Generic Substitution of Orphan Drugs for the Treatment of Rare Diseases: Exploring the Potential Challenges

Generic drugs are important components of measures introduced by healthcare regulatory authorities to reduce treatment costs. In most patients and conditions the switch from a branded drug to its generic counterpart is performed with no major complications. However, evidence from complex diseases suggests that generic substitution requires careful evaluation in some settings and that current bioequivalence criteria may not always be adequate for establishing the interchangeability of branded and generic products. Rare diseases, also called orphan diseases, are a group of heterogeneous diseases that share important characteristics: in addition to their scarcity, most are severe, chronic, highly debilitating, and often present in early childhood. Finding a treatment for a rare disease is challenging. Thanks to incentives that encourage research and development programs in rare diseases, several orphan drugs are currently available. The elevated cost of orphan drugs is a highly debated issue and a cause of limited access to treatment for many patients. As patent protection and the exclusivity period of several orphan drugs will expire soon, generic versions of orphan drugs should reach the market shortly, with great expectations about their impact on the economic burden of rare diseases. However, consistent with other complex diseases, generic substitution may require thoughtful considerations and may be even contraindicated in some rare conditions. This article provides an overview of rare disease characteristics, reviews reports of problematic generic substitution, and discusses why generic substitution of orphan drugs may be challenging and should be undertaken carefully in rare disease patients

Personalized medicine of monoclonal antibodies in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and beyond

The pharmacotherapy of inflammatory bowel diseases (Crohn’s disease and ulcerative colitis) has experienced significant progress with the advent of monoclonal antibodies (mABs). As therapeutic proteins, mABs display peculiar pharmacokinetic characteristics that differentiate them from chemical drugs, such as aminosalicylates, antimetabolites (i.e., azathioprine, 6-mercaptopurine, and methotrexate), and immunosuppressants (corticosteroids and cyclosporine). However, clinical trials have demonstrated that biologic agents may suffer from a pharmacokinetic variability that could influence the desired clinical outcome, beyond primary resistance phenomena. Therefore, therapeutic drug monitoring (TDM) protocols have been elaborated and applied to adaptation drug doses according to the desired plasma concentrations of mABs. This activity is aimed at maximizing the beneficial effects of mABs while sparing patients from toxicities. However, some aspects of TDM are still under discussion, including time-changing therapeutic ranges, proactive and reactive approaches, the performance and availability of instrumental platforms, the widely varying individual characteristics of patients, the severity of the disease, and the coadministration of immunomodulatory drugs. Facing these issues, personalized medicine in IBD may benefit from a combined approach, made by TDM protocols and pharmacogenetic analyses in a timeline that necessarily considers the frailty of patients, the chronic administration of drugs, and the possible worsening of the disease. Therefore, the present review presents and discusses the activities of TDM protocols using mABs in light of the most recent results, with special attention on the integration of other actions aimed at exploiting the most effective and safe therapeutic effects of drugs prescribed in IBD patients

Coupled-mode theory of nonlinear propagation in multimode and single-mode fibers: envelope solitons and self-confinement

A set of equations describing pulse propagation in multimode optical fibers in the presence of an intensity-dependent refractive index is derived by taking advantage of the coupled-mode theory usually employed for describing the influence of fiber imperfections on linear propagation. This approach takes into account in a natural way the role of the waveguide structure in terms of the propagation constants and the spatial configurations of the propagating modes and can be applied to the most general refractive-index distribution. The conditions under which soliton propagation and longitudinal self-confinement can be achieved are examined

Sunitinib in metastatic renal cell carcinoma: The pharmacological basis of the alternative 2/1 schedule

No abstract availabl

Simultaneous, But Not Consecutive, Combination With Folinate Salts Potentiates 5-fluorouracil Antitumor Activity In Vitro and In Vivo

The combination of folinate salts to 5-fluoruracil (5-FU)-based schedules is an established clinical routine in the landscape of the colorectal cancer treatment. The aim of this study was to investigate the pharmacological differences between the sequential administration of folinate salts (1 h before, as in clinical routine) followed by 5-FU and the simultaneous administration of both drugs. Proliferation and apoptotic assays were performed on human colon cancer cells exposed to 5-FU, calcium (CaLV) or disodium (NaLV) levofolinate or their simultaneous and sequential combination for 24 and 72h. TYMS and SLC19A1 gene expression was performed with real time PCR. In vivo experiments were performed in xenografted nude mice, treated with 5-FU escalating doses and CaLV or NaLV alone or in simultaneous and sequential combination. The simultaneous combination of folinate salts and 5-FU was synergistic (NaLV) or additive (CaLV) in a 24h treatment in both cell lines. In contrast, the sequential combination of both folinate salts and 5-FU was antagonistic at 24 and 72h. The simultaneous combination of 5-FU and NaLV or CaLV inhibited TYMS gene expression at 24h, whereas the sequential combination reduced SLC19A1 gene expression. In vivo experiments confirmed the enhanced antitumor activity of the 5-FU+NaLV simultaneous combination with a good toxicity profile, whereas the sequential combination with CaLV failed to potentiate 5-FU activity. In conclusion, only the simultaneous, but not the consecutive, in vitro and in vivo combination of 5-FU and both folinate salt formulations potentiated the antiproliferative effects of the drugs

Precision medicine in lymphoma by innovative instrumental platforms

Since the last years, many efforts have been addressed to the growing field of precision medicine in order to offer individual treatments to every patient on the basis of his/her genetic background. Formerly adopted to achieve new disease classifications as it is still done, innovative platforms, such as microarrays, genome-wide association studies (GWAS) and next generation sequencing (NGS), have made the progress in pharmacogenetics faster and cheaper than previously expected. Several studies in lymphoma patients have demonstrated that these platforms can be used to identify biomarkers predictive of drug efficacy and tolerability, discovering new possible druggable proteins. Indeed, GWAS and NGS allow the investigation of the human genome, finding interesting associations with putative or unexpected targets, which in turns may represent new therapeutic possibilities. Importantly, some objective difficulties have initially hampered the translation of findings in clinical routines, such as the poor quantity/quality of genetic material or the paucity of targets that could be investigated at the same time. At present, some of these technical issues have been partially solved. Furthermore, these analyses are growing in parallel with the development of bioinformatics and its capabilities to manage and analyze big data. Because of pharmacogenetic markers may become important during drug development, regulatory authorities (i.e., EMA, FDA) are preparing ad hoc guidelines and recommendations to include the evaluation of genetic markers in clinical trials. Concerns and difficulties for the adoption of genetic testing in routine are still present, as well as affordability, reliability and the poor confidence of some patients for these tests. However, genetic testing based on predictive markers may offers many advantages to caregivers and patients and their introduction in clinical routine is justified

A new HPLC-UV method compared with HPLC-MS for daptomycin levels in human plasma samples

Application of a new HPLC-UV method on 122 plasma samples of patients from various AOUP wards, after analytical method settings, validation and comparison with a reference LC-MS/MS method. All research activities were performed according to the “Daptolin” protocol (approved by the Pisa University Hospital Ethics Committee, prot. num. 55945

THz spectroscopy on graphene-like materials for bio-compatible devices

Graphene-like (GL) layers and eumelanin-based graphene-like (EUGL) hybrids have been investigated through THz time domain spectroscopy. The interest in these materials lies on their peculiar chemical-physical properties: the former are conductive water stable materials, whereas the latter are biocompatible materials with good conductive and adhesive properties. Both exhibit promising optoelectronic and bioelectronic applications. We measured mixtures of GL layers or EUGL hybrids with KBr, shaped in pellets with uniform thickness, in order to circumvent problems related to sample inhomogeneity and roughness. A mean field theory was applied to extract direct information on permittivity and conductivity. Data have been carefully fitted through the Drude-Smith theory, confirming the conductive nature of the hybrid materials. The results show that EUGL hybrid-based devices can be promising for the next generation of printable bio-circuits

Friction stir welding of AlSi10Mg plates produced by selective laser melting

A preliminary research work is carried out to demonstrate the feasibility of friction stir welding AlSi10Mg plates produced by selective laser melting. The metallurgical evolutions occurring have been studied and discussed on the basis of detailed microstructure observations. The FSW process enhances the structure of the parent material so that the weld presents an overall refinement of the microstructure and a decrease in microporosity in all its zones. Using the friction stir welding technology, sound welds harder than the parent material can be obtained