High dose selection in general toxicity studies for drug development: A pharmaceutical industry perspective

Challenges for data storage during drug development have become increasingly complex as the pharmaceutical industry expands in an environment that requires on-demand availability of data and resources for users across the globe. While the efficiency and relative low cost of cloud services have become increasingly attractive, hesitancy toward the use of cloud services has decreased and there has been a significant shift toward real-world implementation. Within GxP laboratories, the considerations for cloud storage of data include data integrity and security, as well as access control and usage for users around the globe. In this review, challenges and considerations when using cloud storage options for the storage of laboratory-based GxP data are discussed and best practices are defined.

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Advanced Quantification Methods To Improve the 18b Dormancy Model for Assessing the Activity of Tuberculosis Drugs In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00280-20 ◽

2020 ◽

Vol 64 (7) ◽

Author(s):

E. D. Pieterman ◽

M. J. Sarink ◽

C. Sala ◽

S. T. Cole ◽

J. E. M. de Steenwinkel ◽

...

Keyword(s):

Drug Development ◽

Area Under The Curve ◽

High Dose ◽

Current Form ◽

Content Type ◽

Solid Media ◽

Development Pipeline ◽

The Difference ◽

Time Kill

ABSTRACT One of the reasons for the lengthy tuberculosis (TB) treatment is the difficulty to treat the nonmultiplying mycobacterial subpopulation. In order to assess the ability of (new) TB drugs to target this subpopulation, we need to incorporate dormancy models in our preclinical drug development pipeline. In most available dormancy models, it takes a long time to create a dormant state, and it is difficult to identify and quantify this nonmultiplying condition. The Mycobacterium tuberculosis 18b strain might overcome some of these problems, because it is dependent on streptomycin for growth and becomes nonmultiplying after 10 days of streptomycin starvation but still can be cultured on streptomycin-supplemented culture plates. We developed our 18b dormancy time-kill kinetics model to assess the difference in the activity of isoniazid, rifampin, moxifloxacin, and bedaquiline against log-phase growth compared to the nonmultiplying M. tuberculosis subpopulation by CFU counting, including a novel area under the curve (AUC)-based approach as well as time-to-positivity (TTP) measurements. We observed that isoniazid and moxifloxacin were relatively more potent against replicating bacteria, while rifampin and high-dose bedaquiline were equally effective against both subpopulations. Moreover, the TTP data suggest that including a liquid culture-based method could be of additional value, as it identifies a specific mycobacterial subpopulation that is nonculturable on solid media. In conclusion, the results of our study underline that the time-kill kinetics 18b dormancy model in its current form is a useful tool to assess TB drug potency and thus has its place in the TB drug development pipeline.

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Mechanism-based toxicity studies for drug development

Predictive Toxicology in Drug Safety ◽

10.1017/cbo9780511779053.014 ◽

2011 ◽

pp. 230-243 ◽

Cited By ~ 2

Author(s):

Monicah A. Otieno ◽

Lois D. Lehman-McKeeman

Keyword(s):

Drug Development ◽

Toxicity Studies

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Strategic Research and Development Investment Decisions in the Pharmaceutical Industry

Marketing Science ◽

10.1287/mksc.2020.1224 ◽

2020 ◽

Vol 39 (3) ◽

pp. 564-586

Author(s):

Anita Rao

Keyword(s):

Pharmaceutical Industry ◽

Drug Development ◽

Research And Development ◽

Investment Decisions ◽

Strategic Research ◽

Pharmaceutical Firms

Do pharmaceutical firms respond to the actions of their competitors in R&D, and if so, what implications does this have for policies aimed at incentivizing drug development?

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Tg.rasH2 Mice and not CByB6F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies

International Journal of Toxicology ◽

10.1177/1091581817707458 ◽

2017 ◽

Vol 36 (4) ◽

pp. 287-292 ◽

Cited By ~ 1

Author(s):

Madhav G. Paranjpe ◽

Jessica Belich ◽

Tom J. Vidmar ◽

Reem H. Elbekai ◽

Marie McKeon ◽

...

Keyword(s):

Selection Process ◽

Dose Range ◽

Maximum Tolerated Dose ◽

High Dose ◽

Dose Selection ◽

Range Finding ◽

Body Weights ◽

Vehicle Test ◽

High Doses ◽

Dose Levels

Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.

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Approaches to Dose Finding in Neonates, Illustrating the Variability between Neonatal Drug Development Programs

Pharmaceutics ◽

10.3390/pharmaceutics12070685 ◽

2020 ◽

Vol 12 (7) ◽

pp. 685 ◽

Cited By ~ 1

Author(s):

John N. Van den Anker ◽

Susan McCune ◽

Pieter Annaert ◽

Gerri R. Baer ◽

Yeruk Mulugeta ◽

...

Keyword(s):

Drug Development ◽

Safety Information ◽

Disease Process ◽

Development Program ◽

Dose Finding ◽

Development Programs ◽

Sources Of Information ◽

Older Children ◽

Dose Selection

Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be leveraged to optimize dose selection for neonates. Sources may include data from adult studies, pediatric studies, non-clinical (juvenile) animal models, in vitro studies, and in silico models. Depending on the drug development program, each of these modalities could be used to varying degrees and with varying levels of confidence to guide dosing. This paper aims to illustrate the variability between neonatal drug development programs for neonatal diseases that are similar to those seen in other populations (meropenem), neonatal diseases related but not similar to pediatric or adult populations (clopidogrel, thyroid hormone), and diseases unique to neonates (caffeine, surfactant). Extrapolation of efficacy from older children or adults to neonates is infrequently used. Even if a disease process is similar between neonates and children or adults, such as with anti-infectives, additional dosing and safety information will be necessary for labeling, recognizing that dosing in neonates is confounded by maturational PK in addition to body size.

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General toxicity studies of the cadmium and benzo(a)pyrene complex

Trace Elements and Electrolytes ◽

10.5414/tep23134 ◽

2006 ◽

Vol 23 (04) ◽

pp. 134-139

Author(s):

A. Paltanaviciene ◽

D. Zabulyte ◽

J. Kalibatas ◽

V. Drebickas ◽

A. Juozulynas ◽

...

Keyword(s):

Toxicity Studies ◽

General Toxicity

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The oral α and β tubulin inhibitor, VERU-111, for the treatment of metastatic castration-resistant and androgen blocking agent-resistant prostate cancer in nonclinical toxicity studies.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.299 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 299-299

Author(s):

Robert H. Getzenberg ◽

Mario A. Eisenberger ◽

Mark Christopher Markowski ◽

Gary Barnette ◽

Darryl Patrick ◽

...

Keyword(s):

Prostate Cancer ◽

Liver Function ◽

Liver Function Tests ◽

Blocking Agent ◽

Resistance Mechanisms ◽

Multi Drug Resistance ◽

High Dose ◽

Tubulin Inhibitor ◽

Toxicity Studies ◽

Taxane Chemotherapy

299 Background: A dose limiting toxicity of taxane chemotherapy, including docetaxel and cabazitaxel, is neutropenia. VERU-111 is a novel, oral aand btubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance mechanisms. Nonclinical toxicity studies were recently performed in order to assess the effects of daily, high-dose administration of orally dosed daily VERU-111. Methods: Toxicity of VERU-111 was evaluated in a 28-day oral dosing toxicity study which was conducted in both rats and dogs. These studies were performed at an independent facility under GLP conditions. Results: In both species evaluated, at oral doses of ≤3 mg/kg/day (rat) and ≤8 mg/kg/day (dog) there were no significant observed findings of neutropenia, myelosuppression, or abnormal liver function. Conclusions: In contrast to cabazitaxel and docetaxel, which are given once every 3 weeks IV, VERU-111 given oral, daily for 28 days in toxicity studies in dog and rat did not result in neutropenia, and myelosuppression. Furthermore, VERU-111 orally each day did not affect liver function tests. These nonclinical toxicity studies provide the basis for progressing VERU-111 into a Phase 1b/2 study which targets men with metastatic castration and androgen blocking agent (abiraterone and enzalutamide) resistant prostate cancer.

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