Virtual bioequivalence for achlorhydric subjects: The use of PBPK modelling to assess the formulation-dependent effect of achlorhydria

Majority of bioequivalence studies are conducted in healthy volunteers. It has been argued that bioequivalence may not necessarily hold true in relevant patient populations due to a variety of reasons which affect one formulation more than the other for instance in achlorhydric patients where elevated gastric pH may lead to differential effects on formulations which are pH-sensitive with respect to release or dissolution. We therefore examined achlorhydria-related disparity in bioequivalence of levothyroxine and nifedipine formulations using virtual bioequivalence within a physiologically-based pharmacokinetic (PBPK) modelling framework. The in vitro dissolution profiles at neutral pH were incorporated into PBPK models to mimic the achlorhydria with in vitro–in vivo relationship established using bio-relevant pH media. The PBPK models successfully reproduced the outcome of the bioequivalence studies in healthy volunteers under the normal conditions as well as under proton pump inhibitor-induced achlorhydria. The geometric mean test/reference ratios for Cmax and AUC between levothyroxine tablet and capsule in patients receiving proton pump inhibitor were 1.21 (90%CI, 1.13–1.29) and 1.09 (90%CI, 1.02–1.17), respectively. Extension of the virtual bioequivalence study to Japanese elderly, who show high incidence of achlorhydria, indicated bio-inequivalence which Cmax and AUC ratios between nifedipine control-released reference and test formulations were 3.08 (90%CI, 2.81–3.38) and 1.57 (90%CI, 1.43–1.74), respectively. Virtual bioequivalence studies through the PBPK models can highlight the need for conduct of specific studies in elderly Japanese populations where there are discrepancies in pH-sensitivity of dissolution between the test and reference formulations

Review article: time to revisit Child‐Pugh score as the basis for predicting drug clearance in hepatic impairment

From Wiley via Jisc Publications RouterHistory: received 2021-03-04, rev-recd 2021-04-14, accepted 2021-06-04, pub-electronic 2021-07-04Article version: VoRPublication status: PublishedFunder: Egyptian Missions SectorSummary: Background: Prescription information for many drugs entering the market lacks dosage guidance for hepatic impairment. Dedicated studies for assessing the fate of drugs in hepatic impairment commonly stratify patients using Child‐Pugh score. Child‐Pugh is a prognostic clinical score with limitations in reflecting the liver's metabolic capacity. Aims: To demonstrate the need for better drug dosing approaches in hepatic impairment, summarise the current status, identify knowledge gaps related to drug kinetic parameters in hepatic impairment, propose solutions for predicting the liver disease impact on drug exposure and discuss barriers to dosing guidance in those patients. Methods: Relevant reports on dosage adjustment in hepatic impairment were analysed concerning the prediction of the impairment impact on drug kinetics using physiologically‐based pharmacokinetic (PBPK) modelling. Results: PBPK models are suggested as a potential framework to understand drug clearance changes in hepatic impairment. Quantifying changes in abundance and activity of drug‐metabolising enzymes and transporters, understanding the impact of shunting, and accounting for interindividual variations in drug absorption could help in extending the success of these models in hepatically‐impaired populations. These variables might not correlate with Child‐Pugh score as a whole. Therefore, new metabolic activity markers, imaging techniques and other scoring systems are proposed to either support or substitute Child‐Pugh score. Conclusions: Many physiological changes in hepatic impairment determining the fate of drugs do not necessarily correlate with Child‐Pugh score. Quantifying these changes in individual patients is essential in future hepatic impairment studies. Further studies assessing Child‐Pugh alternatives are recommended to allow better prediction of drug exposure

Integration of advanced methods and models to study drug absorption and related processes : An UNGAP perspective

Funding Information: AI acknowledges the support of projects icp009 (ALKOOL) of PRACE-ICEI (grant agreement 800858) for awarding access to Piz Daint, at the Swiss National Supercomputing Centre (CSCS), Switzerland and BG05M2OP001–1.001–0004 (UNITe) of the Bulgarian Ministry of Education and Science. For further details on points raised in this article, please contact [email protected]. Funding Information: Acknowledgements. JAGH is supported by the Biocenter Finland, the Helsinki Institute of Life Sciences, and the Faculty of Pharmacy, University of Helsinki. Publisher Copyright: © 2021 The AuthorsThis collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.Peer reviewe

Variance based global sensitivity analysis of physiologically based pharmacokinetic absorption models for BCS I–IV drugs

Det finns ett flertal faktorer som påverkar arbetsmiljö och en viktig aspekt är ljudmiljön. För att sträva efter en behaglig ljudnivå och undvika buller finns det många lösningar; ljudisolera väggar, alternativt montera absorbenter. I kontorslandskap kan överhörinng via ventilationssystem vara ett problem. Det här arbetet avser att utvärdera ventilationsdons ljudreduktionsförmåga från rum till kanal genom att ta fram en praktisk lämpad beräkningsmodell. Beräkningsmodellen verifierades med mätningar i laboratoriemiljö. Mätningarna var utformande så att de efterliknade vanligt förekommande monteringar av ventilationsdon; olika placeringar av kanalmynningen gentemot en vägg och liknande då de är monterade vid ett undertak. Den utvärderade beräkningsmodellen återfinns i SS-EN 12354-5 2009, och ansågs att kunna ge ett riktningsvärde för praktisk användning. Teoretiskt är den ej optimal och ytterliggare efterarbete krävs.There are several factors that affects the work environment and one important aspect is the sound environment. When striving for a comfortable sound level and avoid noise there are many solutions; sound isolating walls, alternatively mounting absorbents. In offices, cross-talk via ventilation system can be a problem. This study intends to evaluate ventilation devices' ability to reduce sound, from a room to a duct, by derive a model suited for practical use. The model was verified by measurements in a laboratory. The measurements were designed to imitate how ventilation devices is commonly mounted; different placements of the duct opening in relation to a solid wall and similar when mounted on a ceiling of absorbents. The derived model can be found in SS-EN 12354-5 2009, and it was considered to provide a value for practical use. Theoretically, the model is not optimal and more work is required.

Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects

The gut wall consists of many biological elements including enterocytes. Rapid turnover, a prominent feature of the enterocytes, has generally been ignored in the development of enterocyte-targeting drugs, although it has a comparable rate to other kinetic rates. Here, we investigated the impact of enterocyte turnover on the pharmacodynamics of enterocyte-targeting drugs by applying a model accounting for turnover of enterocytes and target proteins. Simulations showed that the pharmacodynamics depend on enterocyte lifespan when drug-target affinity is strong and half-life of target protein is long. Inter-individual variability of enterocyte lifespan, which can be amplified by disease conditions, has a substantial impact on the variability of response. However, our comprehensive literature search showed that the enterocyte turnover causes a marginal impact on currently approved enterocyte-targeting drugs due to their relatively weak target affinities. This study proposes a model-informed drug development approach for selecting enterocyte-targeting drugs and their optimal dosage regimens.QC 20200930</p