Changes and determination of dosing recommendations for medicinal products recently authorised in the European Union

Introduction: The quantity and quality of data for determining the dose and treatment schedule of medicinal products is directly related to how safe and efficacious these medicines are and how successful they can be used to treat patients.

Areas covered: This review provides an analysis of dose-related label modifications of recently approved drugs. It shows which areas could benefit from a better dose–exposure–response understanding, both during initial assessment and after marketing authorisation. This analysis highlights regulators’ considerations in dosage evaluations and provides reflections for drug developers on how to ensure best possible dose selection in the interest of the patients.

Expert opinion: Using modelling and simulation, pharmacogenomics, population pharmacokinetics, physiologically based pharmacokinetic models and drug–drug interaction studies in conjunction with well-designed clinical trials will improve the understanding of the pharmacology of medicines, of the physiology of the disease and of the dose–exposure–response relationship during drug development. More focus should be given to the investigation of dose and regimens for special populations before applying for marketing authorisation. Consequently, regulators could review dose–exposure–response data with more certainty and better define dose recommendations in the label.     

Unfractionated heparin reduces the anti-platelet effects of abciximab but not eptifibatide during PCI.

In 29 patients undergoing percutaneous coronary intervention (PCI), we obtained blood samples at baseline, 10 minutes after standard weight-based abciximab (n=15) or double-bolus eptifibatide (n=14) and 5 minutes after unfractionated heparin (UFH; 70 U/kg bolus). The median percent inhibition was significantly higher in the eptifibatide group compared with the abciximab group both before (96.5% [94-100] vs. 85% [77-89.5] [adenosine diphosphate; ADP]; 89.5% [84-95] vs. 59% [37.5-76.5] [thrombin receptor agonist peptide; TRAP], p<0.001 for both) and after UFH (95% [93-100] vs. 79% [68.8-87.5] [ADP]; 82% [77-93] vs. 51% [34.5-71.3] [TRAP], p<0.001 for both). Addition of UFH significantly reduced platelet inhibition in the abciximab group (85% [77-89.5] vs. 79% [68.8-87.5] [ADP]; 59% [37.5-76.5] vs. 51% [34.5-71.3] [TRAP], p<0.05 for both) but not in the eptifibatide group (96.5% [94-100] vs. 95% [93-100] [ADP]; 89.5% [84-95] vs. 82% [77-93] [TRAP], p=ns for both). Eptifibatide achieved superior platelet inhibition before but especially after UFH compared with abciximab.     

Interleukin-1B and interleukin-1 receptor antagonist gene polymorphisms in Greek multiple sclerosis (MS) patients with bout-onset MS

We investigated the association of specific polymorphisms of the interleukin IL-1b (AvaI ?511 and TaqI +3,953) and IL-1 receptor antagonist (IL-1RN) (a variable number of tandem repeats; VNTR) genes with both the susceptibility to and the clinical characteristics in Greek multiple sclerosis (MS) patients cohort with bout-onset. Genotypes were determined from 351 patients with clinically definite MS and 375 age- and sex-matched healthy controls. Our results showed no significant differences in the distribution of these polymorphisms between MS patients and controls. Furthermore, stratification for clinical characteristics, such as age at disease onset, clinical course, sex, and severity did not provide significant differences between patients and controls. Together, our findings suggest that IL-1B and IL-1RN gene polymorphisms may not be relevant to the susceptibility to MS or the clinical characteristics of Greek MS patients.     

Bounding the Multi-Scale Domain in Numerical Modelling and Meta-Heuristics Optimization: Application to Poroelastic Media with Damageable Cracks

It is very common for natural or synthetic materials to be characterized by a periodic or quasi-periodic micro-structure. This micro-structure, under the different loading conditions may play an important role on the apparent, macroscopic behaviour of the material. Although, fine, detailed information can be implemented at the micro-structure level, it still remains a challenging task to obtain experimental metrics at this scale. In this work, a constitutive law obtained by the asymptotic homogenization of a cracked, damageable, poroelastic medium is first evaluated for multi-scale use. For a given range of micro-scale parameters, due to the complex mechanical behaviour at micro-scale, such multi-scale approaches are needed to describe the (macro) material’s behaviour. To overcome possible limitations regarding input data, meta-heuristics are used to calibrate the micro-scale parameters targeted on a synthetic failure envelope. Results show the validity of the approach to model micro-fractured materials such as coal or crystalline rocks.     

Proposals for model-based paediatric medicinal development within the current European Union regulatory framework

The new paediatric European Union (EU) regulation and the consequent demand for paediatric studies on one hand and the ethical need for minimizing the burden of studies in children on the other hand necessitate optimal techniques in the assessment of safety/efficacy and use of drugs in children. Modelling and simulation (M&S) is one way to circumvent some difficulties in developing medicinal products in children. M&S allows the quantitative use of sparse sampling, characterization and prediction of pharmacokinetics/ pharmacodynamics (PK/PD), extrapolation from adults to children, interpolation between paediatric age subsets, optimal use of scientific literature and in vitro/preclinical data. Together, industry, academia and regulators recognize the usefulness of modelling and simulation in this setting. However, even if M&S is an emerging science, its integration in the EU regulatory decision making is for the time being deficient and M&S expertise is concentrated in big pharmaceutical companies and academic institutions. The European Medicines Agency, acknowledging all the above conditions, organized and hosted a Workshop on Modelling in Paediatric Medicines. The article presents the personal views of the authors on the issues presented and discussed in the workshop. We attempt to identify the regulatory framework for the use of M&S in paediatric medicinal development and to make proposals for model-based paediatric medicinal development. The objective is to open the discussion between industry, academia, paediatricians and regulators on the optimal use of M&S in paediatric medicinal development.     

Telematics enabled virtual simulation system for radiation treatment planning

In this paper, GALENOS, a Telematics Enabled Virtual Simulation System for Radiation Treatment Planning (RTP) is described. The design architecture of GALENOS is in accordance with the dual aim of virtual simulation of RTP, i.e. to allow (a) delineation of target volume and critical organs, and (b) placement of irradiation fields. An important feature of GALENOS is the possibility for on-line tele-collaboration between health care professionals under a secure framework. The advantages of GALENOS include elimination of patient transfers between departments and health care institutions as well as availability of patient data at sites different than those of his/her physical presence.     

Cartilage "shield" grafts in revision tympanoplasty.

OBJECTIVE: To report our experience with cartilage "shield" grafts in revision tympanoplasty. STUDY DESIGN: Retrospective chart review at a tertiary referral center. Patients underwent revision tympanoplasties by replacing the entire tympanic membrane with concha cymba cartilage shaped as a shield. MAIN OUTCOME MEASURES: Successful graft take was defined as having no perforation, graft retraction, or lateralization. Hearing results were analyzed by comparing the preoperative and postoperative pure-tone average air-bone gap and speech discrimination scores. RESULTS: Forty-three patients underwent 46 procedures. Graft take was successful in 43 procedures (93.5%). There was no graft lateralization or displacement into the middle ear. An overall postoperative air-bone gap of 25 dB or less was achieved in 22 of the 39 patients (56.4%), and speech discrimination scores remained unchanged. CONCLUSION: Cartilage shield tympanoplasty is a reliable procedure for revision tympanoplasty patients, with excellent graft take and significant improvement of hearing.