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Furosemide is a widely used diuretic for treating excessive fluid accumulation caused by disease conditions like heart failure and liver cirrhosis. Furosemide tablet formulation exhibits variable pharmacokinetics (PK) with bioavailability ranging from 10 to almost 100%. To explain the variable absorption, we integrated the physicochemical, in vitro dissolution, permeability, distribution, and the elimination parameters of furosemide in a physiologically-based pharmacokinetic (PBPK) model. Although the intravenous PBPK model reasonably described the observed in vivo PK data, the reported low passive permeability failed to capture the observed data after oral administration. To mechanistically justify this discrepancy, we hypothesized that transporter-mediated uptake contributes to the oral absorption of furosemide in conjunction with passive permeability. Our in vitro results confirmed that furosemide is a substrate of intestinal breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), and organic anion transporting polypeptide 2B1 (OATP2B1), but it is not a substrate of P-glycoprotein (P-gp) and MRP2. We then estimated the net transporter-mediated intestinal uptake and integrated it into the PBPK model under both fasting and fed conditions. Our in vitro data and PBPK model suggest that the absorption of furosemide is permeability-limited, and OATP2B1 and MRP4 are important for its permeability across intestinal membrane. Further, as furosemide has been proposed as a probe substrate of renal organic anion transporters (OATs) for assessing clinical drug-drug interactions (DDIs) during drug development, the confounding effects of intestinal transporters identified in this study on furosemide PK should be considered in the clinical transporter DDI studies.

To increase the understanding of how drugs behave following oral administration to the pediatric population, the aim of the present study was to investigate the solubilization of fluconazole and ibuprofen during simulated gastro-intestinal (GI) digestion, using an immediate transfer model mimicking pediatric GI digestion. The effects of infant formula and digestion, on the drug solubilization, were studied using simulated fasted and fed state digestion media in the presence and absence of digestive enzymes. Additionally, the effect of digestion media viscosity on the solubilization process was investigated. It was found that the solubilization of fluconazole was unaffected by all tested parameters, as the entire estimated dose equivalent was solubilized in the aqueous phase throughout all digestion studies. In contrast, the solubilization of ibuprofen was affected by all the tested parameters, i.e. in the fasted state, the solubilization of ibuprofen was limited by its solubility in the aqueous phase of the simulated GI digestion media, whereas the solubilization in the fed state was affected by drug partitioning between the lipid and the aqueous phases, and therefore by the digestion of the lipid phase. Adding Nestle Thicken Up™, containing xanthan gum as a thickening agent, to the digestion medium increased its viscosity, which in turn resulted in a reduced initial digestion rate, increased pH fluctuations, as well as high variability in all drug solubilization data as evident in large standard deviations. Furthermore, the increased digestion medium viscosity decreased the drug recovery from the combined pellet and aqueous phase. The observed viscosity effects might translate into a more variable and lower oral bioavailability.

Decision-making in drug development benefits from an integrated systems approach, where the stakeholders identify and address the critical questions for the system through carefully designed and performed studies. Biopharmaceutics Risk Assessment Roadmap (BioRAM) is such a systems approach for application of systems thinking to patient focused and timely decision-making, suitable for all stages of drug discovery and development. We described the BioRAM therapy-driven drug delivery framework, strategic roadmap, and integrated risk assessment instrument (BioRAM Scoring Grid) in previous publications (J Pharm Sci 103:3377–97, 2014; J Pharm Sci 105:3243–55, 2016). Integration of systems thinking with pharmaceutical development, manufacturing, and clinical sciences and health care is unique to BioRAM where the developed strategy identifies the system and enables risk characterization and balancing for the entire system. Successful decision-making process in BioRAM starts with the Blueprint (BP) meetings. Through shared understanding of the system, the program strategy is developed and captured in the program BP. Here, we provide three semi-hypothetical examples for illustrating risk-based decision-making in high and moderate risk settings. In the high-risk setting, which is a rare disease area, two completely alternate development approaches are considered (gene therapy and small molecule). The two moderate-risk examples represent varied knowledge levels and drivers for the programs. In one moderate-risk example, knowledge leveraging opportunities are drawn from the manufacturing knowledge and clinical performance of a similar drug substance. In the other example, knowledge on acute tolerance patterns for a similar mechanistic pathway is utilized for identifying markers to inform the drug release profile from the dosage form with the necessary “flexibility” for dosing. All examples illustrate implementation of the BioRAM strategy for leveraging knowledge and decision-making to optimize the clinical performance of drug products for patient benefit.

Objective The aim of the present study was to study the oral performance of furosemide in neonates and young infants using a newly developed in vitro model simulating digestion and drug solubilization in the gastrointestinal (GI) tract of the human neonate and young infant population (age 0–2 months). Methods The utilized in vitro model was designed to mimic the digestion and drug solubilization processes occurring in the stomach, and the small intestine of the neonate and young infant population, using physiologically relevant media, volumes and digestive enzymes. Overall the experimental model setup was based on the dynamic in vitro lipolysis model previously described by Fernandez et al. (2009) . The amount of furosemide solubilized in the aqueous phase during a digestion study was used as an estimate for the amount of drug available for absorption in vivo. By varying different factors in the model setup, e.g. presence of food (food-effect), effect of digestion (tested with and without addition of digestive enzymes), and properties of the dosage form, it was possible to estimate the importance of these factors in vivo. Key findings and conclusions The present in vitro data suggest that the oral performance of furosemide in neonates and young infants will be increased by the presence of food (frequent feedings) due to increased drug solubilization, however, not influenced by the GI digestion of this food. The properties of the dosage form (immediate release tablets) did not affect the drug solubilization as compared to administration of the pure drug powder.

The aim of Biopharmaceutics Risk Assessment Roadmap (BioRAM) and the BioRAM Scoring Grid is to facilitate optimization of clinical performance of drug products. BioRAM strategy relies on therapy-driven drug delivery and follows an integrated systems approach for formulating and addressing critical questions and decision-making (J Pharm Sci. 2014,103(11): 3777-97). In BioRAM, risk is defined as not achieving the intended in vivo drug product performance, and success is assessed by time to decision-making and action. Emphasis on time to decision-making and time to action highlights the value of well-formulated critical questions and well-designed and conducted integrated studies. This commentary describes and illustrates application of the BioRAM Scoring Grid, a companion to the BioRAM strategy, which guides implementation of such an integrated strategy encompassing 12 critical areas and 6 assessment stages. Application of the BioRAM Scoring Grid is illustrated using published literature. Organizational considerations for implementing BioRAM strategy, including the interactions, function, and skillsets of the BioRAM group members, are also reviewed. As a creative and innovative systems approach, we believe that BioRAM is going to have a broad-reaching impact, influencing drug development and leading to unique collaborations influencing how we learn, and leverage and share knowledge.

The focus on drug delivery for the pediatric population has been steadily increasing in the last decades. In terms of developing in vitro models simulating characteristics of the targeted pediatric population, with the purpose of predicting drug product performance after oral administration, it is important to simulate the gastro-intestinal conditions and processes the drug will encounter upon oral administration. When a drug is administered in the fed state, which is commonly the case for neonates, as they are typically fed every 3 h, the digestion of the milk will affect the composition of the fluid available for drug dissolution/solubilization. Therefore, in order to predict the solubilized amount of drug available for absorption, an in vitro model simulating digestion in the gastro-intestinal tract should be utilized. In order to simulate the digestion process and the drug solubilization taking place in vivo, the following aspects should be considered; physiologically relevant media, media volume, use of physiological enzymes in proper amounts, as well as correct pH and addition of relevant co-factors, e.g., bile salts and co-enzymes. Furthermore, physiological transit times and appropriate mixing should be considered and mimicked as close as possible. This paper presents a literature review on physiological factors relevant for digestion and drug solubilization in neonates. Based on the available literature data, a novel in vitro digestion model simulating digestion and drug solubilization in the neonate and young infant pediatric population (2 months old and younger) was designed.

The October 2015 FDA/PQRI Conference on Advancing Product Quality provided a forum for the exchange of ideas focused on drug product quality between regulatory agencies, the pharmaceutical industry, and academia. Key topics of the 2015 conference were (i) emerging regulatory initiatives; (ii) regulatory submission, assessment, and inspection; (iii) product and process development; and (iv) manufacturing, risk management, and quality assurance. Key discussion points and recommendations for each track and session have been captured. With powerful advancements in product quality encompassing regulatory, industrial, and technological elements, an era of rapidly improving pharmaceutical quality is underway. At the conference, one theme prevailed through all sessions: regulators, industry, and academia are aligned in their desire for drug product quality on behalf of the ultimate stakeholder–the patient. 3D three dimensional, ANDA abbreviated new drug application, API active pharmaceutical ingredient, ASTM American society for testing and materials, BCS biopharmaceutics classification system, BLA biological license application, CGMP current good manufacturing practice, CMA critical material attribute, CMC chemistry manufacturing and controls, CPP critical process parameters, CQA critical quality attribute, CU content uniformity, DLS dynamic light scattering, DOE design of experiment, EMA European Medicines Agency, EWG Expert Working Group, FDA Food and Drug Administration, GDUFA generic drug user fee amendments, HCl Hydrogen Chloride, ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, IND investigational new drug, IQA integrated quality assessment, IR immediate release, IR information request, ISPE International Society for Pharmaceutical Engineering, MIT Massachusetts Institute of Technology, NDA new drug application, NIPP new inspection protocols project, NIR near-infrared spectroscopy, OPQ office of pharmaceutical quality, PAI pre-approval inspection, PAT process analytical technology, PDUFA prescription drug user fee act, PHS public health service, PQRI Product Quality Research Institute, PQS pharmaceutical quality system, QbD quality by design, QMS quality management system, QRM quality risk management, QTPP quality target product profile, RPM revolutions per minute, RTRT real time release testing, SUPAC scale-up and post-approval changes, UDU uniformity of dosage units, USP U.S. Pharmacopeial Convention.

This report summarizes the results of the "In Vitro-In Vivo Correlations (IVIVC): Critical Variables for Success" survey orga- nized by the In Vitro Release and Dissolution Testing (IVRDT) and the QbD and Product Performance AAPS Focus Groups. This was a web-based survey conducted over a 26-day period from Wednesday, June 29, 2011, to Sunday, July 24, 2011, and results were initially presented at the 2011 AAPS Annual Meeting and Exposition. The goal was to describe the current views from scientists across academia, industry, and regulatory agencies on the adoption, utility, and benefits of IVIVCs and to begin identifying potentially critical variables for their success. Questions in the survey cover their development, use, and success.

Objectives To develop a physiologically based pharmacokinetic (PBPK) model for furosemide immediate release (IR) tablets and modified release (MR) capsules by coupling biorelevant dissolution testing results with pharmacokinetic (PK) and physiologic parameters, and to investigate the key factors influencing furosemide absorption using simulation approaches and the PBPK model. Methods Using solubility, dissolution kinetics, gastrointestinal (GI) parameters and disposition parameters, a PBPK model for furosemide was developed with STELLA software. Solubility and dissolution profiles for both formulations were evaluated in biorelevant and compendial media. The simulated plasma profiles were compared with in-vivo profiles using point estimates of area under plasma concentration-time curve, maximal concentration after the dose and time to maximal concentration after the dose. Key findings Simulated plasma profiles of both furosemide IR tablets and MR capsules were similar to the observed in-vivo profile in terms of PK parameters. Sensitivity analysis of the IR tablet model indicated that both the gastric emptying and absorption rate have an influence on the plasma profile. For the MR capsules, the sensitivity analysis suggested that the release rate in the small intestine, gastric emptying and the absorption rate all have an influence on the plasma profile. Conclusions A predictive model to describe both IR and MR dosage forms containing furosemide was attained. Because sensitivity analysis of the model is able to identify key factors influencing the plasma profile, this in-vitro–in-silico–in-vivo approach could be a useful tool for facilitating formulation development of drug products.

A biopharmaceutics and Quality by Design (QbD) conference was held on June 10-12, 2009 in Rockville, Maryland, USA to provide a forum and identify approaches for enhancing product quality for patient benefit. Presentations concerned the current biopharmaceutical toolbox (i.e., in vitro, in silico, pre-clinical, in vivo, and statistical approaches), as well as case studies, and reflections on new paradigms. Plenary and breakout session discussions evaluated the current state and envisioned a future state that more effectively integrates QbD and biopharmaceutics. Breakout groups discussed the following four topics: Integrating Biopharmaceutical Assessment into the QbD Paradigm, Predictive Statistical Tools, Predictive Mechanistic Tools, and Predictive Analytical Tools. Nine priority areas, further described in this report, were identified for advancing integration of biopharmaceutics and support a more fundamentally based, integrated approach to setting product dissolution/release acceptance criteria. Collaboration among a broad range of disciplines and fostering a knowledge sharing environment that places the patient's needs as the focus of drug development, consistent with science- and risk-based spirit of QbD, were identified as key components of the path forward.