First dose of potential new medicines to humans: how animals help

Greaves, Peter; Williams, Andrew; Eve, Malcolm D.

doi:10.1038/nrd1329

Cited by 225 publications

(133 citation statements)

References 41 publications

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“…However, it should be kept in mind that absorption, elimination, metabolization, and pharmacokinetics, together with toxicology, are the main causes of failure during drug development. 30 Because of this, IQG607 must be verified further in a series of toxicological tests (acute and chronic), to be conducted in cell culture systems (in vitro toxicology), and rodent and non-rodent animal species (in vivo toxicology), and these studies should be extended to investigate its bioavailability, metabolism, and excretion.…”

Section: Resultsmentioning

confidence: 99%

An inorganic complex that inhibits Mycobacterium tuberculosis enoyl reductase as a prototype of a new class of chemotherapeutic agents to treat tuberculosis

Basso¹,

Schneider²,

Santos³

et al. 2010

J. Braz. Chem. Soc.

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Descrevemos a atividade inibitória do IQG607, pentaciano(isoniazida)ferrato(II), frente a cepas de Mycobacterium tuberculosis tanto resistentes quanto sensíveis à isoniazida, assim como a toxicidade oral e a adaptação da síntese química do IQG607 para reatores maiores. O IQG607 representa um potencial agente quimioterápico que inibe um alvo molecular definido.Here we describe the inhibitory activity of IQG607, pentacyano(isoniazid)ferrate(II), on isoniazid-sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis, its oral toxicity, and efforts to adapt IQG607 synthesis to large chemical reactors. IQG607 represents a promising chemotherapeutic agent aiming at the inhibition of a validated and druggable molecular target. Keywords: Mycobacterium tuberculosis, enoyl reductase, toxicology, large-scale synthesis, metallodrug IntroductionTuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. 1 In 2007, there were an estimated 9.27 million cases of TB, and 1.37 million (15%) were also HIV-positive patients, who are more likely to develop active TB. 2 Brazil ranks 14 th in terms of the total number of incident cases amongst the high-burden countries. 2 There were an estimated 0.5 million cases of multidrugresistant TB (MDR-TB), which is caused by strains resistant to, at least, isoniazid and rifampicin. 2 The emergence of extensively drug-resistant (XDR) TB cases, which are found in TB-infected patients whose isolates are MDR and also resistant to a fluoroquinolone and, at least, one second-line injectable agent, 2,3 its widespread distribution, 4 and unprecedented fatality rate, 5 raise the prospect of virtually incurable and deadly TB worldwide. The factors that most influence the emergence of drugresistant strains include inappropriate treatment regimens and patient noncompliance in completing the prescribed courses of therapy due to the lengthy standard "shortcourse" treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol or streptomycin for two months, followed by a combination of isoniazid and rifampicin for additional four months) or when the side effects become unbearable. 6 Moreover, no sustainable control of TB epidemic can be reached in any country without properly addressing this global public health problem, including research as a key component. 7 M. tuberculosis has been considered the world's most successful pathogen, and this is largely due to the ability of the bacillum to persist in host tissues, where drugs that are rapidly bactericidal in vitro require prolonged administration to achieve comparable in vivo effects. 8 Hence, more effective and less toxic anti-tubercular agents are immediately needed to shorten the duration of current treatment, improve the treatment of drug-resistant TB, and to provide effective treatment of latent TB infection.The modern approach in the development of new chemical entities (NCEs) against TB is based on the use of defined molecular targets. This involves (i) the search and identification ...

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Section: Resultsmentioning

confidence: 99%

An inorganic complex that inhibits Mycobacterium tuberculosis enoyl reductase as a prototype of a new class of chemotherapeutic agents to treat tuberculosis

Basso¹,

Schneider²,

Santos³

et al. 2010

J. Braz. Chem. Soc.

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“…[1][2][3][4][5] Prior to clinical testing, all clinical candidates are evaluated in animals to define the spectrum of toxicities that might occur in human subjects and safe doses for clinical testing. 6 However, continued occurrences of clinical safety terminations calls into question the value of nonclinical testing in predicting human risk. 7,8 Nonetheless, when confidence in nonclinical safety data is high compounds are more likely to be safe in humans.…”

Section: Introductionmentioning

confidence: 99%

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

et al. 2017

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Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.

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“…Therefore, the most relevant safety data is derived from toxicology studies with the conjugate. In addition, toxicology studies to evaluate the warhead alone can be limited to a single rodent species (64), as potent cytotoxics have such strong primary pharmacological activity that there are usually minimal species differences in the toxicity profile of these agents (67,68). To complete the safety evaluation, the nonclinical package must also include a genotoxicity assessment of the novel warhead at the time of BLA submission.…”

Section: Safety Assessment Of Novel Warheadsmentioning

confidence: 99%

Antibody Drug Conjugates: Nonclinical Safety Considerations

Hinrichs

Dixit

2015

AAPS J

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Abstract. Antibody drug conjugates (ADCs) are biopharmaceutical molecules consisting of a cytotoxic small molecule covalently linked to a targeted protein carrier via a stable cleavable or noncleavable linker. The process of conjugation yields a highly complex molecule with biochemical properties that are distinct from those of the unconjugated components. The impact of these biochemical differences on the safety and pharmacokinetic (PK) profile of the conjugate must be considered when determining the types of nonclinical safety studies required to support clinical development of ADCs. The hybrid nature of ADCs highlights the need for a science-based approach to safety assessment that incorporates relevant aspects of small and large molecule testing paradigms. This thinking is reflected in current regulatory guidelines, where sections pertaining to conjugates allow for a flexible approach to nonclinical safety testing. The aim of this article is to review regulatory expectations regarding early assessment of nonclinical safety considerations and discuss how recent advances in our understanding of ADCmediated toxicity can be used to guide the types of nonclinical safety studies needed to support ADC clinical development. The review will also explore nonclinical testing strategies that can be used to streamline ADC development by assessing the safety and efficacy of next generation ADC constructs using a rodent screen approach.

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First dose of potential new medicines to humans: how animals help

Cited by 225 publications

References 41 publications

An inorganic complex that inhibits Mycobacterium tuberculosis enoyl reductase as a prototype of a new class of chemotherapeutic agents to treat tuberculosis

An inorganic complex that inhibits Mycobacterium tuberculosis enoyl reductase as a prototype of a new class of chemotherapeutic agents to treat tuberculosis

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

Antibody Drug Conjugates: Nonclinical Safety Considerations

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