Assessing the potential impact of non-proprietary drug copies on quality of medicine and treatment in patients with relapsing multiple sclerosis: the experience with fingolimod

Jorge Correale,1 Erwin Chiquete,2 Snezana Milojevic,3 Nadina Frider,3 Imre Bajusz31Raúl Carrea Institute for Neurological Research, Foundation for the Fight against Infant Neurological Illnesses, Buenos Aires, Argentina; 2Department of Neurology and Psychiatry, Salvador Zubirán National Institute of Medical Science and Nutrition, Mexico City, Mexico; 3Novartis Pharma AG, Basel, SwitzerlandBackground: Fingolimod is a once-daily oral treatment for relapsing multiple sclerosis, the proprietary production processes of which are tightly controlled, owing to its susceptibility to contamination by impurities, including genotoxic impurities. Many markets produce nonproprietary medicines; assessing their efficacy and safety is difficult as regulators may approve nonproprietary drugs without bioequivalence data, genotoxic evaluation, or risk management plans (RMPs). This assessment is especially important for fingolimod given its solubility/bioavailability profile, genotoxicity risk, and low-dose final product (0.5 mg). This paper presents an evaluation of the quality of proprietary and nonproprietary fingolimod variants.Methods: Proprietary fingolimod was used as a reference substance against which eleven nonproprietary fingolimod copies were assessed. The microparticle size distribution of each compound was assessed by laser light diffraction, and inorganic impurity content by sulfated ash testing. Heavy metals content was quantified using inductively coupled plasma optical emission spectrometry, and levels of unspecified impurities by high-performance liquid chromatography. Solubility was assessed in a range of solvents at different pH values. Key information from the fingolimod RMP is also presented.Results: Nonproprietary fingolimod variants exhibited properties out of proprietary or internationally accepted specifications, including differences in particle size distribution and levels of impurities such as heavy metals. For microparticle size and heavy metals, all tested fingolimod copies were out-of-specification by several-fold magnitudes. Proprietary fingolimod has a well-defined RMP, highlighting known and potential mid- to long-term safety risks, and risk-minimization and pharmacovigilance procedures.Conclusion: Nonproprietary fingolimod copies produced by processes less well controlled than or altered from proprietary production processes may reduce product reproducibility and quality, potentially presenting risks to patients. Safety data and risk-minimization strategies for proprietary fingolimod may not apply to the nonproprietary fingolimod copies evaluated here. Market authorization of nonproprietary fingolimod copies should require an appropriate RMP to minimize risks to patients.Keywords: fingolimod, multiple sclerosis, risk management plan, bioequivalence, nonproprietary medicin

Identification of Radiation Treatment of Mineral-Enriched Milk Protein Concentrate by Complex Test Protocols. A Comparison of Thermoluminescence, Electron Spin Resonance and Rheological Investigations

The combined application of thermoluminescence and electron spin resonance spectroscopy in conjunction with dynamic viscosity measurements provides a rather informative picture of radiation-induced processes. Spectroscopic techniques focus on the primary energy distribution following the absorption of high-energy γ-photons and the concomitant free radical formation. Such measurements, for methodological reasons, on milk protein concentrate samples allow the quantitative identification of radiation treatment for a limited period of 2-3 weeks following the radiation treatment. Rheological measurements on suspensions of milk protein concentrate, on the other hand, can reveal accumulating longterm modifications. The effects of chelated iron and selenium complexes added as food ingredient modifiers on the radiation-induced-processes are discussed

Identification of Radiation Treatment of Mineral-Enriched Milk Protein Concentrate by Complex Test Protocols. A Comparison of Thermoluminescence, Electron Spin Resonance and Rheological Investigations

The combined application of thermoluminescence and electron spin resonance spectroscopy in conjunction with dynamic viscosity measurements provides a rather informative picture of radiation-induced processes. Spectroscopic techniques focus on the primary energy distribution following the absorption of high-energy γ-photons and the concomitant free radical formation. Such measurements, for methodological reasons, on milk protein concentrate samples allow the quantitative identification of radiation treatment for a limited period of 2-3 weeks following the radiation treatment. Rheological measurements on suspensions of milk protein concentrate, on the other hand, can reveal accumulating longterm modifications. The effects of chelated iron and selenium complexes added as food ingredient modifiers on the radiation-induced-processes are discussed

Sessile hemocytes as a hematopoietic compartment in Drosophila melanogaster

The blood cells, or hemocytes, in Drosophila participate in the immune response through the production of antimicrobial peptides, the phagocytosis of bacteria, and the encapsulation of larger foreign particles such as parasitic eggs; these immune reactions are mediated by phylogenetically conserved mechanisms. The encapsulation reaction is analogous to the formation of granuloma in vertebrates, and is mediated by large specialized cells, the lamellocytes. The origin of the lamellocytes has not been formally established, although it has been suggested that they are derived from the lymph gland, which is generally considered to be the main hematopoietic organ in the Drosophila larva. However, it was recently observed that a subepidermal population of sessile blood cells is released into the circulation in response to a parasitoid wasp infection. We set out to analyze this phenomenon systematically. As a result, we define the sessile hemocytes as a novel hematopoietic compartment, and the main source of lamellocytes

Exploring protein hotspots by optimized fragment pharmacophores

Fragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pharmacophores, the most general concept of representing drug-target interactions with the theory of protein hotspots, to develop a design protocol for fragment libraries. The SpotXplorer approach compiles small fragment libraries that maximize the coverage of experimentally confirmed binding pharmacophores at the most preferred hotspots. The efficiency of this approach is demonstrated with a pilot library of 96 fragment-sized compounds (SpotXplorer0) that is validated on popular target classes and emerging drug targets. Biochemical screening against a set of GPCRs and proteases retrieves compounds containing an average of 70% of known pharmacophores for these targets. More importantly, SpotXplorer0 screening identifies confirmed hits against recently established challenging targets such as the histone methyltransferase SETD2, the main protease (3CLPro) and the NSP3 macrodomain of SARS-CoV-2