Population Pharmacokinetic Modelling of FE 999049, a Recombinant Human Follicle-Stimulating Hormone, in Healthy Women After Single Ascending Doses

OBJECTIVE: The purpose of this analysis was to develop a population pharmacokinetic model for a novel recombinant human follicle-stimulating hormone (FSH) (FE 999049) expressed from a human cell line of foetal retinal origin (PER.C6(®)) developed for controlled ovarian stimulation prior to assisted reproductive technologies.METHODS: Serum FSH levels were measured following a single subcutaneous FE 999049 injection of 37.5, 75, 150, 225 or 450 IU in 27 pituitary-suppressed healthy female subjects participating in this first-in-human single ascending dose trial. Data was analysed by nonlinear mixed effects population pharmacokinetic modelling in NONMEM 7.2.0.RESULTS: A one-compartment model with first-order absorption and elimination rates was found to best describe the data. A transit model was introduced to describe a delay in the absorption process. The apparent clearance (CL/F) and apparent volume of distribution (V/F) estimates were found to increase with body weight. Body weight was included as an allometrically scaled covariate with a power exponent of 0.75 for CL/F and 1 for V/F.CONCLUSIONS: The single-dose pharmacokinetics of FE 999049 were adequately described by a population pharmacokinetic model. The average drug concentration at steady state is expected to be reduced with increasing body weight

Using random forest and decision tree models for a new vehicle prediction approach in computational toxicology

yesDrug vehicles are chemical carriers that provide beneficial aid to the drugs they bear. Taking advantage of their favourable properties can potentially allow the safer use of drugs that are considered highly toxic. A means for vehicle selection without experimental trial would therefore be of benefit in saving time and money for the industry. Although machine learning is increasingly used in predictive toxicology, to our knowledge there is no reported work in using machine learning techniques to model drug-vehicle relationships for vehicle selection to minimise toxicity. In this paper we demonstrate the use of data mining and machine learning techniques to process, extract and build models based on classifiers (decision trees and random forests) that allow us to predict which vehicle would be most suited to reduce a drug’s toxicity. Using data acquired from the National Institute of Health’s (NIH) Developmental Therapeutics Program (DTP) we propose a methodology using an area under a curve (AUC) approach that allows us to distinguish which vehicle provides the best toxicity profile for a drug and build classification models based on this knowledge. Our results show that we can achieve prediction accuracies of 80 % using random forest models whilst the decision tree models produce accuracies in the 70 % region. We consider our methodology widely applicable within the scientific domain and beyond for comprehensively building classification models for the comparison of functional relationships between two variables

The mechanisms of pharmacokinetic food-drug interactions - A perspective from the UNGAP group

The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives

Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network

Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research

Phytantriol and glyceryl monooleate cubic liquid crystalline phases as sustained-release oral drug delivery systems for poorly water soluble drugs I. Phase behaviour in physiologically-relevant media.

Objectives: the potential utility of liquid crystalline lipid-based formulations in oral drug delivery is expected to depend critically on their structure formation and stability in gastrointestinal fluids. The phase behaviour of lipid-based liquid crystals formed by phytantriol and glyceryl monooleate, known to form a bicontinuous cubic phase in excess water, was therefore assessed in physiologically-relevant simulated gastrointestinal media. Methods: fixed composition phase studies, crossed polarised light microscopy (CPLM) and small angle X-ray scattering (SAXS) were used to determine the phase structures formed in phosphate-buffered saline, simulated gastric and intestinal fluids in the presence of model poorly water soluble drugs cinnarizine, diazepam and vitamin E acetate. Key findings: the phase behaviour of phytantriol in phosphate-buffered saline was very similar to that in water. Increasing concentrations of bile components (bile salts and phospholipids) caused an increase in the lattice parameter of the cubic phase structure for both lipids. Incorporation of cinnarizine and diazepam did not influence the phase behaviour of the phytantriol- or glyceryl monooleate-based systems at physiological temperatures; however, an inverse hexagonal phase formed on incorporation of vitamin E acetate. Conclusions: Phytantriol and glyceryl monooleate have the potential to form stable cubic phase liquid crystalline delivery systems in the gastrointestinal tract. In-vivo studies to assess their sustained-release behaviour are warranted. © 2010, Wiley-Blackwell

Spatial Properties of Reactive Oxygen Species Govern Pathogen-Specific Immune System Responses

Significance: Reactive oxygen species (ROS) are often considered to be undesirable toxic molecules that are generated under conditions of cellular stress, which can cause damage to critical macromolecules such as DNA. However, ROS can also contribute to the pathogenesis of cancer and many other chronic inflammatory disease conditions, including atherosclerosis, metabolic disease, chronic obstructive pulmonary disease, neurodegenerative disease, and autoimmune disease. Recent Advances: The field of ROS biology is expanding, with an emerging paradigm that these reactive species are not generated haphazardly, but instead produced in localized regions or in specific subcellular compartments, and this has important consequences for immune system function. Currently, there is evidence for ROS generation in extracellular spaces, in endosomal compartments, and within mitochondria. Intriguingly, the specific location of ROS production appears to be influenced by the type of invading pathogen (i.e., bacteria, virus, or fungus), the size of the invading pathogen, as well as the expression/subcellular action of pattern recognition receptors and their downstream signaling networks, which sense the presence of these invading pathogens. Critical Issues: ROS are deliberately generated by the immune system, using specific NADPH oxidases that are critically important for pathogen clearance. Professional phagocytic cells can sense a foreign bacterium, initiate phagocytosis, and then within the confines of the phagosome, deliver bursts of ROS to these pathogens. The importance of confining ROS to this specific location is the impetus for this perspective. Future Directions: There are specific knowledge gaps on the fate of the ROS generated by NADPH oxidases/mitochondria, how these ROS are confined to specific locations, as well as the identity of ROS-sensitive targets and how they regulate cellular signaling

Size and Rigidity of Cylindrical Polymer Brushes Dictate Long Circulating Properties In Vivo

Studies of spherical nanoengineered drug delivery systems have suggested that particle size and mechanical properties are key determinants of in vivo behavior; however, for more complex structures, detailed analysis of correlations between in vitro characterization and in vivo disposition is lacking. Anisotropic materials in particular bear unknowns in terms of size tolerances for in vivo clearance and the impact of shape and rigidity. Herein, we employed cylindrical polymer brushes (CPBs) to answer questions related to the impact of size, length and rigidity on the in vivo behavior of PEGylated anisotropic structures, in particular their pharmacokinetics and biodistribution. The modular grafting assembly of CPBs allowed for the systematic tailoring of parameters such as aspect ratio or rigidity while keeping the overall chemical composition the same. CPBs with altered length were produced from polyinitiator backbones with different degrees of polymerization. The side chain grafts consisted of a random copolymer of poly[(ethylene glycol) methyl ether methacrylate] (PEGMA) and poly(glycidyl methacrylate) (PGMA), and rendered the CPBs water-soluble. The epoxy groups of PGMA were subsequently reacted with propargylamine to introduce alkyne groups, which in turn were used to attach radiolabels via copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC). Radiolabeling allowed the pharmacokinetics of intravenously injected CPBs to be followed as well as their deposition into major organs post dosing to rats. To alter the rigidity of the CPBs, core-shell-structured CPBs with polycaprolactone (PCL) as a water-insoluble and crystalline core and PEGMA-co-PGMA as the hydrophilic shell were synthesized. This modular buildup of CPBs allowed their shape and rigidity to be altered, which in turn could be used to influence the in vivo circulation behavior of these anisotropic polymer particles. Increasing the aspect ratio or altering the rigidity of the CPBs led to reduced exposure, higher clearance rates, and increased mononuclear phagocytic system (MPS) organ deposition

Quantitatively Tracking Bio-Nano Interactions of Metal-Phenolic Nanocapsules by Mass Cytometry

Polymer nanocapsules, with a hollow structure, are increasingly finding widespread use as drug delivery carriers; however, quantitatively evaluating the bio-nano interactions of nanocapsules remains challenging. Herein, poly(ethylene glycol) (PEG)-based metal-phenolic network (MPN) nanocapsules of three sizes (50, 100, and 150 nm) are engineered via supramolecular template-assisted assembly and the effect of the nanocapsule size on bio-nano interactions is investigated using in vitro cell experiments, ex vivo whole blood assays, and in vivo rat models. To track the nanocapsules by mass cytometry, a preformed gold nanoparticle (14 nm) is encapsulated into each PEG-MPN nanocapsule. The results reveal that decreasing the size of the PEG-MPN nanocapsules from 150 to 50 nm leads to reduced association (up to 70%) with phagocytic blood cells in human blood and prolongs in vivo systemic exposure in rat models. The findings provide insights into MPN-based nanocapsules and represent a platform for studying bio-nano interactions