Current strategies in the non-clinical safety assessment of biologics: New targets, new molecules, new challenges

Brennan, Frank R.; Andrews, Laura; Arulanandam, Antonio R.; Blümel, Jörg; Fikes, Jim; Grimaldi, Christine; Lansita, Janice A.; Loberg, Lise I.; MacLachlan, Tim; Milton, Mark; Parker, Suezanne; Tibbitts, Jay; Wolf, Jayanthi J.; Allamneni, Krishna P.

doi:10.1016/j.yrtph.2018.07.009

Cited by 13 publications

(6 citation statements)

References 15 publications

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“…Targets for any nonclinical safety study are identifying potential target organs for toxicity and evaluating potential reversibility toxicity. 10 In herbal medicine research, toxicology studies are the first step used to characterize the toxicity profile of a plant by identifying its impact on organ structure and/or functionality, including assessment of the severity and reversibility of toxicity, as well as dose ranges and their relationship to exposure through understanding the injuries that could occur to the kidneys, heart, 3. In the histopathological studies, hematoxylin and eosin stain technique was used, and the sections of the kidneys and liver-treated rats showed normal general structure with no significant difference compared to the control.…”

Section: Discussionmentioning

confidence: 99%

Acute and sub-chronic toxicities of phatra tricholes capsule in experimental animals

Tung,

Binh,

Hien

2024

TCNCYH

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Phatra Tricholes capsule is a multiplant production planned for dyslipidemia patients. Herein, we assessed the potential toxicity of Phatra Tricholes, applying the protocol of acute and sub-chronic oral administration in experimental animal models. According to the WHO guidelines, the acute toxicity study was conducted on Swiss mice. Sub-chronic toxicity studies were conducted in Wistar rats, and oral administration was done at 0.11 and 0.33 g/kg for 30 consecutive days. As a result, Phatra Tricholes capsule used for mice at the highest dose (19.58 g/kg b.w) did not express acute toxicity in mice. Regarding the subchronic toxicity test, after oral administration of Phatra Tricholes, hematological parameters, hepato-renal functions, and microscopic images of the liver and kidney were unchanged compared with the control group. In conclusion, the Phatra Tricholes capsule did not produce acute and subchronic toxicities in Swiss mice and Wistar rats.

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Section: Discussionmentioning

confidence: 99%

Acute and sub-chronic toxicities of phatra tricholes capsule in experimental animals

Tung,

Binh,

Hien

2024

TCNCYH

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“…In such cases, predictions of human risk are built around an integrated safety assessment that is not focused mainly on an NOAEL derived from nonclinical toxicity testing. 9…”

Section: Setting An Noael-examplesmentioning

confidence: 99%

“…While it is inadequate to refer to these types of findings as exaggerated pharmacology that was "anticipated" and therefore "acceptable," these heightened responses may be very useful in development. This is the situation for case study BIO-1 described by Brennan et al 9 in which a monoclonal antibody was being developed to treat autoimmune diseases. The expected pharmacology included inhibition of proinflammatory activities of macrophages.…”

Section: Adverse Findings With No Negative Effect On Product Developmentmentioning

confidence: 99%

Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings in Animal Toxicity Studies

Baldrick

Cosenza²,

Alapatt

et al. 2020

Int J Toxicol

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A challenge for all toxicologists is defining what study findings are actually adverse versus non-adverse in animal toxicity studies, and which ones are relevant for generating a no observed adverse effect level (NOAEL) to assess human risk. This article presents views on this challenge presented by toxicologists, toxicologic pathologists, and regulatory reviewers at the 2019 annual meeting of the American College of Toxicology during a workshop entitled “Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings.” The speakers noted that setting a NOAEL is not always straightforward, not only for small molecules but also for biopharmaceuticals, and that a “weight of evidence” approach often is more useful than a rigid threshold-setting algorithm. Regulators from the US Food and Drug Administration and European Union told how assessment of adverse nonclinical findings is undertaken to allow clinical studies to commence and drug marketing approvals to succeed, along with the process that allows successful dialogs with regulators. Nonclinical case studies of findings judged to be adverse versus non-adverse were presented in relation to the many factors that might halt or delay clinical development. The process of defining adverse findings and the NOAEL in final study reports was discussed, as well as who should be involved in the process.

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“…The main objectives of the nonclinical evaluation of biotherapeutics are: (1) identification of target organs for toxicity and to determine whether the toxicity is reversible after the treatment has stopped; (2) identification of a safe starting dose for human Phase I clinical trials and subsequent dose escalation schemes, which is highly dependent on the patient population for the Phase I trial(s); and (3) provide information to monitor safety parameters in clinical trials [ 5 , 17 , 18 , 19 , 20 ]. Key factors that must be considered for mAb development are: knowledge of the antigen target biology and location of the target, both desired and undesired.…”

Section: Nonclinical Safety Evaluations For Mabsmentioning

confidence: 99%

“…Additional factors include pharmacological properties and mechanism of action of the therapeutic mAb; exposure–response relationships; estimates of pharmacokinetic parameters and how these may relate to the determination of a recovery period; and clearly defined clinical trial design and potential characteristics and co-morbidities of patients [ 5 ]. In the development process, non-clinical studies rarely identify toxicities that are dose limiting and the selection of a pharmacologically relevant species is of paramount importance [ 4 , 5 , 6 , 17 , 18 , 19 , 20 ]. Accordingly, the lack of toxicity related to significant decreased or a lack of pharmacological action in the model negates the use of lack of toxicity to be used as a measure of safety.…”

Section: Nonclinical Safety Evaluations For Mabsmentioning

confidence: 99%

Biotherapeutics: Challenges and Opportunities for Predictive Toxicology of Monoclonal Antibodies

Johnson

2018

IJMS

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Biotherapeutics are a rapidly growing portion of the total pharmaceutical market accounting for almost one-half of recent new drug approvals. A major portion of these approvals each year are monoclonal antibodies (mAbs). During development, non-clinical pharmacology and toxicology testing of mAbs differs from that done with chemical entities since these biotherapeutics are derived from a biological source and therefore the animal models must share the same epitopes (targets) as humans to elicit a pharmacological response. Mechanisms of toxicity of mAbs are both pharmacological and non-pharmacological in nature; however, standard in silico predictive toxicological methods used in research and development of chemical entities currently do not apply to these biotherapeutics. Challenges and potential opportunities exist for new methodologies to provide a more predictive program to assess and monitor potential adverse drug reactions of mAbs for specific patients before and during clinical trials and after market approval.

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Current strategies in the non-clinical safety assessment of biologics: New targets, new molecules, new challenges

Cited by 13 publications

References 15 publications

Acute and sub-chronic toxicities of phatra tricholes capsule in experimental animals

Acute and sub-chronic toxicities of phatra tricholes capsule in experimental animals

Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings in Animal Toxicity Studies

Biotherapeutics: Challenges and Opportunities for Predictive Toxicology of Monoclonal Antibodies

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