waive invivo clinical studies.

The incidence of acute coronary events is increased among people living with HIV (PLWH), but there is no risk estimation score, nor a surrogate biomarker able to predict subclinical coronary artery disease (sCAD). We assessed the performance of: (i) Framingham risk score (FRMs), (ii) peripheral (carotid and femoral) artery atheromatosis, and (iii) coronary artery calcium (CACs) score, to detect the presence of sCAD, in PLWH. In a cohort of PLWH free of cardiovascular disease (CVD), we measured sCAD and CACs by computed tomography, calculated FRMs, and assessed carotid/femoral plaques by ultrasound. In 56 participants (age: 49 ± 10 years, men: 88%, FRMs: 7.2 ± 6.9; mean number of carotid/femoral plaques: 1.4 ± 1.5; CACs >0 present in 59%, median CACs 0.9 [IQR 0-22]): (i) minimal sCAD (stenosis 1%-24%; present in 30%) and mild sCAD (25%-49%, 25%) were effectively detected by FRMs, number of plaques, and CACs [area under the curve (AUC) of CACs was better than that of both FRM and plaques, p < .05]; (ii) moderate sCAD (stenosis 50%-69%; present in 8.9%) was detected by number of plaques and CACs, but similar AUC (0.969 vs. 0.867, respectively, p = NS); and (iii) severe sCAD (70%-99%, present in only 3 [5.4%]) was detected only by CACs. A high prevalence of sCAD in asymptomatic PLWH free of CVD was detected; CACs is a highly efficient biomarker to detect all grades of sCAD, however, the number of carotid/femoral plaques combined is also a very promising - lower cost and radiation free - surrogate biomarker. Future, larger studies are needed to verify these results. © 2021 Mary Ann Liebert Inc.

Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can serve as a powerful framework for predicting the influence as well as the interaction of formulation, genetic polymorphism and co-medication on the pharmacokinetics and pharmacodynamics of drug substances. In this study, flurbiprofen, a potent non-steroid anti-inflammatory drug, was chosen as a model drug. Flurbiprofen has absolute bioavailability of ~95% and linear pharmacokinetics in the dose range of 50&ndash, 300 mg. Its absorption is considered variable and complex, often associated with double peak phenomena, and its pharmacokinetics are characterized by high inter-subject variability, mainly due to its metabolism by the polymorphic CYP2C9 (fmCYP2C9 &ge, 0.71). In this study, by leveraging in vitro, in silico and in vivo data, an integrated PBPK/PD model with mechanistic absorption was developed and evaluated against clinical data from PK, PD, drug-drug and gene-drug interaction studies. The PBPK model successfully predicted (within 2-fold) 36 out of 38 observed concentration-time profiles of flurbiprofen as well as the CYP2C9 genetic effects after administration of different intravenous and oral dosage forms over a dose range of 40&ndash, 300 mg in both Caucasian and Chinese healthy volunteers. All model predictions for Cmax, AUCinf and CL/F were within two-fold of their respective mean or geometric mean values, while 90% of the predictions of Cmax, 81% of the predictions of AUCinf and 74% of the predictions of Cl/F were within 1.25 fold. In addition, the drug-drug and drug-gene interactions were predicted within 1.5-fold of the observed interaction ratios (AUC, Cmax ratios). The validated PBPK model was further expanded by linking it to an inhibitory Emax model describing the analgesic efficacy of flurbiprofen and applying it to explore the effect of formulation and genetic polymorphisms on the onset and duration of pain relief. This comprehensive PBPK/PD analysis, along with a detailed translational biopharmaceutic framework including appropriately designed biorelevant in vitro experiments and in vitro-in vivo extrapolation, provided mechanistic insight on the impact of formulation and genetic variations, two major determinants of the population variability, on the PK/PD of flurbiprofen. Clinically relevant specifications and potential dose adjustments were also proposed. Overall, the present work highlights the value of a translational PBPK/PD approach, tailored to target populations and genotypes, as an approach towards achieving personalized medicine.

Introduction: The course of anosmia and ageusia in COVID-19 patients is not yet clearly known. We present short-term follow-up data concerning mild to moderate disease in home-quarantined COVID-19 patients in Greece. Methods: We provided a symptom questionnaire and instructions for a self-administered home smell-and-taste test to 79 positive COVID-19 patients from 2 tertiary hospitals in Greece. The patients recorded their subjective symptoms before and during infection as well as 4 weeks after the diagnosis. The patients also underwent the home test during infection and 4 weeks later. Results: Twenty-nine patients (36.7%) reported a loss of smell, and 21 (27.8%) reported a loss of taste, with equal prevalences between genders. We observed 2 types of recovery, i.e., a rapid, almost complete recovery, and a second slower and partial recovery. The type of recovery was not age related. A rapid recovery was observed in two thirds of the patients, with their olfactory ratings presenting a trend towards significance in correlation with nasal obstruction. A slow recovery in olfaction was correlated with low intensity ratings in odors with a trigeminal compound. The loss of taste was more pronounced in sweet and salty intensity ratings. Conclusion: Chemosensory deficits associated with COVID-19 infection were quite frequent among the Greek patients with mild or moderate disease who, in most cases, returned to normal within 4 weeks. However, 1 in 3 patients presented with persistent olfactory and gustatory dysfunction in the short term. © 2020 S. Karger AG. All rights reserved.