The European Medicines Agency Experience With Pediatric Dose Selection.

Getting the right dose regimen for children and adolescents is important but poses great scientific, practical, and ethical challenges. At the same time, the availability of data in adults is a huge advantage and needs to be used optimally when designing studies in children and analyzing pediatric data. Furthermore, the processes of maturation and growth are always key when selecting doses for children.

Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: Building model credibility.

The value of in silico methods in drug development and evaluation has been demonstrated repeatedly and convincingly. While their benefits are now unanimously recognized, international standards for their evaluation, accepted by all stakeholders involved, are still to be established. In this white paper, we propose a risk-informed evaluation framework for mechanistic model credibility evaluation.

Commentary on the EMA Reflection Paper on the use of extrapolation in the development of medicines for paediatrics.

Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have legal force and alternative approaches may be taken, but these obviously require more justification. This new series of the BJCP, developed in collaboration with the EMA, aims to address this issue by providing an annotated version of some relevant EMA guidelines and regulatory documents by experts.

Commentary on the MID3 Good Practices Paper.

During the last 10 years the European Medicines Agency (EMA) organized a number of workshops on modeling and simulation, working towards greater integration of modeling and simulation (M&S) in the development and regulatory assessment of medicines. In the 2011 EMA - European Federation of Pharmaceutical Industries and Associations (EFPIA) Workshop on Modelling and Simulation, European regulators agreed to the necessity to build expertise to be able to review M&S data provided by companies in their dossier. This led to the establishment of the EMA Modelling and Simulation Working Group (MSWG).

Edoxaban Exposure-Response Analysis and Clinical Utility Index Assessment in Patients With Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism.

Edoxaban exposure-response relationships from the phase III study evaluating edoxaban for prevention and treatment of venous thromboembolism (VTE) in patients with acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were assessed by parametric time-to-event analysis. Statistical significant exposure-response relationships were recurrent VTE with hazard ratio (HR) based on average edoxaban concentration at steady state (Cav) (HRCav) = 0.98 (i.

Population Pharmacokinetics of Edoxaban in Patients with Non-Valvular Atrial Fibrillation in the ENGAGE AF-TIMI 48 Study, a Phase III Clinical Trial.

Introduction: Edoxaban is a novel factor Xa inhibitor. This study characterizes the population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation (NVAF) included in the phase III ENGAGE AF-TIMI 48 study, evaluates covariates for the dose-exposure relationship in this population, and assesses the impact of protocol-specified dose reductions on exposure using simulations.

Methods: Model development was performed using NONMEM(®) and based on sparse data from the ENGAGE AF-TIMI 48 study augmented with dense data from 13 phase I studies to inform and stabilize the model.

Comparisons of Analysis Methods for Proof-of-Concept Trials.

Drug development struggles with high costs and time consuming processes. Hence, a need for new strategies has been accentuated by many stakeholders in drug development. This study proposes the use of pharmacometric models to rationalize drug development.

Performance of three estimation methods in repeated time-to-event modeling.

It is not uncommon that the outcome measurements, symptoms or side effects, of a clinical trial belong to the family of event type data, e.g., bleeding episodes or emesis events.

Modeling disease progression in acute stroke using clinical assessment scales.

This article demonstrates techniques for describing and predicting disease progression in acute stroke by modeling scores measured using clinical assessment scales, accommodating dropout as an additional source of information. Scores assessed using the National Institutes of Health Stroke Scale and the Barthel Index in acute stroke patients were used to model the time course of disease progression. Simultaneous continuous and probabilistic models for describing the nature and magnitude of score changes were developed, and used to model the trajectory of disease progression using scale scores.

Randomized exposure-controlled trials; impact of randomization and analysis strategies.

Aims: In the literature, five potential benefits of randomizing clinical trials on concentration levels, rather than dose, have been proposed: (i) statistical study power will increase; (ii) study power will be less sensitive to high variability in the pharmacokinetics (PK); (iii) the power of establishing an exposure-response relationship will be robust to correlations between PK and pharmacodynamics (PD); (iv) estimates of the exposure-response relationship are likely to be less biased; and (v) studies will provide a better control of exposure in situations with toxicity issues. The main aim of this study was to investigate if these five statements are valid when the trial results are evaluated using a model-based analysis.

Methods: Quantitative relationships between drug dose, concentration, biomarker and clinical end-point were defined using pharmacometric models.

Diurnal variation in serum levels of cartilage oligomeric matrix protein in patients with knee osteoarthritis or rheumatoid arthritis.

Objective: To monitor changes in serum concentrations of cartilage oligomeric matrix protein (COMP) during a 24-h period to determine any diurnal variation, and to estimate the half life of COMP in the circulation in patients with symptomatic knee osteoarthritis and in those with rheumatoid arthritis.

Methods: Serum samples were drawn every 4 h (7 samples/patient over 24 h) in 10 patients with knee osteoarthritis and 14 patients with rheumatoid arthritis. Osteoarthritis was defined radiographically and clinically (American College of Rheumatology (ACR) criteria) and rheumatoid arthritis according to the 1987 ACR criteria.

Derivatization using dimethylamine for tandem mass spectrometric structure analysis of enzymatically and acidically depolymerized methyl cellulose.

Structure analysis of partially depolymerized methyl cellulose was performed by nanoelectrospray ionization tandem mass spectrometry (nano-ESI-MS/MS) and by matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS). Dimethylamine (DMA) was used for the first time as a reducing end derivatization reagent for oligosaccharides. This is an attractive reagent since it could be easily removed from the reaction mixture.

Use of liquid chromatography-diode-array detection and mass spectrometry for rapid product identification in biotechnological synthesis of a hydroxyprogesterone.

In exploratory scale biotechnological process development, the product must be rapidly identified although a reference compound may not always be available. LC-diode-array detection and MS were used for this purpose in a process producing 9alpha-hydroxyprogesterone from progesterone as substrate. The electrospray ionization mass spectrometer was combined with an ion trap mass spectrometer for the second generation MS.

Polar organic phase liquid chromatography with packed capillary columns using a vancomycin chiral stationary phase.

Vancomycin immobilized on silica served as the chiral stationary phase (CSP) in this investigation with polar organic solvents as the mobile phase in liquid chromatography (LC). It was shown that trace amounts of water were beneficial for improving peak shape and efficiency. To regulate the retention and selectivity an acid and/or base were added to the mobile phase where an excess of acid was shown to be preferential for enantioseparation.

Serpin conformational change in ovalbumin. Enhanced reactive center loop insertion through hinge region mutations.

Ovalbumin is a noninhibitory member of the serpin superfamily that does not spontaneously undergo the loop-to-sheet conformational change upon cleavage of its reactive center that is characteristic of inhibitory serpins. We tested the hypothesis that ovalbumin could be turned into a proteinase inhibitor by increasing the rate of loop insertion through hinge region mutations alone. We found that none of the three variants examined showed any detectable proteinase inhibitory properties.

Characterisation of the complex of plasminogen activator inhibitor type 1 with tissue-type plasminogen activator by mass spectrometry and size-exclusion chromatography.

Glycosylated human plasminogen activator inhibitor type 1 (PAI-1), produced in Chinese hamster ovary (CHO) cells, showed a variety of compounds with different molecular weights when subjected to electrospray mass spectrometry (ES-MS), owing to the heterogeneity of the carbohydrate chains. However, non-glycosylated human PAI-1, produced in E. coli, gave rise to a prominent species with a molecular weight of 42,774, consistent with the amino-acid sequence.

Identification of a new by-product detected in metoprolol tartrate.

A new impurity has been found in some batches of metoprolol tartrate. As the amount exceeded 0.1% it was of interest to deduce the structure.

A metabolic route of omeprazole involving conjugation with glutathione identified in the rat.

A metabolic route of omeprazole involving glutathione has been established through identification of endproducts excreted in the urine of rats after oral administration of 400 mumol/kg of a mixture of [3H]- and [14C]omeprazole. The labeled positions enabled facile tracing of metabolites that were formed through fission of omeprazole, producing [3H]pyridine and [14C]benzimidazole metabolites. The structures of the metabolites were established by HPLC thermospray MS and MS/MS.

Direct derivatization of drugs in untreated biological samples for gas chromatographic analysis.

The possibilities to derivatize an analyte directly in the biological sample are reviewed with examples from our own experiences and from the literature. Techniques, such as extractive acylation, alkylation and benzoylation, are frequently used. Improvement of the extractability of the drug from the matrix is a common feature, especially with hydrophilic compounds, where sometimes cyclizing reactions can be employed.