Molecular insights into GPCR mechanisms for drugs of abuse.

Substance abuse is on the rise, and while many people may use illicit drugs mainly due to their rewarding effects, their societal impact can range from severe, as is the case for opioids, to promising, as is the case for psychedelics. Common with all these drugs' mechanisms of action are G protein-coupled receptors (GPCRs), which lie at the center of how these drugs mediate inebriation, lethality, and therapeutic effects. Opioids like fentanyl, cannabinoids like tetrahydrocannabinol, and psychedelics like lysergic acid diethylamide all directly bind to GPCRs to initiate signaling which elicits their physiological actions. We herein review recent structural studies and provide insights into the molecular mechanisms of opioids, cannabinoids, and psychedelics at their respective GPCR subtypes. We further discuss how such mechanistic insights facilitate drug discovery, either toward the development of novel therapies to combat drug abuse or toward harnessing therapeutic potential.

Can machine learning consistently improve the scoring power of classical scoring functions? Insights into the role of machine learning in scoring functions.

How to accurately estimate protein-ligand binding affinity remains a key challenge in computer-aided drug design (CADD). In many cases, it has been shown that the binding affinities predicted by classical scoring functions (SFs) cannot correlate well with experimentally measured biological activities. In the past few years, machine learning (ML)-based SFs have gradually emerged as potential alternatives and outperformed classical SFs in a series of studies. In this study, to better recognize the potential of classical SFs, we have conducted a comparative assessment of 25 commonly used SFs. Accordingly, the scoring power was systematically estimated by using the state-of-the-art ML methods that replaced the original multiple linear regression method to refit individual energy terms. The results show that the newly-developed ML-based SFs consistently performed better than classical ones. In particular, gradient boosting decision tree (GBDT) and random forest (RF) achieved the best predictions in most cases. The newly-developed ML-based SFs were also tested on another benchmark modified from PDBbind v2007, and the impacts of structural and sequence similarities were evaluated. The results indicated that the superiority of the ML-based SFs could be fully guaranteed when sufficient similar targets were contained in the training set. Moreover, the effect of the combinations of features from multiple SFs was explored, and the results indicated that combining NNscore2.0 with one to four other classical SFs could yield the best scoring power. However, it was not applicable to derive a generic target-specific SF or SF combination.

Pharmacological Probes to Validate Biomarkers for Analgesic Drug Development.

There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.

Guidelines for clinical evaluation of anti-cancer drugs.

Clinical studies intended for regulatory approval must demonstrate the clinical benefits of the drug in a target population. Clinical development of a drug proceeds by stepwise clinical studies; after safety and pharmacokinetics are evaluated and the recommended dosage and administration are determined, efficacy and safety are evaluated in an exploratory manner, and finally clinical benefits are compared with conventional standard therapies. Guidelines for the clinical evaluation of anti-cancer drugs in Japan were established in 1991 and amended in 2006 after molecular-targeted drugs were introduced. Recent progress in the development of drugs acting on the immune system and cancer genomic medicine targeting rare but important molecular subtypes have altered the strategy for development of anti-cancer drugs. It is often difficult to conduct a confirmatory randomized controlled study using overall survival as the primary endpoint in rare molecular subtypes, and the primary evaluation of the efficacy of some drugs and subsequent approval is based on the tumor response. As conducting clinical studies for rare subtypes solely within Japan is difficult, drug development needs to be conducted within a global study. However, this requires robust monitoring to detect possible ethnic differences in pharmacokinetics and drug efficacy. Development using the conditional approval system for drugs enforced in 2020 may be considered, when clinical utility is evaluated based on surrogate endpoints. Because of these changes, we have revised the guidelines for the clinical evaluation of anti-cancer drugs in Japan. To promote global development of anti-cancer drugs involving Japan, the guidelines have been translated into English.

Considerations from the Innovation and Quality Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Guidelines on Model Fitting and Recommendations on Time Course for In Vitro Cytochrome P450 Induction Studies Including Impact on Drug Interaction Risk Assessment.

Translational and ADME Sciences Leadership Group Induction Working Group (IWG) presents an analysis on the time course for cytochrome P450 induction in primary human hepatocytes. Induction of CYP1A2, CYP2B6, and CYP3A4 was evaluated by seven IWG laboratories after incubation with prototypical inducers (omeprazole, phenobarbital, rifampicin, or efavirenz) for 6-72 hours. The effect of incubation duration and model-fitting approaches on induction parameters (Emax and EC50) and drug-drug interaction (DDI) risk assessment was determined. Despite variability in induction response across hepatocyte donors, the following recommendations are proposed: 1) 48 hours should be the primary time point for in vitro assessment of induction based on mRNA level or activity, with no further benefit from 72 hours; 2) when using mRNA, 24-hour incubations provide reliable assessment of induction and DDI risk; 3) if validated using prototypical inducers (>10-fold induction), 12-hour incubations may provide an estimate of induction potential, including characterization as negative if <2-fold induction of mRNA and no concentration dependence; 4) atypical dose-response ("bell-shaped") curves can be addressed by removing points outside an established confidence interval and %CV; 5) when maximum fold induction is well defined, the choice of nonlinear regression model has limited impact on estimated induction parameters; 6) when the maximum fold induction is not well defined, conservative DDI risk assessment can be obtained using sigmoidal three-parameter fit or constraining logistic three- or four-parameter fits to the maximum observed fold induction; 7) preliminary data suggest initial slope of the fold induction curve can be used to estimate Emax/EC50 and for induction risk assessment. SIGNIFICANCE STATEMENT: Regulatory agencies provide inconsistent guidance on the optimum length of time to evaluate cytochrome P450 induction in human hepatocytes, with EMA recommending 72 hours and FDA suggesting 48-72 hours. The Induction Working Group analyzed a large data set generated by seven member companies and determined that induction response and drug-drug risk assessment determined after 48-hour incubations were representative of 72-hour incubations. Additional recommendations are provided on model-fitting techniques for induction parameter estimation and addressing atypical concentration-response curves.

The Costs of Contradictory Messages About Live Vaccines in Pregnancy.

The increased risk of harm from COVID-19 infection in pregnancy highlights the importance of including pregnant people in COVID-19 vaccine development and deployment. Promising vaccines being developed include replication-competent platforms, which are typically contraindicated during pregnancy because of theoretical risk. However, replicating vaccines are administered in and around pregnancy, either inadvertently because of unknown pregnancy status or when recommended.The historical cases of Ebola virus, yellow fever, and rubella demonstrate that contradictory messages around the safety of live vaccines in pregnancy have critical public health costs. First, restricting study or use of replicating vaccines in pregnancy may delay or deny access to the only available protection against deadly diseases. Additionally, not vaccinating pregnant people may slow epidemic control. Finally, uncertainty and worry around the safety of live vaccines may lead to terminations of otherwise desired pregnancies after inadvertent vaccination in pregnancy.If one of the vaccines deployed to combat the current global COVID-19 pandemic is replication competent, historical cases offer important lessons for ethical and effective protection for pregnant populations.

Good management practices of venomous snakes in captivity to produce biological venom-based medicines: achieving replicability and contributing to pharmaceutical industry.

One of the factors responsible for lack of reproducible findings may be attributed to the raw material used. To date, there are no apparent studies examining reproducibility using venoms for the development of new toxin-based drugs with respect to regulatory agencies' policies. For this reason, protocols were implemented to produce animal toxins with quality, traceability, and strict compliance with Good Manufacturing Practices. This required validation of the production chain from the arrival of the animal to the vivarium, followed by handling, housing, as well as compliance with respect to extraction, freeze-drying, and, finally, storage protocols, aimed at generating compounds to serve as candidate molecules applicable in clinical trials. Currently, to produce quality snake venoms to support reproductive studies, the Center for the Study of Venoms and Venomous Animals (CEVAP) from São Paulo State University (UNESP), São Paulo, Brazil has 449 microchipped snakes through rigid and standardized operating procedures for safety, health, and welfare of animals. Snakes were frequently subjected to vet clinical examination, anthelmintic, and antiparasitic treatment. Venom milk used to destroy prey was collected from each animal in individual plastic microtubes to avoid contamination and for traceability. In addition, venoms were submitted to microbiological, and biochemical toxicological analyses. It is noteworthy that investigators are responsible for caring, maintaining, and manipulating snakes and ensuring their health in captivity. This review aimed to contribute to the pharmaceutical industry the experimental experience and entire snake venom production chain required to generate quality products for therapeutic human consumption.

Current state and comparison of the clinical development of bevacizumab, rituximab and trastuzumab biosimilars.

Monoclonal antibodies are highly complex, large and biologic products with a substantial impact on the clinical management of a variety of diseases including cancer. The expiry of patents for essential monoclonal antibodies in cancer care such as bevacizumab, rituximab and trastuzumab, has prompted the global development of biosimilars to balance the biologics market. However, an understanding of the different approach of biosimilar development compared with its reference medicinal product, especially in the context of clinical trial design and end point selection may help oncologists integrating biosimilars into clinical practice. Herein, we reviewed the clinical development of biosimilars in oncology comparing the available clinical data of proposed biosimilars of bevacizumab, rituximab and trastuzumab.

Lay abstract In the last decades, patients with cancer have been treated with novel medicines as bevacizumab, rituximab and trastuzumab produced or derived by a biologic source. The expiry of patents for these biologic medicines brings the opportunity to develop similar biologic products, known as biosimilars. However, to be authorized and commercialized, biosimilars need to demonstrate their equivalence in quality, efficacy and safety to the reference medicinal product through a complete development process. An understanding of the different approach of biosimilar development compared with its reference medicinal product especially in the context of the clinical studies trials may help oncologists integrating biosimilars into clinical practice. Herein, we reviewed the clinical development of biosimilars in oncology comparing the available clinical data of proposed biosimilars of bevacizumab, rituximab and trastuzumab.

A Review of the Main Considerations for Formulation Development in Preclinical Toxicology Studies.

The main considerations for the development of a formulation for preclinical safety assessment testing are explored. Intravenous, inhalation, oral and dermal dosing are given focus and although different dose routes do present their own individual challenges there are common themes that emerge. In each case it is necessary to maximise exposure to achieve high doses to satisfy regulatory requirements for safety assessment testing. This often involves producing formulations that are at the limits of solubility and maximum volumes possible for administration to different test species by the chosen route. It is concluded that for all routes it is important to thoroughly explore the stability of the test item in the proposed formulation matrix well ahead of dosing any animals, giving careful consideration to which excipients are used and what their underlying toxicity profile may be for the relevant preclinical species. In addition, determining the maximum achievable concentrations and weighing that against the maximum volumes that can be given by the chosen route in all the test species at an early stage will also give a read on whether it would be theoretically possible to achieve suitably high enough doses to support clinical work. Not doing so can cause delays in the development programme and may have ethical repercussions.

Development and Regulatory Challenges for Peptide Therapeutics.

There has been an increased interest in and activity for the use of peptide therapeutics to treat a variety of human diseases. The number of peptide drugs entering clinical development and the market has increased significantly over the past decade despite inherent challenges of peptide therapeutic discovery, development, and patient-friendly delivery. Disparities in interpretation and application of existing regulatory guidances to innovative synthetic and conjugated peptide assets have resulted in challenges for both regulators and sponsors. The Symposium on Development and Regulatory Challenges for Peptide Therapeutics at the 40th Annual Meeting of the American College of Toxicology held in November of 2019 focused on the following specific topics: (1) peptide therapeutic progress and future directions, and approaches to discover, optimize, assess, and deliver combination peptide therapeutics for treatment of diseases; (2) toxicological considerations to advance peptide drug-device combination products for efficient development and optimal patient benefit and adherence; (3) industry and regulatory perspectives on the regulation of synthetic and conjugated peptide products, including exploration of regulatory classifications, interpretations, and application of the existing guidances International Council for Harmonisation (ICH) M3(R2) and ICH S6(R1) in determining nonclinical study recommendations; and (4) presentation of the 2016 Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee working group assessment of genotoxicity testing requirements. Perspectives were shared from industry and regulatory scientists working in the peptide therapeutics field followed by an open forum panel discussion to discuss questions drafted for the peptide therapeutics scientific community, which will be discussed in more detail.

Predicting Drug-Target Interactions Based on the Ensemble Models of Multiple Feature Pairs.

Backgroud: The prediction of drug-target interactions (DTIs) is of great significance in drug development. It is time-consuming and expensive in traditional experimental methods. Machine learning can reduce the cost of prediction and is limited by the characteristics of imbalanced datasets and problems of essential feature selection. METHODS: The prediction method based on the Ensemble model of Multiple Feature Pairs (Ensemble-MFP) is introduced. Firstly, three negative sets are generated according to the Euclidean distance of three feature pairs. Then, the negative samples of the validation set/test set are randomly selected from the union set of the three negative sets in the validation set/test set. At the same time, the ensemble model with weight is optimized and applied to the test set. RESULTS: The area under the receiver operating characteristic curve (area under ROC, AUC) in three out of four sub-datasets in gold standard datasets was more than 94.0% in the prediction of new drugs. The effectiveness of the proposed method is also shown with the comparison of state-of-the-art methods and demonstration of predicted drug-target pairs. CONCLUSION: The Ensemble-MFP can weigh the existing feature pairs and has a good prediction effect for general prediction on new drugs.

Critical Tools in Tableting Research: Using Compaction Simulator and Quality by Design (QbD) to Evaluate Lubricants' Effect in Direct Compressible Formulation.

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.

Demystifying the estimand framework: a case study using patient-reported outcomes in oncology.

Patient-reported outcome (PRO) measures describe how a patient feels or functions and are increasingly being used in benefit-risk assessments in the development of cancer drugs. However, PRO research objectives are often ill-defined in clinical cancer trials, which can lead to misleading conclusions about patient experiences. The estimand framework is a structured approach to aligning a clinical trial objective with the study design, including endpoints and analysis. The estimand framework uses a multidisciplinary approach and can improve design, analysis, and interpretation of PRO results. On the basis of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E9(R1) addendum, we provide an overview of the estimand framework intended for a multistakeholder audience. We apply the estimand framework to a hypothetical trial for breast cancer, using physical function to develop specific PRO research objectives. This Policy Review is not an endorsement of a specific study design or outcome; rather, it is meant to show the application of principles of the estimand framework to research study design and add to ongoing discussion. Use of the estimand framework to review medical products and label PROs in oncology can improve communication between stakeholders and ultimately provide a clearer interpretation of patient experience in the development of oncological drugs.

Liver safety assessment in clinical trials of new agents for chronic hepatitis B.

Investigational agents that reduce or eliminate covalently closed circular DNA (cccDNA) or enhance host immunity against hepatitis B virus (HBV)-infected hepatocytes are intended to induce a durable off-treatment clearance of hepatitis B surface antigen (HBsAg) (referred to as functional cure). The aim of this paper was to highlight challenges in interpreting liver safety data in clinical trials of these agents when given alone or in combination regimens. The incidence, grading and management of spontaneous serum ALT flares in untreated chronic HBV patients are reviewed along with a summary of serum ALT flares observed during the registration trials for peginterferon and nucleos(t)ide reverse transcriptase inhibitors. Recommendations regarding the detection, management and interpretation of liver safety biomarker data in future clinical trials as well as suggested inclusion and exclusion criteria for phase 1/2 vs phase 3 studies are provided. Criteria to help classify liver safety signals as being due to the intended therapeutic response, emergence of drug-resistant HBV virions, or idiosyncratic drug-induced liver injury are provided along with a review of the role of an expert hepatic adjudication panel in assessing a compound's hepatotoxicity profile. Finally, an algorithmic approach to the differential diagnosis and recommended medical evaluation and management of individual clinical trial patients that develop a liver safety signal is provided along with the rationale to collect and test research blood samples for future mechanistic studies.

Are newer insulin analogues better for people with Type 1 diabetes?

Achieving optimal blood glucose control in Type 1 diabetes is a delicate balance between ensuring tight glycaemic control and achieving this without the expense of hypoglycaemia and weight gain, two major factors impacting quality of life. This is a real challenge for people with Type 1 diabetes and underpins many of the struggles they face in self-managing on a day-to-day basis. The main goals of insulin delivery are to try to simulate the physiology of ß-cell insulin secretion as closely as possible and to overcome the challenges of peripheral insulin administration by achieving rapidity of onset with mealtime insulins and stability of the glucose-lowering effects of long-acting insulins. Since the early days of human insulin use, there have been many developments in insulin formulations that aim to achieve these goals as much as possible, thus contributing to better glycaemic control whilst minimizing hypoglycaemia. In the present review we discuss the currently available insulin analogues and the challenges of achieving glucose control using current analogues in those on multiple daily injections, and appraise the evidence base for newer-generation insulin analogues, such as insulin degludec, glargine U300, faster-acting insulin aspart and BioChaperone lispro. We also highlight new insulins in development and unmet needs in people with Type 1 diabetes.

Translational Scoring of Candidate Treatments for Alzheimer's Disease: A Systematic Approach.

BACKGROUND: There are many failures in treatment development for Alzheimer's disease (AD). Some of these failures are the result of development programs that lacked critical information about candidate drugs as these were advanced from one phase of development to the next. Translational scoring (TS) has been proposed as a means of increasing the rigor with which treatment development programs are executed. Previously, these approaches were not specific to AD or to the phase of drug development. Detailed information on the characteristics needed to advance a candidate agent from one phase to the next is the basis for success in subsequent phases. SUMMARY: The TS approach is presented with a score range of 0-25 for agents entering phases 1, 2, and 3 of development and those that have completed phase 3 and are being considered for regulatory review. Each phase has 5 essential categories scored from 0-5 indicating the completeness of the data available when the agent is being considered for promotion to the next phase. Lower scores suggest that the development program should be reexamined for missing information while higher scores increase the confidence that the agent has the potential to succeed in the next phase. Scoring guidelines are provided and examples of scores for drugs in recent development programs are provided to illustrate the principles of TS. Key Messages: Successful development of drugs for AD treatment requires disciplined informed decision-making at each phase of development. TS is a methodology for more rigorous drug development to help ensure that inadequately characterized drugs are not advanced and that the development platform at each phase is optimal to support success at the next phase.

Integration of Patient Reported Outcomes in Drug Development in Genitourinary Cancers.

PURPOSE OF REVIEW: Patient reported outcomes (PROs) are increasingly utilized in cancer drug development, and are of particular importance in genitourinary cancers due to symptom burden, multiple treatment options with similar efficacy, and often prolonged duration of disease. Here we review current data and perspectives related to use of PROs in drug development for genitourinary cancers, including insights on the regulatory process for drug approval. RECENT FINDINGS: The FDA is committed to incorporating PRO data into the regulatory process for development and approval of new cancer drugs, but challenges exist due to lack of standardization of PRO instrument choice and analytic approach, missing data, and difficulty isolating treatment effect from disease-related effects. We review guidance for standardization of PRO methodology that is nonetheless tailored to disease state and anticipated effects of treatment. PRO and efficacy data should be simultaneously analyzed and reported for best clinical practice. Multiple disease-specific PRO instruments exist for genitourinary cancers. While clinicians, researchers, and regulatory bodies alike recognize the importance of PROs in cancer drug development, challenges remain regarding implementation of best practices.

Hispanic/Latinos and Skincare: Disparities in Product Development, Marketing, and Toxicity.

“Hispanic” and “Latino” (also known as Mestizo) describe a diverse racial and ethnic group, with a range of cultures, languages, and biological ancestry. It includes individuals of Mexican, Central-to-South American, and Spanish-Caribbean (eg, Cuban, Puerto Rican, and Dominican) descent.1 Individuals of Hispanic/Latino race and ethnicity represent a heterogenous group of people with different skin tones and Fitzpatrick phototypes. Hispanic/Latinos are the fastest growing population in the United States (US) - projected to increase from 55 million in 2014 to 119 million in 2060, an increase of 115%.2 By 2060, more than one-quarter (29%) of the US is projected to be Hispanic/Latino.2.

Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications.

Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of 'hidden cardiotoxicity', defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments.