Drug Development Science Research Articles

Moving Beyond Boundaries: Utilization of Longitudinal Exposure-Response Model for Bounded Outcome Score to Inform Decision Making in the Accelerated Drug Development Paradigm.

As drug development scientists strive to accelerate availability of therapies for patients, model-informed drug development (MIDD) plays an important role in contextualizing existing information and facilitating decision making. This paper describes an example of MIDD, where modeling and simulation informed decision making in the circumstance of a combined phase 2b and single pivotal study for ritlecitinib (JAK3/TEC family kinases inhibitor). Longitudinal exposure-response (ER) modeling was conducted to describe ritlecitinib efficacy in alopecia areata patients. The Severity of Alopecia Tool (SALT) score (a continuous bounded outcome [CBO] score [0-100]) was used as the efficacy response. The average concentration during the time interval between two adjacent SALT scores was used as the exposure metric driving efficacy. The developed model well described the longitudinal SALT profile of ritlecitinib as well as the frequency of boundary data. The CBO model indicated tested doses in the phase 2b/3 clinical trial are in the ascending region of ER and contextualized a loading dose effect that impacted onset of efficacy without long-term benefit. It also identified disease severity as the only covariate impacting efficacy. The model-based simulation further informed impact of treatment interruption on the loss of efficacy in the absence of a dedicated treatment withdrawal study. Results indicated temporary treatment interruption ≤ 6 weeks is not expected to result in significant loss of efficacy. The CBO modeling approach and simulation supported the single pivotal trial strategy and guided dose selection in the accelerated drug development program of ritlecitinib, which can be applied to many indications where efficacy is measured on a bounded scale.

Phytochemicals: a new arsenal in drug discovery

In ancient times traditional herbs were used to treat different diseases such as stomach discomfort, toothache, body pain and inflammation, diarrhea, malaria, typhoid, diabetes, and so on. Medicinally important plants are recognized to have chemicals or phytochemicals that could be useful for illness treatment or medication manufacture. These compounds occur naturally in plant parts (leaves, stems, barks, and roots) and are referred to as secondary metabolites because, like primary metabolites, they are synthesized to protect the plant rather than for growth. Fortunately for humans, the majority of these secondary metabolites have therapeutic properties that are useful against a variety of diseases and health problems. Resistance to antibiotics is one of the world's most critical health challenges, with numerous infections rapidly gaining resistance to conventional antimicrobials. There is currently no viable therapeutic agent with the ability to reverse antimicrobial resistance, and several leading laboratories are working hard to find new antimicrobials. Plant-based chemical compounds have received comparatively little attention in the context of antimicrobial medication development. Natural chemicals have piqued the interest of drug development scientists because of their structural diversity, chemical novelty, abundance, and bioactivity. Cancer is currently a major problem. Despite the numerous interventions available, a huge number of patients die each year as a result of cancer disorders. The rising research direction in healthcare pharmacy is the development of an effective and side-effect-free anticancer medication. Chemical entities found in plants have proven to be particularly promising in this area. Bioactive phytochemicals are preferred because they act differentially on cancer cells while leaving normal cells alone. This review provides an overview of the utility of medicinal plants as well as secondary metabolites of plants as drug sources, the drug discovery process, the efficacy and safety of phytochemicals, current applications, developments in screening technologies, challenges, and future directions.

This is NOT the End for Immunotherapy in Parkinson's Disease - A Perspective from Early Drug Development Scientists.

This is NOT the End for Immunotherapy in Parkinson's Disease - A Perspective from Early Drug Development Scientists.

Using an animal model to predict the effective human dose for oral multiple sclerosis drugs.

The objective of this study was to determine the potential usefulness of an animal model to predict the appropriate dose of newly developed drugs for treating relapsing remitting multiple sclerosis (RRMS). Conversion of the lowest effective dose (LEffD) for mice and rats in the experimental autoimmune encephalomyelitis (EAE) model was used to predict the human effective dose utilizing the body surface area correction factor found in the 2005 US Food and Drug Administration (FDA) Guidance for Industry in selecting safe starting doses for clinical trials. Predictions were also tested by comparison with doses estimated by scaling up the LEffD in the model by the human to animal clearance ratio. Although initial proof-of-concept studies of oral fingolimod tested the efficacy and safety of 1.25 and 5mg in treating RRMS, the EAE animal model predicted the approved dose of this drug, 0.5mg daily. This approach would have also provided useful predictions of the approved human oral doses for cladribine, dimethyl fumarate, ozanimod, ponesimod, siponimod, and teriflunomide, drugs developed with more than one supposed mechanism of action. The procedure was not useful for i.v. dosed drugs, including monoclonal antibodies. We maintain that drug development scientists should always examine a simple allometric method to predict the therapeutic effective dose in humans. Then, following clinical studies, we believe that the animal model might be expected to yield useful predictions of other drugs developed to treat the same condition. The methodology may not always be predictive, but the approach is so simple it should be investigated.

Exploration of Site-Specific Drug Targeting-A Review on EPR-, Stimuli-, Chemical-, and Receptor-Based Approaches as Potential Drug Targeting Methods in Cancer Treatment.

Cancer has been one of the most dominant causes of mortality globally over the last few decades. In cancer treatment, the selective targeting of tumor cells is indispensable, making it a better replacement for conventional chemotherapies by diminishing their adverse side effects. While designing a drug to be delivered selectively in the target organ, the drug development scientists should focus on various factors such as the type of cancer they are dealing with according to which drug, targeting moieties, and pharmaceutical carriers should be targeted. All published articles have been collected regarding cancer and drug-targeting approaches from well reputed databases including MEDLINE, Embase, Cochrane Library, CENTRAL and ClinicalTrials.gov, Science Direct, PubMed, Scopus, Wiley, and Springer. The articles published between January 2010 and December 2020 were considered. Due to the existence of various mechanisms, it is challenging to choose which one is appropriate for a specific case. Moreover, a combination of more than one approach is often utilized to achieve optimal drug effects. In this review, we have summarized and highlighted central mechanisms of how the targeted drug delivery system works in the specific diseased microenvironment, along with the strategies to make an approach more effective. We have also included some pictorial illustrations to have a precise idea about different types of drug targeting. The core contribution of this work includes providing a cancer drug development scientist with a broad preliminary idea to choose the appropriate approach among the various targeted drug delivery mechanisms. Also, the study will contribute to improving anticancer treatment approaches by providing a pathway for lesser side effects observed in conventional chemotherapeutic techniques.

A Basis for Pharmaceutical Sciences "Quality Assurance": Quality Assurance of Health Foods, Foods with Health Claims, and Pharmaceutics

The author believes that the three pillars of pharmaceutical sciences (PS) in Japan are drug development science, medical pharmacy, and quality management science. Of these, the most PS-like science is quality management science, both historically and presently. Considering the balance of safety and efficacy is the basis of PS. The definition of "quality" is the degree to which a set of inherent properties of a product, system, or process fulfills requirements in Q9 of International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). In our society, pharmaceutical science graduates including pharmacists, are active participants, not only in the pharmaceutical industry, including a pharmacy, but also in the food industry, especially for quality assurance and quality control. This report presents a focused overview of quality in health foods, foods with health claims, and pharmaceutical products and discusses the importance of a curriculum focusing on quality assurance, control, and management in pharmaceutical education.

Predicting human pharmacokinetics from preclinical data: clearance.

We have streamlined known in vitro methods used to predict the clearance (CL) of small molecules in humans in this tutorial. There have been many publications on in vitro methods that are used at different steps of human CL prediction. The steps from initial intrinsic CL measurement in vitro to the final application of the well-stirred model to obtain predicted hepatic CL (CLH) are somewhat complicated. Except for the experts on drug metabolism and PBPK, many drug development scientists found it hard to figure out the entire picture of human CL prediction. To help readers overcome this barrier, we introduce each method briefly and demonstrate its usage in the chain of related equations destined to the CLH. Despite efforts in the laboratory steps, huge in vitro (predicted CLH)-in vivo (observed CLH) discrepancy is not rare. A simple remedy to this discrepancy is to correct human predicted CLH using the ratio of in vitro-in vivo CLH obtained from animal species.

Global perspectives: COVID-19 in the eyes of a physician pharmacologist

Emergence of global pandemic coronavirus-2019 (COVID-19) has brought the whole world to a standstill. This viewpoint critically appraises factors that have contributed to its huge morbidity and mortality burden worldwide, and proffers solutions. First, the paper examines how drug development scientists and formulation experts could develop novel combination therapies from pre-existing drugs that will disrupt future coronaviruses replication and RNA synthesis. The author discusses the development of novel barrier topical therapies that would prevent the respiratory viruses from gaining entry into host cells. Finally, the article looked at the science of vaccines and why it is the main exit strategy out of this crisis, as well as suggested novel treatment strategies for pharmacologists and clinical scientists globally, particularly in terms of finding new preventive antiviral barrier ointments and possible curative drug treatment.

Rethinking Drug Repositioning and Development with Artificial Intelligence, Machine Learning, and Omics.

Pharmaceutical industry and the art and science of drug development are sorely in need of novel transformative technologies in the current age of digital health and artificial intelligence (AI). Often described as game-changing technologies, AI and machine learning algorithms have slowly but surely begun to revolutionize pharmaceutical industry and drug development over the past 5 years. In this expert review, we describe the most frequently used machine learning algorithms in drug development pipelines and the -omics databases well poised to support machine learning and drug discovery. Subsequently, we analyze the emerging new computational approaches to drug discovery and the in silico pipelines for drug repositioning and the synergies among -omics system sciences, AI and machine learning. As with system sciences, AI and machine learning embody a system scale and Big Data driven vision for drug discovery and development. We conclude with a future outlook on the ways in which machine learning approaches can be implemented to buttress and expedite drug discovery and precision medicine. As AI and machine learning are rapidly entering pharmaceutical industry and the art and science of drug development, we need to critically examine the attendant prospects and challenges to benefit patients and public health.

Japanese initiative for education in pharmaceutical medicine and clinical research training

Development of new medicines has become increasingly difficult with less possibility of success in seeds-finding and ever rising operational costs. Failure to comply with ethical standards for human research protection also erodes social trust in clinical development. In order to develop competence of professionals in medicines development such as clinical investigators and drug development scientists, a variety of educational courses and training programs have been developed and executed worldwide. As Japan is no exception and shares the same concerns, significant governmental and non-governmental efforts have been made to invest in the development of academic educational courses and adherence to international standards. This article introduces examples of the adoption of technologies to realize a user-friendly and sustainable learning management as well as an adaptation of syllabuses and core curricula to meet international standards in the era of global medicines development.

Japanese Initiative for Education in Pharmaceutical Medicine and Clinical Research Training

Development of new medicines has become increasingly difficult with less possibility of success in seeds-finding and ever rising operational costs. Failure to comply with ethical standards for human research protection also erodes social trust in clinical development. In order to develop competence of professionals in medicines development such as clinical investigators and drug development scientists, a variety of educational courses and training programs have been developed and executed worldwide. As Japan is no exception and shares the same concerns, significant governmental and non-governmental efforts have been made to invest in the development of academic educational courses and adherence to international standards. This article introduces examples of the adoption of technologies to realize a user-friendly and sustainable learning management as well as an adaptation of syllabuses and core curricula to meet international standards in the era of global medicines development.

Experimental cocrystal screening and solution based scale-up cocrystallization methods.

Cocrystals are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. If one of the components is an active pharmaceutical ingredient (API), the term pharmaceutical cocrystal is often used. There is a growing interest among drug development scientists in exploring cocrystals, as means to address physicochemical, biopharmaceutical and mechanical properties and expand solid form diversity of the API. Conventionally, coformers are selected based on crystal engineering principles, and the equimolar mixtures of API and coformers are subjected to solution-based crystallization that are commonly employed in polymorph and salt screening. However, the availability of new knowledge on cocrystal phase behaviour in solid state and solutions has spurred the development and implementation of more rational experimental cocrystal screening as well as scale-up methods. This review aims to provide overview of commonly employed solid form screening techniques in drug development with an emphasis on cocrystal screening methodologies. The latest developments in understanding and the use of cocrystal phase diagrams in both screening and solution based scale-up methods are also presented. Final section is devoted to reviewing the state of the art research covering solution based scale-up cocrystallization process for different cocrystals besides more recent continuous crystallization methods.

2L-piRNA: A Two-Layer Ensemble Classifier for Identifying Piwi-Interacting RNAs and Their Function.

Involved with important cellular or gene functions and implicated with many kinds of cancers, piRNAs, or piwi-interacting RNAs, are of small non-coding RNA with around 19–33 nt in length. Given a small non-coding RNA molecule, can we predict whether it is of piRNA according to its sequence information alone? Furthermore, there are two types of piRNA: one has the function of instructing target mRNA deadenylation, and the other does not. Can we discriminate one from the other? With the avalanche of RNA sequences emerging in the postgenomic age, it is urgent to address the two problems for both basic research and drug development. Unfortunately, to the best of our knowledge, so far no computational methods whatsoever could be used to deal with the second problem, let alone deal with the two problems together. Here, by incorporating the physicochemical properties of nucleotides into the pseudo K-tuple nucleotide composition (PseKNC), we proposed a powerful predictor called 2L-piRNA. It is a two-layer ensemble classifier, in which the first layer is for identifying whether a query RNA molecule is piRNA or non-piRNA, and the second layer for identifying whether a piRNA is with or without the function of instructing target mRNA deadenylation. Rigorous cross-validations have indicated that the success rates achieved by the proposed predictor are quite high. For the convenience of most biologists and drug development scientists, the web server for 2L-piRNA has been established at http://bioinformatics.hitsz.edu.cn/2L-piRNA/, by which users can easily get their desired results without the need to go through the mathematical details.

Paving the critical path of drug development: the CDER perspective.

Improving the science of drug development and regulation is important in fulfilling the public health mission of the US Food and Drug Administration (FDA). A decade on from the launch of the Critical Path Initiative, the FDA's Center for Drug Evaluation and Research (CDER) is now participating in more than 20 science-driven consortia to achieve this goal.

Prevalence of Acid-Reducing Agents (ARA) in Cancer Populations and ARA Drug–Drug Interaction Potential for Molecular Targeted Agents in Clinical Development

Acid-reducing agents (ARAs) are the most commonly prescribed medications in North America and Western Europe. There are currently no data describing the prevalence of their use among cancer patients. However, this is a paramount question due to the potential for significant drug-drug interactions (DDIs) between ARAs, most commonly proton pump inhibitors (PPIs), and orally administered cancer therapeutics that display pH-dependent solubility, which may lead to decreased drug absorption and decreased therapeutic benefit. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility, but there are currently no data describing the potential for this ARA-DDI liability among targeted agents currently in clinical development. The objectives of this study were to (1) determine the prevalence of ARA use among different cancer populations and (2) investigate the prevalence of orally administered cancer therapeutics currently in development that may be liable for an ARA-DDI. To address the question of ARA use among cancer patients, a retrospective cross-sectional analysis was performed using two large healthcare databases: Thomson Reuters MarketScan (N = 1,776,443) and the U.S. Department of Veterans Affairs (VA, N = 1,171,833). Among all cancer patients, the total prevalence proportion of ARA use (no. of cancer patients receiving an ARA/total no. of cancer patients) was 20% and 33% for the MarketScan and VA databases, respectively. PPIs were the most commonly prescribed agent, comprising 79% and 65% of all cancer patients receiving a prescription for an ARA (no. of cancer patients receiving a PPI /no. of cancer patients receiving an ARA) for the MarketScan and VA databases, respectively. To estimate the ARA-DDI liability of orally administered molecular targeted cancer therapeutics currently in development, two publicly available databases, (1) Kinase SARfari and (2) canSAR, were examined. For those orally administered clinical candidates that had available structures, the pKa's and corresponding relative solubilities were calculated for a normal fasting pH of 1.2 and an "ARA-hypochlorhydric" pH of 4. Taking calculated pKa's and relative solubilities into consideration, clinical candidates were classified based on their risk for an ARA-DDI. More than one-quarter (28%) of the molecules investigated are at high risk for an ARA-DDI, and of those high risk molecules, nearly three-quarters (73%) are being clinically evaluated for at least one of five cancer types with the highest prevalence of ARA use (gastrointestinal, pancreatic, lung, glioblastoma multiforme, gastrointestinal stromal tumor (GIST)). These data strongly suggest that with the clinical development of ARA-DDI-susceptible cancer therapeutics will come continued challenges for drug-development scientists, oncologists, and regulatory agencies in ensuring that patients achieve safe and efficacious exposures of their cancer therapeutics and thus optimal patient outcomes.

Sir David Jack: an extraordinary drug discoverer and developer

Sir David Jack, FRS, was a remarkable man, driven by altruistic intent, a passionate and exceptional scientist, who was able to apply the full power of his impressive intellect to the discovery of new and important medicines for the benefit of patients in need. This involved not only a critical focus on basic discovery, but also the proper application of drug development sciences (pharmacology, drug metabolism, toxicology, analytical chemistry, chemical manufacturing, pharmaceutics and clinical medicine) to ensure that a sound scientific idea at the bench could be turned into the reality of a useful medicine for patients. His broad, applied and integrated approach to drug discovery is what makes David Jack stand out, even among others highly regarded and acknowledged for their contributions to medical research and drug discovery. In addition he was a great leader and commanded the respect of all who worked for him, no matter where they worked in the organization. All he asked was that each and every employee focused on the task in hand, namely to find ‘better medicines for the treatment of poorly-treated common diseases’. He repeatedly espoused the idea that if you did not know ‘how in general terms’ what you were doing might eventually lead to this end then you should not be doing it. If such focused efforts proved to be successful, patients would benefit and so would the company and the resulting revenue generated would provide yet more opportunity to find different or further improved medicines. With David’s vision and leadership an amazingly impressive number of important new medicines materialized from the Allen and Hanburys site at Ware, including inhaled beclamethasone diproprionate (Becotide®), fluticasone proprionate (Flixotide®), salbutamol/albuterol (Ventolin®) and salmeterol (Serevent®) for asthma therapy, labetalol (Trandate®) for hypertension, ranitidine (Zantac®) for gastric acid diseases, ondansetron (Zofran®) for the treatment of emesis associated with cancer chemotherapy and sumatriptan (Imigran®/Imitrex®) for the treatment of

Core competencies for pharmaceutical physicians and drug development scientists

Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine), are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes (LO) of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain LO anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide.

Diabetes Drug Is Linked With Bladder Cancer Risk

Efron said the issue is whether researchers and the FDA want to just follow protocols or whether they want to find the true answers to their questions. “In situations where you are really trying to learn something, you should admit there is bias but get the question right.” Others are also calling for changes in policies that permit only intention-totreat analyses. Researchers at the Harvard School of Public Health in Boston argue that there is no guarantee that intention-to-treat analysis can accurately estimate the clinical effectiveness of treatment and recommend that different analytic methods be used to assess findings of all randomized clinical trials with substantial lack of adherence to the intervention by trial participants or loss to follow-up of participants (Hernan MA and Hernandez-Diaz S. Clin Trials. 2012; 9[1]:48-55). Despite such calls for change in assessing clinical data, persuading an agency like the FDA to consider alternative methods to determine whether trial results are rigorous enough to serve as the basis for approving or rejecting a drug will take time, said Carl C. Peck, MD, adjunct professor at UCSF’s Center for Drug Development Science and a former director of the FDA’s Center for Drug Evaluation and Research. TheFDAlikesintention-to-treatdesign because it isconservative, saidPeck,who isalso the founderandchairmanofNDA Partners, a consultancy group for companiesdevelopingdrugsandmedicaldevices.“TheFDAhasthetaskofprotecting thepublichealthbycreatingahighstandardforsafetyandeffectiveness,andthey have another duty laid on them by Congress, and that is consistencyanduniformity,”Pecksaid.“It’sacombinationofall of those thatmakes theFDAveryconservative,riskaverse,andslowtochange.”

TP receptor antagonists (TXRAs): expensive irrelevance or wonder drugs strangled at birth?

TP receptor antagonists (TXRAs): expensive irrelevance or wonder drugs strangled at birth?

Studies on in vitro availability, degradation, and thermal properties of naltrexone-loaded biodegradable microspheres

Purpose: Following the report that continuous exposure of naltrexone (NTX) to drug-dependent pregnant women is safe and effective, the work was designed to develop NTX-loaded controlled delivery systems capable of making NTX available from 1 month to 4 months or greater by a single parenteral administration. Such drug-delivery systems will be useful in alleviating problems such as fetal alcohol syndrome in pregnant women and other problems associated with alcoholism.Methods: These studies were designed to investigate in vitro drug availability and microsphere degradation (investigated by gel permeation chromatography (GPC) peak areas of water-soluble fragments released into incubation medium, changes in molecular weight with degradation time, and changes in the glass transition temperature with degradation time) of NTX-loaded poly(d,l-lactide-co-glycolide) (PDLLAGA) microspheres.Results: Data showed that in vitro drug availability and degradation were affected by the initial molecular weight of the copolymers, the type of copolymers (lactide-co-glycolide ratio), the source of the polymer (the manufacturer), and the nature of the drug (anhydrous versus regular NTX).Conclusion: Drug-development scientists interested in NTX-loaded microspheres for the design of controlled release devices using these polyesters should take adequate cognizance of the variables that affect drug availability from NTX-loaded microspheres. The copolymers are suitable for the fabrication of NTX-loaded microspheres capable of sustained drug release from 30 to 150 days.