Predictability of clinical adverse reactions of drugs by general pharmacology studies.

Igarashi, Toshiji; Nakane, Sadao; Kitagawa, Toshikazu

doi:10.2131/jts.20.77

Cited by 70 publications

(25 citation statements)

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“…Several attempts have been taken so far to evaluate the correlation of toxicity between animals and humans based on large dataset of ADRs (JPMA, 1992(JPMA, , 1993(JPMA, and 1994Igarashi et al, 1995;Olson et al, 2000). Similar to the most of the past studies, the present study did not attempt to collect nonclinical toxicity that was not associated with ADRs in humans (false positives) or toxicity that was not observed both in animals and humans (true negatives) since the data collection effort was impractical given the large size of the dataset.…”

Section: Discussionmentioning

confidence: 99%

“…Over the past several years, only a few analyses based mostly on a limited dataset size have been conducted to evaluate the correlation of toxicity between animals and humans (Litchfield, 1962;Owens, 1962;Schein et al, 1970;Grieshaber and Marsoni, 1986). In the 1990s, the Japanese Pharmaceutical Manufacturers Association (JPMA) conducted systematic and retrospective concordance analyses based on commercial compendiums of approved drugs as well as questionnaire surveys of drugs, both approved and terminated during development due to significant toxicity (JPMA, 1992(JPMA, , 1993(JPMA, and 1994Igarashi et al, 1995). As part of this effort, Igarashi et al (1995) reviewed a total of 141 approved drugs in Japan and showed that general pharmacology studies of cardiovascular functions, spontaneous locomotor activity and intestinal transport are useful in predicting ADRs.…”

Section: Introductionmentioning

confidence: 99%

“…In the 1990s, the Japanese Pharmaceutical Manufacturers Association (JPMA) conducted systematic and retrospective concordance analyses based on commercial compendiums of approved drugs as well as questionnaire surveys of drugs, both approved and terminated during development due to significant toxicity (JPMA, 1992(JPMA, , 1993(JPMA, and 1994Igarashi et al, 1995). As part of this effort, Igarashi et al (1995) reviewed a total of 141 approved drugs in Japan and showed that general pharmacology studies of cardiovascular functions, spontaneous locomotor activity and intestinal transport are useful in predicting ADRs. One of the landmark studies on the concordance of toxicity was conducted by Olson et al (2000) which examined 150 drugs with 221 significant ADRs that had to be responsible for termination of development, had to have resulted in a limitation of the clinical dosage, had to have required drug level monitoring and perhaps dose adjustment, or had to have restricted the target patient population.…”

Section: Introductionmentioning

confidence: 99%

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Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan

et al. 2013

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-The objective of this study was to elucidate the range of abilities of nonclinical safety assessment for predicting adverse drug reactions (ADRs) in humans. The dataset included 1256 ADRs with an incidence rate of 5% or more collected from 142 drugs approved in Japan from 2001 to 2010 (excluding anticancer agents and vaccines). Gastrointestinal, neurological and hepatobiliary ADRs were relatively common, followed by hematological, cutaneous, systemic and cardiovascular ADRs in the dataset. The analysis revealed that 48% of ADRs were predictable based on a comprehensive nonclinical safety assessment considering animal toxicity. Hematological and ocular ADRs, infection, and application site reactions showed a correlation of more than 70%, while musculoskeletal, respiratory and neurological ADRs showed a correlation of less than 30%. In addition to subjective patient perceptions, several laboratory parameters routinely monitored both in animals and humans showed a lower correlation, e.g., abnormalities in hepatobiliary and metabolic parameters, and blood pressure increase. Large molecule drugs showed lower correlation than small molecule drugs; ADRs were observed in various organs and consideration of pharmacological action did not significantly contribute to the prediction. It was also confirmed that the current standard of toxicology testing regarding dosing duration and dose level is adequate to Correspondence: Takako Ohkura

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan

et al. 2013

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“…A review of SP studies performed in Japan included 88 noncancer drugs that showed a good correlation between rodent intestinal transport and general adverse effects such as anorexia and constipation in humans (Igarashi et al 1995). In the review of conventional toxicology studies that included histopathology of the gastrointestinal tract, Olson and colleagues (2000) showed good concordance between gastrointestinal effects in animals and humans, particularly for nonsteroidal anti-inflammatory drugs, anti-infective, and anticancer agents.…”

Section: Translation Of Nonclinical Findings To Humansmentioning

confidence: 99%

Gastrointestinal Safety Pharmacology in Drug Discovery and Development

Al‐Saffar

Costa²,

Delaunois³

et al. 2015

Principles of Safety Pharmacology

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Although the basic structure of the gastrointestinal tract (GIT) is similar across species, there are significant differences in the anatomy, physiology, and biochemistry between humans and laboratory animals, which should be taken into account when conducting a gastrointestinal (GI) assessment. Historically, the percentage of cases of drug attrition associated with GI-related adverse effects is small; however, this incidence has increased over the last few years. Drug-related GI effects are very diverse, usually functional in nature, and not limited to a single pharmacological class. The most common GI signs are nausea and vomiting, diarrhea, constipation, and gastric ulceration. Despite being generally not life-threatening, they can greatly affect patient compliance and quality of life. There is therefore a real need for improved and/or more extensive GI screening of candidate drugs in preclinical development, which may help to better predict clinical effects. Models to identify drug effects on GI function cover GI motility, nausea and emesis liability, secretory function (mainly gastric secretion), and absorption aspects. Both in vitro and in vivo assessments are described in this chapter. Drug-induced effects on GI function can be assessed in stand-alone safety pharmacology studies or as endpoints integrated into toxicology studies. In silico approaches are also being developed, such as the gut-on-a-chip model, but await further optimization and validation before routine use in drug development. GI injuries are still in their infancy with regard to biomarkers, probably due to their greater diversity. Nevertheless, several potential blood, stool, and breath biomarkers have been investigated. However, additional validation studies are necessary to assess the relevance of these biomarkers and their predictive value for GI injuries.

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“…Efforts continue to construct databases relating the similarities and differences between animal and human responses to pharmaceutical agents (Igarashi et al 1995;Olsen et al 2000). As an example, non-clinical safety studies, including safety pharmacology studies, are typically conducted in normal, healthy, young adult or adult animals.…”

Section: Ib4 Future Of Safety Pharmacologymentioning

confidence: 99%

Status of Safety Pharmacology and Present Guidelines

Hock¹

2006

Drug Discovery and Evaluation

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Predictability of clinical adverse reactions of drugs by general pharmacology studies.

Cited by 70 publications

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Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan

Potentials and limitations of nonclinical safety assessment for predicting clinical adverse drug reactions: correlation analysis of 142 approved drugs in Japan

Gastrointestinal Safety Pharmacology in Drug Discovery and Development

Status of Safety Pharmacology and Present Guidelines

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