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Protein kinases are an important class of drug targets with approval of 40 drugs treating diseases in immunology, inflammation and oncology. Early enablement of parallel synthetic chemistry produced large numbers of compound sets for screening, many of which were dominated by classic sp2–sp2 coupling reactions. This resulted in relatively lipophilic molecules that had unfavorable ADME properties. With the advances in synthetic organic chemistry and kinase crystallography, medicinal chemists have the power to rationally design and synthesize potent small molecule binders of kinases in drug like chemical space. Coupled with the recent focus on efficiency, more kinase inhibitors overlap potency, selectivity and ADME. Kinases can be targeted with ATP competitive inhibitors, but the architecture of the binding pockets are dynamic and the corresponding electrostatics, size and shape of the pockets can have a big impact on small molecule properties. In addition, allosteric binding pockets present other, unique pockets with different ligand requirements. In this chapter, we explore the properties of kinase pockets and the properties of small molecules targeting different pockets of the kinase landscape. In addition, property comparisons are made from different kinase inhibitor sets, including type I and II kinase inhibitors and the most recent approved drug set.

Auranofin is an FDA approved drug for the treatment of rheumatoid arthritis. In a repurposing effort, it has been extensively tested as an anticancer drug throughout the past decade. Regardless of the potent cytotoxicity observed for auranofin, there are many reports on lack of selectivity. Inspired by the structure of auranofin, and aiming to improve the cytotoxic selectivity, we decided to evaluate the cytotoxicity of the Au(I)-phosphine series of compounds. The correlation between chemical structure and reactivity of the compounds with model biomolecules such as N-Ac-Cys and ZnFs was deeply discussed in Chaps. 1 and 3 . Furthermore, the very same aspects that govern reactivity in the molecular level, such as the basicity and bulkiness of the phosphine ligand, σ-donating properties and lability of the co-ligands L (L = Cl or 4-dimethylaminopyridine, dmap) and overall charge of the compounds (neutral vs. cationic) are also expected to play a role in cytotoxic response, establishing an interesting set of parameters that can be correlated.

Turmeric used widely in Indian cooking and its active metabolite curcumin have been shown to have beneficial effects in a very large number of disease conditions, including cancers, allergies, atherosclerosis, aging, neurodegenerative diseases, hepatic disorders, obesity, diabetes, psoriasis, and autoimmune diseases. Interestingly, curcumin is reported to act on numerous molecular targets, ranging from genes, transcription factors, cell signaling, and cell death processes. It can also interact with –SH groups in proteins and redox reagents as well as form complexes with metal ions. Over 100 clinical trials (completed and ongoing) for a large number of diseases with a preponderance of cancer trials have indicated positive outcomes, but with the invariable conclusion that large-scale validation using randomized trials are needed. However, curcumin is not an approved drug even for a single ailment, while it is certified as a GRAS molecule by FDA. A main reason advanced is its poor bioavailability and rapid metabolism indicative of poor pharmacokinetic and pharmacodynamic properties. In recent times, several nano and other formulations of curcumin and its derivatives have been reported with improved druggable properties. Studies in mice model of malaria indicate that curcumin is very effective to treat experimental malaria. As an adjunct drug, it is very effective in preventing parasite recrudescence in the mouse model and treating experimental cerebral malaria. Therefore, in addition to the direct mechanisms proposed based on in situ presence of curcumin transiently, it may also have long-term effects mediated by immune memory effects even with specific cancer antigens generated by the primary anticancer drug. Studies suggest that curcumin, as an adjunct drug, can decrease the dosage of the primary drug and prevent resistance development. Appropriate use of nano and other formulations of curcumin would be an option to explore curcumin as an adjunct drug for the treatment of a large number of afflictions. Studies with infectious diseases can give clear-cut results for the assessment of efficacy in a shorter time frame. Thus, curcumin may still prove to be a valuable adjunct drug, although it does not satisfy the demands of medicinal chemistry.

Molecular profiling and functional assessment of signalling pathways of advanced solid tumours are becoming increasingly available. However, their clinical utility in guiding patients' treatment remains unknown. Here, we assessed whether molecular profiling helps physicians in therapeutic decision making by analysing the molecular profiles of 1057 advanced cancer patient samples after failing at least one standard of care treatment using a combination of next-generation sequencing (NGS), immunohistochemistry (IHC) and other specific tests. The resulting information was interpreted and personalized treatments for each patient were suggested. Our data showed that NGS alone provided the oncologist with useful information in 10-50% of cases (depending on cancer type), whereas the addition of IHC/other tests increased extensively the usefulness of the information provided. Using internet surveys, we investigated how therapy recommendations influenced treatment choice of the oncologist. For patients who were still alive after the provision of the molecular information (76.8%), 60.4% of their oncologists followed report recommendations. Most treatment decisions (93.4%) were made based on the combination of NGS and IHC/other tests, and an approved drug- rather than clinical trial enrolment- was the main treatment choice. Most common reasons given by physicians to explain the non-adherence to recommendations were drug availability and cost, which remain barriers to personalised precision medicine. Finally, we observed that 27% of patients treated with the suggested therapies had an overall survival > 12 months. Our study demonstrates that the combination of NGS and IHC/other tests provides the most useful information in aiding treatment decisions by oncologists in routine clinical practice., SCOPUS: ar.j, info:eu-repo/semantics/published

OBJECTIVES/SPECIFIC AIMS: Since 1971, Naloxone has been the only FDA approved opioid antagonist indicated for use after opioid overdose. New formulations of Naloxone have been introduced into the market, including an injectable, auto-injector, and nasal spray. However, Naloxone is short-acting and as such often requires multiple doses and may induce severe withdrawal symptoms. This study examines the regulatory framework to understand the evolution of products indicated to treat opioid overdose and the landscape of therapies in development. Furthermore, this study examines how the Food and Drug Administration (FDA) and other government agencies have approached the opioid crisis. METHODS/STUDY POPULATION: A PubMed search of “naloxone AND opioid overdose” with the filter “humans” was conducted to understand Naloxone’s regulatory framework. The term “naloxone” was searched on the Drugs@FDA: Approved Drug Products database. Additionally, “nalmefene” was searched on ClinicalTrials.gov. To examine the opioid antagonist market landscape, a PubMed search of “opioid antagonist AND opioid overdose” with the filters “humans” and “clinical trial,” and a ClinicalTrials.gov search of “opioid antagonist and opioid overdose,” were conducted. Government agency reports were reviewed and cataloged. RESULTS/ANTICIPATED RESULTS: Preliminary findings suggest a lack of innovation in the development of novel opioid antagonists. Most literature review findings focused on already-marketed Naloxone products, including the original injectable approved in 1971, the 2014 Evzio Auto-Injector, and the 2015 Narcan Nasal Spray (Figure 1). For example, there were 14 results yielded from the FDA approvals database, but none of these results represented a new opioid antagonist molecule. A longer-acting opioid antagonist, Nalmefene injectable, was approved in 1995 but has since been removed from the market due to low sales. Our initial ClinicalTrials.gov search using condition “opioid overdose” and other terms “opioid antagonist”,revealed no new studies being conducted on alternative opioid antagonist treatments for opioid overdose. Findings only focused on the distribution, co-dispensing, intervention, pharmacokinetics/pharmacodynamics (PK/PD) of Naloxone (Figure 2). However, a Google search yielded one new trial with an opioid antagonist by Opiant Pharmaceuticals, almost fifty years after FDA’s approval of Naloxone. A ClinicalTrials.gov search was then performed using the search term “nalmefene” to find whether Opiant Pharmaceuticals’ trial was in the ClinicalTrials.gov database. However, the Opiant trial is phase I, and as such does not require reporting on ClinicalTrials.gov. In 2017, the National Institutes of Health (NIH) launched an initiative for longer-acting opioid antagonist formulations. In 2018, Opiant Pharmaceuticals announced positive phase I results for intranasal Nalmefene. The potential return of Nalmefene in intranasal form may play a significant role in reducing overdoses, especially in cases where a longer-acting opioid antagonist is necessary. Opiant Pharmaceuticals’ trial commenced after the NIH announced their initiative; furthermore, the NIH’s National Institute on Drug Abuse granted the company $7.4 million to further the investigation of this drug. We will continue to research drugs that have previously been studied for the indication of treating opioid overdose in the United States and abroad and catalog them. DISCUSSION/SIGNIFICANCE OF IMPACT: The abuse and misuse of opioids in the United States has caused an epidemic accounting for over 115 opioid-overdose deaths each day, devastating our nation, both socially and economically. The United States spends $78.5 billion annually to combat the misuse of these drugs. Due to the severity of the opioid crisis, efforts to better understand approved therapies and investigational products in development to treat opioid overdose will be of significance moving forward. This research can inform agencies who are developing strategies to reduce opioid overdoses and pharmaceutical product developers about the current opioid antagonist landscape.

The selection of the right drug targets is critically important for the successful and cost-effective development and clinical testing of drugs. A 2009 paper reported an in silico prospective prediction of the clinical potential of 156 targets of clinical trial drugs (all of these targets were without an approved drug at the time of the paper's publication). Eight years later, the assessment of the clinical status of these targets revealed impressive capability of the in silico method in prospectively predicting the clinical success of drug targets.

Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) have been in clinical development as anticancer agents since 1998. There have been 18 Hsp90 inhibitors (Hsp90i) that have entered the clinic, all of which, though structurally distinct, target the ATP-binding Bergerat fold of the chaperone N-terminus. Currently, there are five Hsp90 inhibitors in clinical trial and no approved drug in this class. One impediment to development of a clinically efficacious Hsp90 inhibitor has been the very low percentage of clinical trials that have codeveloped a predictive or pharmacodynamic marker of the anticancer activity inherent in this class of drugs. Here, we provide an overview of the clinical development of Hsp90 inhibitors, review the pharmacodynamic assays that have been employed in the past, and highlight new approaches to Hsp90 inhibitor clinical development.

Naltrexone-bupropion is a recently approved drug combination for chronic weight management. In this article, we discuss the rationale for its use as a combination followed by a comprehensive review of safety and efficacy data from major preclinical, phase II and III clinical trials.

The FDA’s Guidance for Industry, Patient-Reported Outcomes (PRO) Measures: Use in Medical Product Development to Support Labeling Claims (i.e. “PRO Guidance”; 2009) outlines the agency’s perspectives on how PRO measures, used to support efficacy end-points in therapeutics clinical trial programs, may be evaluated by the FDA. Prior reviews have attempted to identify PRO-based statements in product labels in order to evaluate the potential impacts of the PRO guidance on the rate of approvals of PRO-based claims, but none have been enacted after 2010. An in-depth search identified drug product labels approved by the FDA from January 2006 through to December 2014, with efficacy statements supported by PRO measures. Drug product labels were sorted by chemical type and year of approval, and the differences between time periods before and after the finalization of the PRO Guidance were reviewed with statistical tests. Results showed a reduction in the overall approvals of label-based efficacy statements ...

Introduction: Leishmaniasis, and most tropical diseases, are rare/orphan diseases in the developed world but not rare worldwide. Classic treatment is with parenteral agents, namely, pentavalent antimony and amphotericin B deoxycholate. Miltefosine is the first oral agent for all forms of leishmaniasis. The target regimen is 2.5 mg/kg/day for 28 days, with a maximum dose of 150 mg/day (one 50 mg capsule each with breakfast, lunch and dinner).Areas covered: Clinical studies visceral, cutaneous and mucosal leishmaniasis treated with miltefosine.Expert opinion: The 2014 FDA approval of the miltefosine New Drug Application for visceral, cutaneous and mucosal leishmaniasis was a breakthrough in several ways. In a clinical sense, miltefosine was recognized in the US, after previously being approved in Europe and in the developing world, as the first oral treatment for any form of leishmaniasis. In a regulatory sense, miltefosine was the first drug solely developed for leishmaniasis. In a financial sense, the $12...

We have examined the effect of eight different protein classes (channels, GPCRs, kinases, ligases, nuclear receptors, proteases, phosphatases, transporters) on the benchmarking performance of the CANDO drug discovery and repurposing platform (http://protinfo.org/cando). The first version of the CANDO platform utilizes a matrix of predicted interactions between 48278 proteins and 3733 human ingestible compounds (including FDA approved drugs and supplements) that map to 2030 indications/diseases using a hierarchical chem and bio-informatic fragment based docking with dynamics protocol (> one billion predicted interactions considered). The platform uses similarity of compound-proteome interaction signatures as indicative of similar functional behavior and benchmarking accuracy is calculated across 1439 indications/diseases with more than one approved drug. The CANDO platform yields a significant correlation (0.99, p-value < 0.0001) between the number of proteins considered and benchmarking accuracy obtained indicating the importance of multitargeting for drug discovery. Average benchmarking accuracies range from 6.2 % to 7.6 % for the eight classes when the top 10 ranked compounds are considered, in contrast to a range of 5.5 % to 11.7 % obtained for the comparison/control sets consisting of 10, 100, 1000, and 10000 single best performing proteins. These results are generally two orders of magnitude better than the average accuracy of 0.2% obtained when randomly generated (fully scrambled) matrices are used. Different indications perform well when different classes are used but the best accuracies (up to 11.7% for the top 10 ranked compounds) are achieved when a combination of classes are used containing the broadest distribution of protein folds. Our results illustrate the utility of the CANDO approach and the consideration of different protein classes for devising indication specific protocols for drug repurposing as well as drug discovery.

Cell therapy products are regulated by the Ministry of Food and Drug Safety under the Pharmaceutical Affairs Act in Korea. Sixteen cell therapy products including three stem cells were approved for marketing authorization, and 155 clinical protocols have been approved. Due to the lack of complete understanding of various cellular product characteristics and limited experience on these products, there are many regulatory challenges to the reliable evaluation of safety and efficacy of these products. These challenges include, not limited to, lack of appropriate animal model for preclinical studies, difficulty in translating preclinical results to clinical design, short half life and limited amount autologous cell samples for testing, difficulty in maintaining blindness of control group in clinical study especially when invasive operation is required, concern over tumor or ectopic tissue formation and so on. For various regulatory challenges, a regulatory approach is the risk-based, case-by-case and science-based review with flexibility, balancing risk and benefits. In addition to periodic safety update reporting after marketing authorization, re-examination of a drug and re-evaluation of a drug exist to monitor the safety of an approved drug. There is a system for cell therapy product only, which requires mandatory safety reporting for every use of the approved cellular product for specific time period.

Summary Of all the aspects of non-alcoholic fatty liver disease (NAFLD), the slowest advances have occurred in the therapeutic field. Thirty-five years after its formal description and after 15 years of intense scrutiny from researchers worldwide, there is still no approved drug for the treatment of non-alcoholic steatohepatits (NASH). In the meantime, progress in the understanding of pathophysiology, diagnosis – both invasive and non-invasive, epidemiology and even natural history have been substantial or, at times, spectacular. In contrast, hepatitis C virus (HCV) therapy underwent constant improvement and even before the great acceleration of the past few years, patients were already being offered approved therapies that were increasingly more efficient. What then explains such a slow pace of therapeutic advances in NASH, and will this change in the near future? Here we will review commonly-held myths that have diverted attention from therapy of NASH, obstacles that have slowed down industrial development of drugs for this indication, and recent achievements that will create better conditions for drug development programs. We will also briefly review current knowledge of non-pharmacological and pharmacological management in this early era of NASH therapies.

Precision medicine signals the beginning of an era in which each patient is a distinct individual from a diagnostic, treatment and health management perspective. In this article, we present a description of a methodology to develop a therapy, based on kinase inhibitors, and a strategy to retarget a therapy in rapid response to a patient's relapse. The idea is to translate the genomic data of an evolving cancer into a three-dimensional structure to enable a better understanding of the mechanism of resistance, and to then control it with a specific and precise drug targeting therapy based on the SNP resistance mutation. In many cases, a combination of approved drug treatments can assist in controlling the disease. However, the clinical trials selection process is changing from randomised populations to selected populations so that genetic tests can more clearly define the presence of specific mutations in the relapsing patient. This knowledge of the subpopulation will also help identify new small molecules that target multiple kinases based on their specificity profiles. The tendency at present is to define an eligibility criteria based on the genetics of the patients. Key Concepts The crystallographic characterisation of kinase inhibitor complexes drove the approval of 27 drugs targeting kinome. Organising the kinase three-dimensional (3D) structures in a uniquely aligned library has enabled us to predict the functionality, in a 3D space, of any variants that are found in a patient's genome. Accurate specificity profiles of approved kinase inhibitors inform a rational combination of inhibitors for a specific genetic subpopulation of patients. Kinase inhibitor therapy can be matched to critical mutations in the kinase 3D structure and a companion diagnostics approach can then be used in specific clinical trial to more accurately select patients. The targeting of both the kinase-activating mutation and the drug-resistant mutations can be optimised by the chemistry of the intermediate conformations of the DFG motif. The drug resistance requires frequent genetic monitoring utilising a liquid biopsy. Overcoming the drug resistance on the target is possible by combining approved drugs based on the enhanced knowledge of the highly accurate specificity profiles. Keywords: kinase; cancer; drug design; drug resistance; Gleevec®; activating mutations; predictive personalised medicine

Shigellosis is an endemic disease prevalent in developing and poor countries due to fecal-oral transmission resulting a significant morbidity and mortality rate. Emergence of multidrug resistant (MDR) in Shigella sp. reveals the inefficacy towards the first line antibiotics like quinolones, cotrimoxazole and ampicillin against it. There is continuous need to monitor the characteristics and antibiotic resistance patterns of this pathogen regarding the identification of new potential therapeutic drug targets. Availability of complete protein of different Shigella species viz flexneri, body, dysentery and son has made it possible to carry out the Insilico analysis of its protein for the identification of potential vaccine and drug targets. Subtractive proteomics approach is being used to mine the list of proteins present in different Shigella species which are non-homologous to human and essential for the survival of the pathogen. The metabolic chokepoint analysis also enriches the list of essential protein and adds those proteins in the list which are uniquely found in pathogenic pathway, catalyzed by single enzyme and involved in multi pathways. Screening of essential proteins against human gut flora and approved drug targets revealed the targets which are non-homologous to human gut flora and homologous to the approved drug targets. Broad spectrum drug targets screening revealed a list of highly conserved proteins of various pathogens including different Shigella species. Probably the drug developed against these targets may be useful in treating multiple diseases or diseases which results due to co-infection of different pathogens. Subcellular localization prediction revealed a list protein, which could be potential vaccine targets in different Shigella species. Virtual screening against these identified targets might be useful in the discovery of novel Drug against MDR Shigella species.

Various inhibitors have been developed for neuraminidase but resistance against these drugs in many viral strains makes it an advantageous and interesting task to discover compounds which can be more promising in preventing viral infection through neuraminidase. Virtual screening methods have been proved as an efficient in silico approach for drug discovery processes. In the present study, we used ligand based virtual screening process for identifying potent inhibitors against viral neuraminidase enzyme. The approach utilized in this study has been successful in identifying 15 compounds which may be potential inhibitors of neuraminidase. These compounds were screened via three screening platforms (MVD, PyRx, and FRED) by setting oseltamivir as reference compound, which is an FDA approved drug against influenza virus. These compounds were then filtered by their in silico ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) values and only 12 of them were found to have comparatively better results. The results of the present study are reported herein so that researchers, who are having required laboratory facilities for synthesizing drugs, can utilize findings of this study for developing new drugs against influenza with better efficacy.

Inherent and acquired multiple drug resistance (MDR) to chemotherapeutic drugs is a major obstacle in cancer treatment. The ATP Binding Cassettes (ABC) transporter super family that act as extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins have prominent roles in cancer MDR. One of the most efficient strategies to modulate this active drug efflux from the cells is to physically block the pump proteins and thus change the balance between drug influx and efflux toward an accumulation of drug inside the cell, which eventually cumulates into cell death. MDR modulators (also known as chemosensitizers) were found among drugs approved for non-cancer indications. Yet, toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Previous reports have shown that drugs belonging to the selective serotonin reuptake inhibitors (SSRI) family, which are clinically used as antidepressants, can act as effective chemosensitizers both in vitro and in vivo in tumor bearing mouse models. Here, we set out to explore whether sertraline (Zoloft®), a molecule belonging to the SSRI family, can be used as an MDR modulator. Combining sertraline with another FDA approved drug, Doxil® (pegylated liposomal doxorubicin), is expected to enhance the effect of chemotherapy while potentially reducing adverse effects. Our findings reveal that sertraline acts as a pump modulator in cellular models of MDR. In addition, in an aggressive and highly resistant human ovarian xenograft mouse model the use of sertraline in combination with Doxil® generated substantial reduction in tumor progression, with extension of the median survival of tumor-bearing mice. Taken together, our results show that sertraline could act as a clinically relevant cancer MDR inhibitor. Moreover, combining two FDA approved drugs, DOXIL®, which favor the influx of chemotherapy inside the malignant cell with sertraline, which blocks the extrusion pumps, could readily be available for clinical translation in the battle against resistant tumors.

BACKGROUND Although pharmacotherapy is not the cornerstone of obesity treatment, it is a valuable tool that could be considered for patients who have not had adequate benefit from lifestyle interventions or who have difficulty maintaining initial weight loss over longer periods. CONTENT This review focuses on the role of antiobesity drugs, the mechanisms by which the drugs work, potential pharmacological targets in the neural control of food intake and regulation of body weight, the history of antiobesity drugs, a summary of efficacy and safety data from clinical trials, and the clinical application of pharmacotherapy. Currently, 5 approved drug therapies are available in the US for long-term weight management, with only 2 of these meeting the stronger Food and Drug Administration (FDA) criteria of 5% weight loss relative to a placebo after 1 year and others receiving approval based on the categorical criterion of the proportions of patients achieving 5% weight loss. Interpretation of the results of clinical trials conducted before regulatory agency approval is limited by high dropout rates; thus, the results might not be replicable in clinical practice settings. Many patients who are suitable candidates for pharmacotherapy are not using the new drugs due to lack of insurance coverage and high out-of-pocket costs. SUMMARY With the availability of 4 new drugs since 2012, clinicians in the US now have more tools for long-term weight management. The quality of pharmacotherapy clinical investigations needs considerable improvement. Future research should focus on examining the mediators and moderators of response.

Autism spectrum disorder (ASD) is characterized by deficits in social communication and restricted interests/repetitive behaviors, for which there are currently no approved drug treatments. The core symptoms of ASD vary widely in severity and are often accompanied by other neuropsychiatric disorders. Drug discovery has been challenging because of the lack of understanding of the underlying pathophysiology of ASD as well as the heterogeneity of symptoms and symptom severity. Areas covered: In this review, the author discusses animal models of ASD used as targets for drug discovery, focusing primarily on non-syndromic models, primarily rodents. They highlight the wide range of drug targets examined in animal models. While very little of this work has resulted in drug therapy for the behavioral symptoms of ASD yet, it has increased our knowledge of the biology of ASD that is critical for driving drug discovery and has already provided many new drug targets for investigation. Expert opinion: The information gathered from the animal models of ASD is increasing our understanding of the underlying pathophysiology for ASD and is leading to better therapeutic targets. However, the issue of small sample size, heterogeneity within clinical samples, and a lack of replicable outcome measures must be addressed to move forward.

Amphetamine (AMP), an indirectly acting psychostimulant approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults, is among the most long-standing therapeutic agents in all of clinical psychopharmacology. This review focuses on AMP absorption, metabolism, and elimination brought to bear on comparative pharmacokinetics in its various formulations. A comprehensive search of the published literature was conducted using MEDLINE (PubMed) and Google Scholar databases through April 2017 to retrieve all pertinent in vitro and human studies for review and synthesis. Additionally, Food and Drug Administration (FDA) databases were accessed for otherwise unavailable data when possible. Initially available as racemic (dl)-AMP, this drug was later supplanted by enantiopure (d)-AMPH or enantioenriched (75:25 dl)-AMP formulations; although racemic AMP returned as an approved drug to treat ADHD in 2014. Presently, there are several immediate-release (IR) formulations available, including d-AMP, dl-AMP, and mixed amphetamine salts, which are neither racemic nor the pure d-enantiomer (i.e., a 3:1 mixture of d-AMP and l-AMP). Furthermore, new modified-release AMP formulations, including an oral suspension and an orally disintegrating tablet, are now available. A lysine-bonded prodrug form of d-AMP also serves as a treatment option. Oral AMP is rapidly absorbed, with high absolute bioavailability, followed by extensive metabolism involving multiple enzymes. Some metabolic pathways exhibit stereoselective biotransformations favoring the l-isomer substrate. Drug exposure exhibits dose-proportional pharmacokinetics. Body weight is a fundamental determinant of differences in observed AMP plasma concentrations. IR formulations typically provide a T

Zika virus (ZIKV) has become a global public health emergency due to its rapidly expanding range and its ability to cause severe congenital defects such as microcephaly. However, there are no FDA-approved therapies or vaccines against ZIKV infection. Through our screening of viral entry inhibitors, we found that chloroquine (CQ), a commonly used antimalarial and a FDA-approved drug that has also been repurposed against other pathogens, could significantly inhibit ZIKV infection in vitro, by blocking virus internalization. We also demonstrated that CQ attenuates ZIKV-associated morbidity and mortality in mice. Finally, we proved that CQ protects fetal mice from microcephaly caused by ZIKV infection. Our methodology of focusing on previously identified antivirals in screens for effectiveness against ZIKV proved to be a rapid and efficient means of discovering new ZIKV therapeutics. Selecting drugs that were previously FDA-approved, such as CQ, also improves the likelihood that they may more quickly reach stages of clinical testing and use by the public., Highlights • 5 out 16 tested Ebola virus entry inhibitors can inhibit ZIKV entry efficiently • Chloroquine can inhibit ZIKV internalization in vitro and reduce ZIKV-associated morbidity and mortality in mice • Chloroquine prevents ZIKV-associated congenital microcephaly in mice Zika virus (ZIKV) is an emerging virus which can cause birth defects, however there are currently no effective treatments or vaccines. We tested the effects of 16 verified Ebola virus cell entry inhibitors on ZIKV infection, and found that chloroquine (CQ) could prevent ZIKV infection in cell cultures, consistent with results from a previous study. We then demonstrated that CQ can reduce ZIKV-associated morbidity and mortality in mice. Most importantly, it protects fetal mice from microcephaly caused by ZIKV infection. Therefore, CQ is a potential drug which would be used to treat ZIKV infection after clinical test.

Consideration by the US Drug Enforcement Administration and Food and Drug Administration of placing kratom into Schedule I of the Controlled Substances Act (CSA) requires its evaluation of abuse potential in the context of public health. The objective of the study is to provide a review of kratom abuse potential and its evaluation according to the 8 factors of the CSA. Kratom leaves and extracts have been used for centuries in Southeast Asia and elsewhere to manage pain and other disorders and, by mid-twentieth century, to manage opioid withdrawal. Kratom has some opioid effects but low respiratory depression and abuse potential compared to opioids of abuse. This appears due to its non-opioid-derived and resembling molecular structure recently referred to as biased agonists. By the early 2000s, kratom was increasingly used in the US as a natural remedy to improve mood and quality of life and as substitutes for prescription and illicit opioids for managing pain and opioid withdrawal by people seeking abstinence from opioids. There has been no documented threat to public health that would appear to warrant emergency scheduling of the products and placement in Schedule I of the CSA carries risks of creating serious public health problems. Although kratom appears to have pharmacological properties that support some level of scheduling, if it was an approved drug, placing it into Schedule I, thus banning it, risks creating public health problems that do not presently exist. Furthermore, appropriate regulation by FDA is vital to ensure appropriate and safe use.

Purpose Next-generation sequencing (NGS) identifies potentially targetable alterations by US Food and Drug Administration (FDA)–approved drugs and/or by available experimental agents that may not have otherwise been contemplated. Many targeted drugs have been developed for diverse solid cancers; a smaller number of genomically targeted drugs have been approved for lymphoid malignancies. Materials and Methods We analyzed NGS results from 60 patients with various lymphoid malignancies and found 224 alterations (median per patient, three alterations). Results Forty-nine patients (82%) had potentially actionable alterations with the use of FDA-approved drugs and/or experimental therapies; only 11 patients (18%) had no theoretically actionable alterations. Only three patients (5%) had an alteration for which an approved drug in the disease is available (on label); 45 patients (75%) had an alteration for which an approved drug is available for another disease (off label). The median number of alterations per patient potentially actionable by an FDA-approved drug was one. Of note, 19 (32%) of 60 patients had intermediate to high tumor mutational burden, which may predict response to certain immunotherapy agents. Conclusion NGS identifies alterations that may be pharmacologically tractable in most patients with lymphoid malignancies, albeit with drugs that have usually been developed in the context of solid tumors. These observations merit expanded exploration in the clinical trials setting.

Background The critically important issue on emergence of drug-resistant malarial parasites is compounded by cross resistance, where resistance to one drug confers resistance to other chemically similar drugs or those that share mode of action. This aspect requires discovery of new anti-malarial compounds or formulation of new combination therapy. The current study attempts to contribute towards accelerating anti-malarial drug development efforts, by exploring the potential of existing FDA-approved drugs to target proteins of Plasmodium falciparum. Methods Using comparative sequence and structure analyses, FDA-approved drugs, originally developed against other pathogens, were identified as potential repurpose-able candidates against P. falciparum. The rationale behind the undertaken approach is the likeliness of small molecules to bind to homologous targets. Such a study of evolutionary relationships between established targets and P. falciparum proteins aided in identification of approved drug candidates that can be explored for their anti-malarial potential. Results Seventy-one FDA-approved drugs were identified that could be repurposed against P. falciparum. A total of 89 potential targets were recognized, of which about 70 are known to participate in parasite housekeeping machinery, protein biosynthesis, metabolic pathways and cell growth and differentiation, which can be prioritized for chemotherapeutic interventions. An additional aspect of prioritization of predicted repurpose-able drugs has been explored on the basis of ability of the drugs to permeate cell membranes, i.e., lipophilicity, since the parasite resides within a parasitophorous vacuole, within the erythrocyte, during the blood stages of infection. Based on this consideration, 46 of 71 FDA-approved drugs have been identified as feasible repurpose-able candidates against P. falciparum, and form a first-line for laboratory investigations. At least five of the drugs identified in the current analysis correspond to existing antibacterial agents already under use as repurposed anti-malarial agents. Conclusions The drug-target associations predicted, primarily by taking advantage of evolutionary information, provide a valuable resource of attractive and feasible candidate drugs that can be readily taken through further stages of anti-malarial drug development pipeline. Electronic supplementary material The online version of this article (doi:10.1186/s12936-017-1937-2) contains supplementary material, which is available to authorized users.

Background Adamantiades-Behcet9s disease (ABD) is a chronic systemic vasculitic disease. Because of multiorgan involvement with diagnostic and therapeutic challenges for physicians, treatment decisions can be very difficult. Objectives To retrospectively assess the use of medication for ABD-therapy in view of 1.) current guidelines and 2.) approval by authorities in a Middle-European tertiary care center. Methods Data between 1997 and 2016 from a Middle-European ABD-cohort were retrospectively analysed. First, medical treatment was evaluated for conformity with the EULAR-recommendations for ABD-management and the anti-TNF therapy recommendations by Sfikakis et al. (1,2). Second, medical treatment was evaluated for use according to indications approved by authorities. Therefore official prescribing informations of the Bundesamt fur Sicherheit im Gesundheitswesen (BASG)/European Medicines Agency (EMA), exemplary for Europe, and the Food and Drug Administration (FDA), exemplary for the USA, were screened (3–5). The study was approved by the local ethics committee. Results A total of 174 medical interventions were identified in 76 patients. Until 2008, treatment of ABD was based only on few clinical trials. According to EULAR-recommendations 93,7% were considered as being treated appropriately, including 55.2% of therapeutic approaches exactly matching the recommendations. 88.9% of TNF-inhibitors were indicated according to the anti-TNF-therapy recommendations (n=8/9). Out of 27 used drugs only prednisolone was approved by BASG/EMA- and FDA-authorities for a general indication including ABD, and cyclosporin A had the specific BASG/EMA-indication for ABD-uveitis. Another 12 medications had the indications for different symptoms of ABD, and thirteen medications were not authority-approved for any ABD-treatment. Conclusions Approvals by BASG/EMA- and FDA-authorities are often missing the indication of ABD. Therefore physicians not only face the complexity of ABD as a rare multiorgan disease, but also have to treat their ABD-patients with unapproved drugs. We propose that medications recommended by international guidelines for the management of rare diseases should be recognized by BASG/EMA- and FDA-authorities, even in case of low evidence. References Hatemi G, Silman A, Bang D, et al. EULAR recommendations for the management of Behcet disease. AnnRheumDis. 2008;67:1656. Sfikakis PP, Markomichelakis N, Alpsoy E et al. Anti-TNF therapy in the management of Behcet9s disease-review and basis for recommendations. Rheumatol. 2007;46:736. BASG. Arzneispezialitatenregister, 20/09/2016 [Internet]. https://aspregister.basg.gv.at/aspregister/faces/aspregister.jspx?_afrLoop=31622307107626619&_afrWindowMode=0&_adf.ctrl-state=kimc6lskg_4. EMA. European Medicines Agency - Find medicine - European public assessment reports [Internet] http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124. FDA. Drugs@FDA: FDA Approved Drug Products, citated 20.09.2016 [Internet]. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Disclosure of Interest None declared

Small cell lung cancer (SCLC) is a very aggressive malignancy characterized by high cellular proliferation and early metastatic spread. In fact, although SCLC is a chemosensitive and radiosensitive disease, the initial responsiveness to chemotherapy is usually followed by development of resistance and the prognosis remains poor with a median survival of less than 12 months in patients with extensive disease (ED-SCLC). Furthermore, no significant progress has been made over the last years, with no newly approved drug. For all these reasons, SCLC represents for the oncologists a major challenge and an exciting field of clinical research. In this review, we analyze the most promising advances in development for SCLC with a special focus on antiangiogenic treatments, immunotherapy, novel chemotherapeutic and targeted agents.

Daily repeated wound dressing changes will lead to additional trauma to newly formed tissue and prolonging the healing process. In this letter, we designed and fabricated an easily removable wound dressing material. To accomplish this, we first generated cross-linkable supramonomers through host–guest noncovalent interaction, followed by radical copolymerization of acrylamide with supramonomer as cross-linker to fabricate supramolecular hydrogels. Benefiting from the dynamic nature of the supramonomer, the supramolecular hydrogel is able to dissolve upon exposure to memantine, an FDA approved drug, making it easily removed from a wound, representing a promising candidate for the new generation of wound dressing.

Natural compounds capable of inducing apoptosis in cancer cells have always been of considerable interest as potential anti-cancer agents. Many such compounds are under screening and development with their potential evolution as a clinical drug benefiting many of the cancer patients. Guggulsterone (GS), a phytosterol isolated gum resin of the tree Commiphora mukul has been widely used in Indian traditional medicine as a remedy for various diseses. GS has been shown to possess cancer chemopreventive and therapeutic potential as established by in vitro and in vivo studies. GS has been shown to target constitutively activated survival pathways such as PI3-kinase/AKT, JAK/STAT, and NFκB signaling pathways that are involved in the regulation of growth and inflammatory responses via regulation of antiapoptotic and inflammatory genes. The current review focuses on the molecular targets of GS, cellular responses, and the animal model studies in various cancers. The mechanistic action of GS in different types of cancers also forms a part of this review. The perspective of translating this natural compound into a clinically approved drug with its pros and cons is also discussed.

In the last decade, the availability of new drugs for the treatment of Multiple Myeloma (MM) significantly improved patients' outcomes, but also raised attention towards a new spectrum of adverse events. Recently, four novel agents with different mechanisms of action (carfilzomib, elotuzumab, daratumumab and panobinostat) have been approved for the treatment of MM. This review aims at providing physicians with the tools to recognize and handle toxicity issues related with these new treatments. Areas covered: This review focuses on the management of drug related adverse events of the latest approved drug combinations. New drug combinations under development and still in the phase of approval will be briefly discussed. PubMed was searched using the terms 'toxicity', 'carfilzomib', 'elotuzumab' 'daratumumab' and 'panobinostat'. Phase II and III clinical trials and previously published analyses on toxicities were reviewed. For new drug combination abstracts presented at the latest ASH, ASCO and EHA meetings as well as clinicaltrial.gov website was searched and reviewed. Expert commentary: With the development of newer drugs and the availability of different treatment options for MM patients, an accurate evaluation of treatment side effects, their prompt recognition and management is mandatory for all clinical hematologists.

Developing a new drug is a high-risk and high-reward enterprise. The high risk is reflected by the low success rate of turning a new molecular entity (NME) into an approved drug even after the NME has successfully met the preclinical testing requirements. In this chapter, we offer a high-level summary of the clinical testing which is composed of four distinct phases under a traditional development plan. We discuss deviations from the traditional development plan and new regulatory approval pathways. We offer some examples of recent advancements in clinical trial designs and conclude the chapter with a short summary of the salient points covered in the chapter.

Zika virus (ZIKV) has recently infected around 2 million people around the world and presently there is no USFDA approved drug in the market. In the present study, molecular docking analysis of two essential non-structural proteins NS2B/NS3 protease and NS3 helicase, which are involved in viral replication, has been reported. Identification of potential inhibitors could be considered as a strategy for treatment of the ZIKV infection. Using structure based drug design, docking of 1, 15,203 compounds were performed for both the proteins and 10 ligands were identified for each protein, which may serve as potential inhibitors. These molecules can further be validated in experimental studies.

Translating preclinical epilepsy therapy research into clinical therapeutic products requires an understanding of the regulatory requirements pertaining to drug development. In this chapter, we discuss regulatory considerations in the development of new molecular entities, or the repurposing of approved drugs for the treatment of epilepsy, as an investigator moves a potential drug therapy through discovery, preclinical and clinical development, and approval. We provide an overview of relevant guidances and harmonization by regulatory agencies, and the regulatory process and requirements for studying drugs in humans. Specifically, this chapter summarizes the process for submitting and maintaining an investigation new drug (IND) application, and provides an overview of the required IND content, including preclinical pharmacology and toxicology study summaries; chemistry, manufacturing, and controls information; previous human experience; and the clinical investigation plan. These components are discussed with an emphasis on preclinical testing specific for epilepsy. Last, the topics of repurposing an approved drug and obtaining orphan drug designation are highlighted as special considerations that may be important for investigator-initiated research in epilepsy.

Pharmaceutical products must undergo a battery of preclinical general toxicology studies to provide information regarding the safety of a potential new drug prior to initiation of the various clinical trials in humans, which are necessary before a molecule can become an approved drug. The order of the general toxicology studies begins with acute screening and progresses through longer durations of exposure up to as much as 1 year in length. In this chapter, numerous regional and global considerations regarding the influence rendered on the types of general toxicology study designs needed for regulatory submission are discussed. This chapter also covers how to integrate general toxicology assessments into the preclinical program. By understanding the intricacies of the general toxicology plan, the hope is that it will facilitate smoother transitions as the potential drug candidate moves forward in development.

Alzheimer’s disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.

In any biomedical and chemical context, a truthful description of chemical constitution requires coverage of both structure and purity. This qualification affects all drug molecules, regardless of development stage (early discovery to approved drug) and source (natural product or synthetic). Purity assessment is particularly critical in discovery programs and whenever chemistry is linked with biological and/or therapeutic outcome. Compared with chromatography and elemental analysis, quantitative NMR (qNMR) uses nearly universal detection and provides a versatile and orthogonal means of purity evaluation. Absolute qNMR with flexible calibration captures analytes that frequently escape detection (water, sorbents). Widely accepted structural NMR workflows require minimal or no adjustments to become practical 1H qNMR (qHNMR) procedures with simultaneous qualitative and (absolute) quantitative capability. This study reviews underlying concepts, provides a framework for standard qHNMR purity assays, and shows h...

The diversity of elements among U.S. Food and Drug Administration (FDA) approved pharmaceuticals is analyzed and reported, with a focus on atoms other than carbon, hydrogen, oxygen, and nitrogen. Our analysis reveals that sulfur, chlorine, fluorine, and phosphorous represent about 90% of elemental substitutions, with sulfur being the fifth most used element followed closely by chlorine, then fluorine and finally phosphorous in the eighth place. The remaining 10% of substitutions are represented by 16 other elements of which bromine, iodine, and iron occur most frequently. The most detailed parts of our analysis are focused on chlorinated drugs as a function of approval date, disease condition, chlorine attachment, and structure. To better aid our chlorine drug analyses, a new poster showcasing the structures of chlorinated pharmaceuticals was created specifically for this study. Phosphorus, bromine, and iodine containing drugs are analyzed closely as well, followed by a discussion about other elements.

Obesity is a major co-morbidity with hypertension and diabetes mellitus. There are few drugs for treatment of obesity like orlistat and recentlty approved drug lorcaserin. Lorcaserin has serotonergic properties and acts as an anorectic. It may cause serious side effects, including serotonin syndrome, particularly when taken with certain medicines that increase serotonin levels or activate serotonin receptors. Although, mainstay and first line of approach of treatment will always remain in having low calorie diet and increase in physical activity. Lorcaserin has come as a new hope to achieve success in treating obese patients but still a long road with further extensive research to be undertaken in the treatment of obesity.

This review summarizes patent applications in the past 5 years for the management of brain tumors and metastases. Most of the recent patents discuss one of the following strategies: the development of new drug entities that specifically target the brain cells, the blood–brain barrier and the tumor cells, tailor-designing a novel carrier system that is able to perform multitasks and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a US FDA approved drug with a targeting moiety, diagnostic moiety or PK modifying moiety, or the use of innovative nontraditional approaches such as genetic engineering, stem cells and vaccinations. Until now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are actively ongoing to take brain tumor targeting, and novel and targeted CNS delivery systems to potential clinical application.

Oxazolidinones comprise an important class of antibacterial protein synthesis inhibitors. Myelosuppression and monoamine oxidase inhibition (MAOI) are key independent causes for limiting adverse effects in therapy with the sole approved drug of this class, linezolid. This annotation describes a novel oxazolidinone agent, (S)-5-((isoxazol-3-ylamino)methyl)-3-(2,3,5-trifluoro-4-(4-oxo-3,4-dihydropyridin-1(2H)-yl)phenyl)oxazolidin-2-one (MRX-I), distinguished by its high activity against Gram-positive pathogens coupled with markedly reduced potential for myelosuppression and MAOI. The medical need, medicinal chemistry rationale, preclinical data, and phase I clinical trial summary for this new agent are reviewed herein.

SummaryWhat is known and objectives In vitro companion diagnostic devices (CDx) provide information on pharmacogenomic biomarkers (PGBMs) to enable the safe and effective use of targeted agents for personalized therapy. These devices require specific regulations that strike a balance between scientific evidence and financial burden. The aims were to compare approval of PGBMs and CDx in the USA and Japan and to help inform current discussions on personalized medicine. Methods We analysed published documentation from the USA and Japan for CDx and PGBMs, listed by the US Food and Drug Administration (FDA). Aspects evaluated were aim, approval state and therapeutic area. Coverage by the National Health Insurance in Japan was also investigated. Results and discussion Thirty-eight PGBMs were listed in the FDA table as of March 2013. In the USA, the aim was efficacy in 55% (21/38). The largest therapeutic area was oncology (39%, 15/38). Fifty-three per cent (20/38) of the PGBMs had a corresponding CDx approved. Of the 38 PGBMs in the FDA table, six had no approved drug in Japan; in 16 of the remaining 32 PGBMs, the aim was efficacy. The largest therapeutic area was oncology (34%, 11/32). Of the 32 PGBMs, 15 were associated with an approved and/or covered CDx, with only 11 having an approved CDx. Four PGBMs had a covered CDx without prior approval in Japan. What is new and conclusion Our study confirms that there is still a substantial gap in the approval of PGBMs and CDx between Japan and the USA. Complementary coverage of unapproved CDx by the National Health Insurance, however, is raising access to a similar level in both countries. Because the number of expensive personalized medicines and CDx is increasing, patient access will continue to be an important challenge to healthcare systems in all countries.

Purpose To evaluate the advantages and disadvantages of pre-approval requirements for safety data to detect cardiovascular (CV) risk contained in the December 2008 U.S. Food and Drug Administration (FDA) guidance for developing type 2 diabetes drugs compared with the February 2008 FDA draft guidance from the perspective of diabetes population health. Methods We applied the incremental net health benefit (INHB) framework to quantify the benefits and risks of investigational diabetes drugs using a common survival metric (life-years [LYs]). We constructed a decision analytic model for clinical program development consistent with the requirements of each guidance and simulated diabetes drugs, some of which had elevated CV risk. Assuming constant research budgets, we estimate the impact of increased trial size on drugs investigated. We aggregate treatment benefit and CV risks for each approved drug over a 35-year horizon under each guidance. Results The quantitative analysis suggests that the December 2008 guidance adversely impacts diabetes population health. INHB was −1.80 million LYs, attributable to delayed access to diabetes therapies (−0.18 million LYs) and fewer drugs (−1.64 million LYs), but partially offset by reduced CV risk exposure (0.02 million LYs). Results were robust in sensitivity analyses. Conclusion The health outcomes impact of all potential benefits and risks should be evaluated in a common survival measure, including health gain from avoided adverse events, lost health benefits from delayed or forgone efficacious products, and impact of alternative policy approaches. Quantitative analysis of the December 2008 FDA guidance for diabetes therapies indicates that negative impact on patient health will result. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.

Therapeutic drug monitoring (TDM) is necessary for certain drugs to ensure that the levels are sufficient to be effective, but not so high as to cause adverse effects. This review summarizes the literature regarding TDM for newer-generation extended-spectrum triazoles, including when TDM may be necessary for each drug and why, and laboratory techniques used for the measurement of levels of these drugs. The document includes recommendations for the use of TDM for each triazole that is discussed., Invasive fungal infections cause significant morbidity and mortality in patients with concomitant underlying immunosuppressive diseases. The recent addition of new triazoles to the antifungal armamentarium has allowed for extended-spectrum activity and flexibility of administration. Over the years, clinical use has raised concerns about the degree of drug exposure following standard approved drug dosing, questioning the need for therapeutic drug monitoring (TDM). Accordingly, the present guidelines focus on TDM of triazole antifungal agents. A review of the rationale for triazole TDM, the targeted patient populations and available laboratory methods, as well as practical recommendations based on current evidence from an extended literature review are provided in the present document.

Chronic pulmonary hypertension (PH) is associated with right ventricular failure and high mortality regardless of the underlying disease. Currently, therapies can improve clinical outcomes in specific subsets of patients, but have little impact on the progression of pulmonary vascular remodeling. Upon new advances in vector development and delivery techniques, gene therapy is a novel strategy in this field with the potential of overcoming the main limitations of approved drug therapies: modulation of novel anti-remodeling targets and selective pulmonary vasculature targeting with minimal systemic effects. In the recent years, several reports have shown that gene transfer to the pulmonary vascular system is feasible in rodent models of PH. Our group has focused on the translation of airway delivery of viral vectors in small and large animals. Here, we describe a procedure to achieve vector transduction at the distal vasculature in animal models of PH and the methods to evaluate the outcomes of this intervention as a promising new approach in pulmonary vascular diseases.

Electronic clinical decision support systems (CDSS) require drug information that can be processed by computers. The goal of this project was to determine and evaluate a compilation of variables that comprehensively capture the information contained in the summary of product characteristic (SmPC) and unequivocally describe the drug, its dosage options, and clinical pharmacokinetics. An expert panel defined and structured a set of variables and drafted a guideline to extract and enter information on dosage and clinical pharmacokinetics from textual SmPCs as published by the European Medicines Agency (EMA). The set of variables was iteratively revised and evaluated by data extraction and variable allocation of roughly 7% of all centrally approved drugs. The information contained in the SmPC was allocated to three information clusters consisting of 260 variables. The cluster “drug characterization” specifies the nature of the drug. The cluster “dosage” provides information on approved drug dosages and defines corresponding specific conditions. The cluster “clinical pharmacokinetics” includes pharmacokinetic parameters of relevance for dosing in clinical practice. A first evaluation demonstrated that, despite the complexity of the current free text SmPCs, dosage and pharmacokinetic information can be reliably extracted from the SmPCs and comprehensively described by a limited set of variables. By proposing a compilation of variables well describing drug dosage and clinical pharmacokinetics, the project represents a step forward towards the development of a comprehensive database system serving as information source for sophisticated CDSS.

Introduction: Co-formulated rilpivirine, emtricitabine and tenofovir alafenamide (RPV/F/TAF) is the 6th single-tablet combination antiretroviral medication approved within the past decade for the treatment of HIV-1 infection. It was approved based on positive bioequivalence studies with already approved drugs with its component compounds, RPV and the single tablet regimen- elvitegravir, cobicistat, F/TAF.Areas covered: This article reviews the chemical, pharmacodynamic and pharmacokinetic properties, key drug interactions, and the efficacy, safety, tolerability and optimal clinical uses of the medication and/or its components in different patient populations. The article incorporates pre-clinical and clinical trial data available from Google, Google scholar, PubMed database, conference abstracts as well as US FDA approved drug prescribing information up till September 30, 2016.Expert commentary: RPV/F/TAF is a once-daily administered, well tolerated, and effective antiretroviral regimen that shoul...

11061 Background: TRB is FDA approved drug for the treatment of liposarcoma (Lipo) and leiomyosarcoma (LMS). The aim of this study was to evaluate potential biomarkers associated with prolonged benefit in patients treated with TRB at our center prior to 2016. Methods: We performed a retrospective search of UW/FHCRC CASIS database to identify patients treated with TRB prior to 2016. Demographic variables and clinical variables (such as histology and treatment) were retrieved. Statistics were performed with R 3.4.1 software. Pairwise Pearson’s correlation was calculated for the # of prior chemotherapy regimens with # of TRB cycles. The Kaplan-Meir method was used to evaluate overall survival (OS). Log-rank test was conducted to compare groups in terms of OS. Results: 145 sarcoma patients treated with TRB were identified with a mean follow up of 5 years (generally on NCT01427582 or NCT01343277). Patients averaged 1.9 prior chemotherapy regimens prior to TRB (range 0-7 regimens) and received an average of 5.6 TRB doses (range 1-25 doses). Subtypes are listed on table. The # of prior regimens was negatively correlated with the # of TRB cycles that patients received (pairwise correlation coefficient = -1.77; p=0.034), suggesting that multiple prior treatment lines either made TRB less tolerable or made sarcoma less sensitive to TRB. The median OS for this heavily treated metastatic population was 0.5 years. However, patients who were able to stay on TRB for more than 5 cycles had a significantly higher OS (p=0.001). While only 23% of patients who received less than 5 cycles of TRB were alive at 5 years (95% CI: 0.15, 0.32), 53% of those who received 5 or more cycles of (95% CI: 0.39, 0.65) were alive at 5 years. Conclusions: TRB may be more effective when administered as an earlier line of therapy. Patients who are able to stay on TRB for a longer duration had a significant improvement in OS. Detailed subset analysis will be presented as will initial findings of our biomarker work. These retrospective data warrant further evaluation. Clinical trial information: NCT01427582 or NCT01343277. [Table: see text]

e12571 Background: There is no approved drug therapy for CNS mets from mBC. Eribulin mesylate (eribulin) is a microtubule inhibitor approved for treatment of mBC patients (pts) who have received at least 2 prior chemotherapy regimens. Previously reported cases have demonstrated significant CNS responses in mBC pts treated with eribulin. This study evaluates the CNS response in pts with mBC treated with eribulin. Methods: CASE7113 was a prospective phase II single-arm study to evaluate the 12-week CNS progression free survival (12-wk CNS-PFS) of pts with mBC and CNS mets treated with eribulin. 20 pts were to be enrolled to demonstrate a 40% 12-wk CNS-PFS (95% CI, 8.5% - 61.5%). All pts had radiologically confirmed mBC CNS lesions with at least one lesion that did not receive prior radiation or surgical resection. Eribulin was administered at standard dose of 1.4mg/m2 IV on days 1 and 8 of a 21 day-cycle. Pts underwent baseline and 12-week brain MRI. The study was closed due to slow accrual; an analysis of enrolled pts was performed. Results: 9 female pts were enrolled; median age was 56 (32-82) years. 55% and 67% had ER+ and/or PR+ and Her2+ mBC respectfully. 1 pt had triple negative breast cancer (TNBC). Median number of prior therapies was 3 (0-12). The 12-wk CNS-PFS (95% CI) was 88.9% (51.8% - 99.7%), the median PFS (95% CI) was 22.6 (4.3 - 31.9) weeks, the median OS (95% CI) was 15.7 (4.0 - 27.3) months. 4 pts achieved stable disease and 1 pt had a partial response. There were no unexpected toxicities. Conclusions: For mBCa pts with CNS mets, this estimate of 12-wk CNS-PFS suggests activity of eribulin and merits further investigation in this population in the context of clinical trials. Clinical trial information: NCT02581839.