Pub Date : 2024-09-28DOI: 10.1016/j.yrtph.2024.105709
Robert H. Heflich , Michelle E. Bishop , Roberta A. Mittelstaedt , Jian Yan , Sharon K. Guerrero , Audrey M. Sims , Kamela Mitchell , Nyosha Moore , Xilin Li , Nan Mei , Rosalie K. Elespuru , Sruthi T. King , David A. Keire , Naomi L. Kruhlak , Robert T. Dorsam , Andre S. Raw , Karen L. Davis Bruno , Timothy J. McGovern , Aisar H. Atrakchi
Accurately determining the mutagenicity of small-molecule N-nitrosamine drug impurities and nitrosamine drug substance-related impurities (NDSRIs) is critical to identifying mutagenic and cancer hazards. In the current study we have evaluated several approaches for enhancing assay sensitivity for evaluating the mutagenicity of N-nitrosamines in the bacterial reverse mutagenicity (Ames) test. Preincubation assays were conducted using five activation conditions: no exogenous metabolic activation and metabolic activation mixes employing both 10% and 30% liver S9 from hamsters and rats pretreated with inducers of enzymatic activity. In addition, preincubations were conducted for both 60 min and 30 min. These test variables were evaluated by testing 12 small-molecule N-nitrosamines and 17 NDSRIs for mutagenicity in Salmonella typhimurium tester strains TA98, TA100, TA1535, and TA1537, and Escherichia coli strain WP2 uvrA (pKM101). Eighteen of the 29 N-nitrosamine test substances tested positive under one or more of the testing conditions and all 18 positives could be detected by using tester strains TA1535 and WP2 uvrA (pKM101), preincubations of 30 min, and S9 mixes containing 30% hamster liver S9. In general, the conditions under which NDSRIs were mutagenic were similar to those found for small-molecule N-nitrosamines.
{"title":"Optimizing the detection of N-nitrosamine mutagenicity in the Ames test","authors":"Robert H. Heflich , Michelle E. Bishop , Roberta A. Mittelstaedt , Jian Yan , Sharon K. Guerrero , Audrey M. Sims , Kamela Mitchell , Nyosha Moore , Xilin Li , Nan Mei , Rosalie K. Elespuru , Sruthi T. King , David A. Keire , Naomi L. Kruhlak , Robert T. Dorsam , Andre S. Raw , Karen L. Davis Bruno , Timothy J. McGovern , Aisar H. Atrakchi","doi":"10.1016/j.yrtph.2024.105709","DOIUrl":"10.1016/j.yrtph.2024.105709","url":null,"abstract":"<div><div>Accurately determining the mutagenicity of small-molecule <em>N</em>-nitrosamine drug impurities and nitrosamine drug substance-related impurities (NDSRIs) is critical to identifying mutagenic and cancer hazards. In the current study we have evaluated several approaches for enhancing assay sensitivity for evaluating the mutagenicity of <em>N</em>-nitrosamines in the bacterial reverse mutagenicity (Ames) test. Preincubation assays were conducted using five activation conditions: no exogenous metabolic activation and metabolic activation mixes employing both 10% and 30% liver S9 from hamsters and rats pretreated with inducers of enzymatic activity. In addition, preincubations were conducted for both 60 min and 30 min. These test variables were evaluated by testing 12 small-molecule <em>N</em>-nitrosamines and 17 NDSRIs for mutagenicity in <em>Salmonella typhimurium</em> tester strains TA98, TA100, TA1535, and TA1537, and <em>Escherichia coli</em> strain WP2 uvrA (pKM101). Eighteen of the 29 <em>N</em>-nitrosamine test substances tested positive under one or more of the testing conditions and all 18 positives could be detected by using tester strains TA1535 and WP2 uvrA (pKM101), preincubations of 30 min, and S9 mixes containing 30% hamster liver S9. In general, the conditions under which NDSRIs were mutagenic were similar to those found for small-molecule <em>N</em>-nitrosamines.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"153 ","pages":"Article 105709"},"PeriodicalIF":3.0,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.yrtph.2024.105710
Payal Rana , Brett Hollingshead , Raja Mangipudy
The registration of biotherapeutics for chronic indications requires 6-month toxicity studies. However, extensive experience has shown that the non-clinical safety profiles of biotherapeutics are generally predictable. This suggests that conducting multiple studies, especially a 6-month study may not be necessary. In a meta-analysis of biologics developed for non-oncology indications over last 25 years at Pfizer, we compared organ system findings between short-term (1–3 month) and long-term (6-month) animal studies. Our goal was to determine if there were differences in the safety profiles between the two study durations and their relevance to human risk assessment. Our analysis revealed that most clinically relevant toxicities could be detected in shorter-term studies (87%; 26/30 programs). This suggests either an undifferentiated safety profile between short-and long-term studies, or anticipated toxicities based on the modality, such as immunogenicity or exaggerated pharmacology. However, for 4 out of 30 programs (13%), long-term studies did identify either potential new toxicities or more severe manifestation of exaggerated pharmacology, leading to modifications in clinical trial designs and human risk assessment. Our experience suggests that 3-month toxicity studies may be sufficient to support late-stage clinical development for a majority of standard biotherapeutic programs. This pragmatic and science-based approach aligns with the goal of advancing 3R's initiatives in nonclinical safety assessment.
{"title":"Rethinking the necessity of long-term toxicity studies for biotherapeutics using weight of evidence assessment","authors":"Payal Rana , Brett Hollingshead , Raja Mangipudy","doi":"10.1016/j.yrtph.2024.105710","DOIUrl":"10.1016/j.yrtph.2024.105710","url":null,"abstract":"<div><div>The registration of biotherapeutics for chronic indications requires 6-month toxicity studies. However, extensive experience has shown that the non-clinical safety profiles of biotherapeutics are generally predictable. This suggests that conducting multiple studies, especially a 6-month study may not be necessary. In a meta-analysis of biologics developed for non-oncology indications over last 25 years at Pfizer, we compared organ system findings between short-term (1–3 month) and long-term (6-month) animal studies. Our goal was to determine if there were differences in the safety profiles between the two study durations and their relevance to human risk assessment. Our analysis revealed that most clinically relevant toxicities could be detected in shorter-term studies (87%; 26/30 programs). This suggests either an undifferentiated safety profile between short-and long-term studies, or anticipated toxicities based on the modality, such as immunogenicity or exaggerated pharmacology. However, for 4 out of 30 programs (13%), long-term studies did identify either potential new toxicities or more severe manifestation of exaggerated pharmacology, leading to modifications in clinical trial designs and human risk assessment. Our experience suggests that 3-month toxicity studies may be sufficient to support late-stage clinical development for a majority of standard biotherapeutic programs. This pragmatic and science-based approach aligns with the goal of advancing 3R's initiatives in nonclinical safety assessment.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"153 ","pages":"Article 105710"},"PeriodicalIF":3.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.yrtph.2024.105712
Akira Kawashima, Kaoru Inoue
We recently conducted a detailed hazard assessment of tetramethylammonium hydroxide (TMAH), a priority chemical substance under the Japan Chemical Substances Control Law. During this assessment, there was debate regarding the reduced heart weight observed in the treated male groups in the 28-day rat oral repeated-dose toxicity study. This finding was not observed in females in this study and in both sexes of oral toxicity studies for tetramethylammonium chloride (TMAC) or tetramethylammonium hydrogen phthalate (TMAHP). Unpublished individual data from the oral TMAH developmental and reproductive toxicity (DART) screening study were also obtained; no effect on heart weight was observed. In addition, background data on rat heart weight from six 28-day oral toxicity studies conducted in the same facility, year, strain, age, and breeder as the TMAH study were obtained from the Japan Existing Chemical Substances Database (JECDB). These investigations suggest that the statistically significant lower heart weight in the treated males in the 28-day toxicity study is likely caused by an incidental skewing of individuals with heavier heart weights toward control male groups and is not due to TMAH treatment. Thus, it is worthwhile to include as much relevant data as possible to confirm or refute unexpected findings in toxicity studies.
{"title":"Re-evaluation of the reduced heart weights in male rats in a 28-day oral repeated-dose toxicity study of tetramethylammonium hydroxide","authors":"Akira Kawashima, Kaoru Inoue","doi":"10.1016/j.yrtph.2024.105712","DOIUrl":"10.1016/j.yrtph.2024.105712","url":null,"abstract":"<div><div>We recently conducted a detailed hazard assessment of tetramethylammonium hydroxide (TMAH), a priority chemical substance under the Japan Chemical Substances Control Law. During this assessment, there was debate regarding the reduced heart weight observed in the treated male groups in the 28-day rat oral repeated-dose toxicity study. This finding was not observed in females in this study and in both sexes of oral toxicity studies for tetramethylammonium chloride (TMAC) or tetramethylammonium hydrogen phthalate (TMAHP). Unpublished individual data from the oral TMAH developmental and reproductive toxicity (DART) screening study were also obtained; no effect on heart weight was observed. In addition, background data on rat heart weight from six 28-day oral toxicity studies conducted in the same facility, year, strain, age, and breeder as the TMAH study were obtained from the Japan Existing Chemical Substances Database (JECDB). These investigations suggest that the statistically significant lower heart weight in the treated males in the 28-day toxicity study is likely caused by an incidental skewing of individuals with heavier heart weights toward control male groups and is not due to TMAH treatment. Thus, it is worthwhile to include as much relevant data as possible to confirm or refute unexpected findings in toxicity studies.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"153 ","pages":"Article 105712"},"PeriodicalIF":3.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1016/j.yrtph.2024.105704
Joel Bercu , Olivier Dirat , Krista Dobo , Robert Jolly , Michelle Kenyon , James Harvey , Raphael Nudelman , Graham Smith , Alejandra Trejo-Martin , Michael Urquhart
The carcinogenicity potency categorization approach (CPCA) derived and harmonized by Health Authorities was a significant milestone, as it defined molecular properties that allowed for the rapid evaluation of the chemical structures of N-nitrosamine drug substance related impurities (NDSRIs) and the assignment of associated lifetime Acceptable Intake (AI) limits to inform on appropriate impurity control strategies in certain drug products. Nonetheless, it is important to continue to refine and improve on the CPCA based upon data-derived evidence. Herein, we focus on the default CPCA AI for NDSRIs, which is largely based on the small molecule N-nitrosamines (NAs). Considering the carcinogenic potency of NAs with a molecular weight >200 Da (NDSRIs molecular weight is typically 200–600 Da), we propose that in the absence of any compound specific data, the lowest lifetime Acceptable Intake for NAs, such as NDSRIs, should be 10x less (i.e., 150 ng/day) than the ICH M7 Threshold of Toxicological Concern of 1500 ng/day, (even for NDSRIs that are considered CPCA Category 1 and 2) which would conservatively result in a theoretical cancer risk of <1 in 100,000.
由卫生当局制定和统一的致癌性效力分类方法（CPCA）是一个重要的里程碑，因为它定义了分子特性，从而可以快速评估与 N-亚硝胺药物物质相关的杂质（NDSRIs）的化学结构，并指定相关的终生可接受摄入量限值，为某些药物产品中适当的杂质控制策略提供信息。尽管如此，基于数据证据继续完善和改进 CPCA 仍然非常重要。在此，我们重点讨论 NDSRIs 的默认 CPCA AI，该 AI 主要基于小分子 N-亚硝胺（NAs）。考虑到分子量大于 200 Da 的 NAs 的致癌性（NDSRIs 的分子量通常为 200-600 Da），我们建议，在没有任何特定化合物数据的情况下，NDSRIs 等 NAs 的最低终生可摄入量应比 ICO 值低 10 倍（即 150 纳克/天）、150 纳克/天），低于 ICH M7 毒理学关注阈值（1500 纳克/天）（即使是被视为 CPCA 第 1 类和第 2 类的 NDSRIs）。
{"title":"N-Nitrosamine drug substance related impurities (NDSRIs) – A proposal for the addition of subcategories to carcinogenic potency categorization approach categories 1 and 2 for NDSRIs with a molecular weight > 200 Da","authors":"Joel Bercu , Olivier Dirat , Krista Dobo , Robert Jolly , Michelle Kenyon , James Harvey , Raphael Nudelman , Graham Smith , Alejandra Trejo-Martin , Michael Urquhart","doi":"10.1016/j.yrtph.2024.105704","DOIUrl":"10.1016/j.yrtph.2024.105704","url":null,"abstract":"<div><div>The carcinogenicity potency categorization approach (CPCA) derived and harmonized by Health Authorities was a significant milestone, as it defined molecular properties that allowed for the rapid evaluation of the chemical structures of N-nitrosamine drug substance related impurities (NDSRIs) and the assignment of associated lifetime Acceptable Intake (AI) limits to inform on appropriate impurity control strategies in certain drug products. Nonetheless, it is important to continue to refine and improve on the CPCA based upon data-derived evidence. Herein, we focus on the default CPCA AI for NDSRIs, which is largely based on the small molecule N-nitrosamines (NAs). Considering the carcinogenic potency of NAs with a molecular weight >200 Da (NDSRIs molecular weight is typically 200–600 Da), we propose that in the absence of any compound specific data, the lowest lifetime Acceptable Intake for NAs, such as NDSRIs, should be 10x less (i.e., 150 ng/day) than the ICH M7 Threshold of Toxicological Concern of 1500 ng/day, (even for NDSRIs that are considered CPCA Category 1 and 2) which would conservatively result in a theoretical cancer risk of <1 in 100,000.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"154 ","pages":"Article 105704"},"PeriodicalIF":3.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1016/j.yrtph.2024.105705
Wen Tsin Poh, Johnson Stanslas
Regulatory studies have revolutionised over time. Today, the focus has shifted from animal toxicity testing to non-animal for regulatory safety testing. This move is in line with the international 3Rs (Replacement, Reduction, and Refinement) principle and has also changed the regulator's perspective. The 3R principle has stimulated changes in policy, regulations, and new approaches to safety assessment in drug development in many countries. The 3Rs approach has led to the discovery and application of new technologies and more human-relevant in vitro approaches that minimise the use of animals including non-human primates, in research and improve animal welfare. In 2016, the European Medicines Agency published the Guidelines on the principles of regulatory acceptance of 3Rs testing approaches, followed by a conceptual paper in 2023 to align with current 3R standards. Additionally, the United States Food and Drug Administration passed new legislation in 2023 that no longer requires all new human drugs to be tested on animals, which will change the current testing paradigm. This review paper provides the adoption of the 3Rs and the current regulatory perspective regarding their implementation.
{"title":"The new paradigm in animal testing – “3Rs alternatives”","authors":"Wen Tsin Poh, Johnson Stanslas","doi":"10.1016/j.yrtph.2024.105705","DOIUrl":"10.1016/j.yrtph.2024.105705","url":null,"abstract":"<div><div>Regulatory studies have revolutionised over time. Today, the focus has shifted from animal toxicity testing to non-animal for regulatory safety testing. This move is in line with the international 3Rs (Replacement, Reduction, and Refinement) principle and has also changed the regulator's perspective. The 3R principle has stimulated changes in policy, regulations, and new approaches to safety assessment in drug development in many countries. The 3Rs approach has led to the discovery and application of new technologies and more human-relevant <em>in vitro</em> approaches that minimise the use of animals including non-human primates, in research and improve animal welfare. In 2016, the European Medicines Agency published the Guidelines on the principles of regulatory acceptance of 3Rs testing approaches, followed by a conceptual paper in 2023 to align with current 3R standards. Additionally, the United States Food and Drug Administration passed new legislation in 2023 that no longer requires all new human drugs to be tested on animals, which will change the current testing paradigm. This review paper provides the adoption of the 3Rs and the current regulatory perspective regarding their implementation.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"153 ","pages":"Article 105705"},"PeriodicalIF":3.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1016/j.yrtph.2024.105708
Igor Koturbash , R. Philip Yeager , Constance A. Mitchell , Stephen Ferguson , Victor J. Navarro , Mary F. Paine , Amy L. Roe
Botanical supplements and herbal products are widely used by consumers for various purported health benefits, and their popularity is increasing. Some of these natural products can have adverse effects on liver function and/or interact with prescription and over-the-counter (OTC) medications. Ensuring the safety of these readily available products is a crucial public health concern; however, not all regulatory authorities require premarket safety review and/or testing. To address and discuss these and other emerging needs related to botanical safety, a symposium was held at the Society of Toxicology Annual Meeting in Salt Lake City (UT) on March 11, 2024. The symposium addressed the latest research on botanical-induced liver toxicity and botanical-drug interactions, including new approach methods to screen for toxicity, challenges in assessing the safety of botanicals, and relating human adverse events to specific products. The presentations and robust panel discussion between the speakers and audience highlighted the need for further research and collaboration to improve the safety of botanical supplements and herbal products, with the ultimate goal of protecting consumer health. Although utility of many of the modern tools presented in the symposium requires further study, the synergistic efforts of diverse experts hold promise for effective prediction and evaluation of botanical-induced hepatotoxicity and botanical-drug interaction potential.
{"title":"Botanical-induced toxicity: Liver injury and botanical-drug interactions. A report on a society of Toxicology Annual Meeting symposium","authors":"Igor Koturbash , R. Philip Yeager , Constance A. Mitchell , Stephen Ferguson , Victor J. Navarro , Mary F. Paine , Amy L. Roe","doi":"10.1016/j.yrtph.2024.105708","DOIUrl":"10.1016/j.yrtph.2024.105708","url":null,"abstract":"<div><div>Botanical supplements and herbal products are widely used by consumers for various purported health benefits, and their popularity is increasing. Some of these natural products can have adverse effects on liver function and/or interact with prescription and over-the-counter (OTC) medications. Ensuring the safety of these readily available products is a crucial public health concern; however, not all regulatory authorities require premarket safety review and/or testing. To address and discuss these and other emerging needs related to botanical safety, a symposium was held at the Society of Toxicology Annual Meeting in Salt Lake City (UT) on March 11, 2024. The symposium addressed the latest research on botanical-induced liver toxicity and botanical-drug interactions, including new approach methods to screen for toxicity, challenges in assessing the safety of botanicals, and relating human adverse events to specific products. The presentations and robust panel discussion between the speakers and audience highlighted the need for further research and collaboration to improve the safety of botanical supplements and herbal products, with the ultimate goal of protecting consumer health. Although utility of many of the modern tools presented in the symposium requires further study, the synergistic efforts of diverse experts hold promise for effective prediction and evaluation of botanical-induced hepatotoxicity and botanical-drug interaction potential.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"153 ","pages":"Article 105708"},"PeriodicalIF":3.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0273230024001491/pdfft?md5=b5bac393db266260b93676b9c48f5214&pid=1-s2.0-S0273230024001491-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1016/j.yrtph.2024.105707
Qiran Chen , Zhoumeng Lin , Jennifer L. Davis , Emily Toney , Maaike O. Clapham , Xue Wu , Lisa A. Tell
Florfenicol is a broad-spectrum and bacteriostatic antibiotic with a time-dependent killing action. It is commonly used to treat respiratory diseases in goats in an extra-label manner. This study aimed to determine the plasma pharmacokinetics and milk residue depletion profiles and calculate the milk withdrawal interval (WDI) of florfenicol and its main metabolite florfenicol amine in lactating goats. Five healthy lactating goats were administered with 40 mg/kg florfenicol by subcutaneous injection, twice, 96 h apart. Plasma and milk samples were collected up to 864 h post the first injection. Non-compartmental analysis was used to estimate the plasma pharmacokinetic parameters. Milk WDIs were calculated using the U.S. Food and Drug Administration (FDA) method and European Medicines Agency (EMA) method. A Monte Carlo simulation was performed to generate simulated data for five virtual animals to meet the data requirement of the FDA method. The calculated milk WDIs based on florfenicol, florfenicol amine, and the combined (the sum of florfenicol and florfenicol amine) were 720.28, 690.45, and 872.69 h after the last injection using the FDA method. In conclusion, this study improves our understanding on the plasma pharmacokinetics and milk residue depletion kinetics of florfenicol and florfenicol amine in lactating ruminants after subcutaneous injections.
{"title":"Residue depletion profiles and withdrawal intervals of florfenicol and its metabolite florfenicol amine in plasma and milk of lactating goats after repeated subcutaneous administrations","authors":"Qiran Chen , Zhoumeng Lin , Jennifer L. Davis , Emily Toney , Maaike O. Clapham , Xue Wu , Lisa A. Tell","doi":"10.1016/j.yrtph.2024.105707","DOIUrl":"10.1016/j.yrtph.2024.105707","url":null,"abstract":"<div><div>Florfenicol is a broad-spectrum and bacteriostatic antibiotic with a time-dependent killing action. It is commonly used to treat respiratory diseases in goats in an extra-label manner. This study aimed to determine the plasma pharmacokinetics and milk residue depletion profiles and calculate the milk withdrawal interval (WDI) of florfenicol and its main metabolite florfenicol amine in lactating goats. Five healthy lactating goats were administered with 40 mg/kg florfenicol by subcutaneous injection, twice, 96 h apart. Plasma and milk samples were collected up to 864 h post the first injection. Non-compartmental analysis was used to estimate the plasma pharmacokinetic parameters. Milk WDIs were calculated using the U.S. Food and Drug Administration (FDA) method and European Medicines Agency (EMA) method. A Monte Carlo simulation was performed to generate simulated data for five virtual animals to meet the data requirement of the FDA method. The calculated milk WDIs based on florfenicol, florfenicol amine, and the combined (the sum of florfenicol and florfenicol amine) were 720.28, 690.45, and 872.69 h after the last injection using the FDA method. In conclusion, this study improves our understanding on the plasma pharmacokinetics and milk residue depletion kinetics of florfenicol and florfenicol amine in lactating ruminants after subcutaneous injections.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"153 ","pages":"Article 105707"},"PeriodicalIF":3.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1016/j.yrtph.2024.105703
Liang-Cheng Chen, Te-Wei Lee, Chih-Hsien Chang
The neurobehavioral assessment of N,N-bis(2-mercapatoethly)-N′,N′-diethylenediamine (BMEDA), which can form a chelate with rhenium-188 (188Re) to produce the 188Re-BMEDA-liposome, was evaluated. The purpose of this study was to evaluate the potential neurobehavioral changes by using the functional observational battery observation procedures when intravenous injection of BMEDA to Sprague-Dawley rats. Rats were administered BMEDA at dose levels of 1, 2, and 5 mg/kg. No mortalities were observed. There are some observations related to BMEDA treatment found in the 5 mg/kg dose group at 10 min post-dose. Tremor was observed in one male rat and seven female rats. The increased respiration, vocalization, not easy to handle and/or loss of tone in the limb were observed in both males and females, and increased body temperature was observed in male animals. Based on the results, a single intravenous dose of BMEDA administered to rats resulted in increased respiration, vocalization, not easy to handle and/or loss of tone in the limb increasing at the dose level of 5 mg/kg. No neurobehavioral effects were noted after BMEDA administration up to the dose level of 2 mg/kg. The information of this study will provides a point of reference to design appropriately therapeutic studies for future human use.
{"title":"Neurobehavioral assessment of BMEDA by modified Irwin test in Sprague-Dawley rats","authors":"Liang-Cheng Chen, Te-Wei Lee, Chih-Hsien Chang","doi":"10.1016/j.yrtph.2024.105703","DOIUrl":"10.1016/j.yrtph.2024.105703","url":null,"abstract":"<div><div>The neurobehavioral assessment of N,N-bis(2-mercapatoethly)-N′,N′-diethylenediamine (BMEDA), which can form a chelate with rhenium-188 (<sup>188</sup>Re) to produce the <sup>188</sup>Re-BMEDA-liposome, was evaluated. The purpose of this study was to evaluate the potential neurobehavioral changes by using the functional observational battery observation procedures when intravenous injection of BMEDA to Sprague-Dawley rats. Rats were administered BMEDA at dose levels of 1, 2, and 5 mg/kg. No mortalities were observed. There are some observations related to BMEDA treatment found in the 5 mg/kg dose group at 10 min post-dose. Tremor was observed in one male rat and seven female rats. The increased respiration, vocalization, not easy to handle and/or loss of tone in the limb were observed in both males and females, and increased body temperature was observed in male animals. Based on the results, a single intravenous dose of BMEDA administered to rats resulted in increased respiration, vocalization, not easy to handle and/or loss of tone in the limb increasing at the dose level of 5 mg/kg. No neurobehavioral effects were noted after BMEDA administration up to the dose level of 2 mg/kg. The information of this study will provides a point of reference to design appropriately therapeutic studies for future human use.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"153 ","pages":"Article 105703"},"PeriodicalIF":3.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1016/j.yrtph.2024.105702
Yadvinder Bhuller , Morgan Gale , Fevrelyn Yadao , Daniel Krewski
The 12th World Congress on Alternatives and Animal Use in the Life Sciences provided a platform for mobilizing and exchanging knowledge on the advancements in science and technology. It also provided an opportunity for experts to discuss how to accelerate the adoption of new strategies and tools. One of these recommendations advocated the need to bridge the gap between the next generation of scientists who have yet to learn about ‘New Approach Methodologies’ (NAMs) and the current generation of thought leaders who have pioneered the development and validation of these non-animal approaches to toxicological risk assessment. Consequently, a mini-course, held at Canada's University of Ottawa, was developed for students, aged 13–16 years, interested in learning about risk science and how NAMs can be used to inform human health risk assessment. This course also served as a platform for creating a virtual training roadmap, provided in this paper, thereby bringing this knowledge to a broader audience of learners who are establishing their careers in the field of risk science.
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Pub Date : 2024-09-16DOI: 10.1016/j.yrtph.2024.105706
G.S. Friedrichs , M.M. Abernathy , D. Ackley , M. Clark , J.K. DaSilva , C.M. Foley , A. Greiter-Wilke , K.A Henderson , J.J. Kremer , B.H. Morimoto , S. Paglialunga , M.K. Pugsley , C.P. Regan , E.I. Rossman , J.A. Segretti , M. Traebert , H.M. Vargas , T.A. Wisialowski
Optimization of ICH safety guideline studies for inclusion into regulatory submissions is critical for resource conservation, animal use reduction, and efficient drug development. The ICH S7A guidance for Safety Pharmacology (SP) studies adopted in 2001 identified the core battery of studies to evaluate the acute safety of putative pharmaceutical molecules prior to First in Human (FIH) trials. To assess the utility of respiratory studies in predicting clinical AE's, seven pharmaceutical companies pooled preclinical and clinical respiratory findings. A large database of novel molecules included all relevant data from standard S7A respiratory (n = 459) and FIH studies (n = 309). The data were analyzed with respect to the progression of these molecules, clinical adverse event reporting of these same molecules, and achieved exposures. These S7A respiratory assay findings had no impact on compound progression, and only 12 of 309 drug candidates were ‘positive’ preclinically and reported a respiratory-related AE in clinical trials (i.e. cough, dyspnea, etc.), an overall incidence rate of 3.9%. Contingency tables/statistics support a lack of concordance of these preclinical assays. Overall, our extensive analysis clearly indicated that the preclinical respiratory assay fails to provide any prognostic value for detecting clinically relevant respiratory adverse events.
优化 ICH 安全性指南研究以纳入监管申请对于节约资源、减少动物使用和高效药物开发至关重要。2001 年通过的 ICH S7A 安全药理学（SP）研究指南确定了在首次人体试验（FIH）之前评估潜在药物分子急性安全性的核心研究系列。为了评估呼吸系统研究在预测临床 AE 方面的效用，七家制药公司汇集了临床前和临床呼吸系统研究结果。新型分子的大型数据库包括标准 S7A 呼吸系统研究（n = 459）和 FIH 研究（n = 309）的所有相关数据。分析数据涉及这些分子的进展、这些分子的临床不良事件报告以及达到的暴露量。这些 S7A 呼吸检测结果对化合物的进展没有影响，309 种候选药物中只有 12 种在临床前呈 "阳性"，并在临床试验中报告了呼吸相关的 AE（如咳嗽、呼吸困难等），总发生率为 3.9%。或然率表/统计数据表明这些临床前检测结果缺乏一致性。总之，我们的大量分析清楚地表明，临床前呼吸测定无法为检测临床相关的呼吸不良事件提供任何预后价值。
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