Clinical and Nonclinical Adverse Effects of Kinase Inhibitors

Keller, Douglas A.; Brennan, Richard; Leach, Karen L.

doi:10.1002/9783527673643.ch16

Cited by 7 publications

(9 citation statements)

References 126 publications

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“…Some ocular toxicities, such as retinal vein occlusion (MEK) or conjunctivitis (EGFR), may have species-specific correlates or manifest differently in the different species (8). Visual disturbances that are subjectively reported by the patient, such as is seen with crizotinib, cannot be monitored in standard nonclinical toxicology studies, but may be detectable by specialized electroretinography measurements.…”

Section: Nonclinical To Clinical Correlation In Aes Of Kismentioning

confidence: 99%

“…Visual disturbances that are subjectively reported by the patient, such as is seen with crizotinib, cannot be monitored in standard nonclinical toxicology studies, but may be detectable by specialized electroretinography measurements. Similarly, hypothyroidism observed clinically with some KIs manifests as a regression of thyroid vasculature and increased levels of thyroid-stimulating hormone in mice (8).…”

Section: Nonclinical To Clinical Correlation In Aes Of Kismentioning

confidence: 99%

“…Toxicities arising in rapidturnover tissues due to perturbation of signaling through highly conserved cell proliferation and survival pathways are well predicted in nonclinical studies, such as dermatotoxicity with EGFR inhibitors and gastrointestinal toxicity with KIs targeting a number of kinases (8,9). Cardiovascular AEs have been serious and dose limiting for many approved KIs and nonclinical prediction of these toxicities is often difficult.…”

Section: Nonclinical To Clinical Correlation In Aes Of Kismentioning

confidence: 99%

“…Causes of hepatotoxicity are multifactorial and the interplay of the various factors is not well understood (8). There is a high rate of false positives for renal toxicity in animal studies (8).…”

Section: Nonclinical To Clinical Correlation In Aes Of Kismentioning

confidence: 99%

“…Although KIs are generally safer than cytotoxic chemotherapeutic agents, clinical practice revealed a number of AEs associated with kinase inhibition, some of them serious and dose limiting (8).…”

Section: Nonclinical To Clinical Correlation In Aes Of Kismentioning

confidence: 99%

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Nonclinical Evaluations of Small-Molecule Oncology Drugs: Integration into Clinical Dose Optimization and Toxicity Management

Dambach¹,

Simpson

Jones

et al. 2016

Clinical Cancer Research

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Multidisciplinary approaches that incorporate nonclinical pharmacologic and toxicologic characterization of small-molecule oncology drugs into clinical development programs may facilitate improved benefit-risk profiles and clinical toxicity management in patients. The performance of the current nonclinical safety-testing scheme was discussed, highlighting current strengths and areas for improvement. While current nonclinical testing appears to predict the clinical outcome where the prevalence of specific adverse effects are high, nonclinical testing becomes less reliable for predicting clinical adverse effects that occur infrequently, as with some kinase inhibitors. Although adverse effects associated with kinase inhibitors can often be predicted on the basis of target biology, drugs can be promiscuous and inhibit targets with poorly defined function and associated risks. Improvements in adverse effect databases and better characterization of the biologic activities of drug targets may enable better use of computational modeling approaches in predicting adverse effects with kinase inhibitors. Assessing safety of a lead candidate in parallel with other drug properties enables incorporation of a molecule's best features during chemical design, eliminates the worst molecules early, and permits timely investigation/characterization of toxicity mechanisms for identified liabilities. A safety lead optimization and candidate identification strategy that reduces intrinsic toxicity and metabolic risk and enhances selectivity can deliver selective kinase inhibitors that demonstrate on-target adverse effects identified nonclinically. Integrating clinical and nonclinical data during drug development can facilitate better identification and management of oncology drugs. Follow-up nonclinical studies may be used to better understand the risks in a given patient population and minimize or manage these risks more appropriately.

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Section: Nonclinical To Clinical Correlation In Aes Of Kismentioning

confidence: 99%

Section: Nonclinical To Clinical Correlation In Aes Of Kismentioning

confidence: 99%

Section: Nonclinical To Clinical Correlation In Aes Of Kismentioning

confidence: 99%

Section: Nonclinical To Clinical Correlation In Aes Of Kismentioning

confidence: 99%

Section: Nonclinical To Clinical Correlation In Aes Of Kismentioning

confidence: 99%

See 3 more Smart Citations

Nonclinical Evaluations of Small-Molecule Oncology Drugs: Integration into Clinical Dose Optimization and Toxicity Management

Dambach¹,

Simpson

Jones

et al. 2016

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

On the use of juvenile animal studies to support oncology medicine development in children

Andrews

Keller

2016

Reproductive Toxicology

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Binding Kinetics Survey of the Drugged Kinome

et al. 2018

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Target residence time is emerging as an important optimization parameter in drug discovery, yet target and off-target engagement dynamics have not been clearly linked to the clinical performance of drugs. Here we developed high-throughput binding kinetics assays to characterize the interactions of 270 protein kinase inhibitors with 40 clinically relevant targets. Analysis of the results revealed that on-rates are better correlated with affinity than off-rates and that the fraction of slowly dissociating drug–target complexes increases from early/preclinical to late stage and FDA-approved compounds, suggesting distinct contributions by each parameter to clinical success. Combining binding parameters with PK/ADME properties, we illustrate in silico and in cells how kinetic selectivity could be exploited as an optimization strategy. Furthermore, using bio- and chemoinformatics we uncovered structural features influencing rate constants. Our results underscore the value of binding kinetics information in rational drug design and provide a resource for future studies on this subject.

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Clinical and Nonclinical Adverse Effects of Kinase Inhibitors

Cited by 7 publications

References 126 publications

Nonclinical Evaluations of Small-Molecule Oncology Drugs: Integration into Clinical Dose Optimization and Toxicity Management

Nonclinical Evaluations of Small-Molecule Oncology Drugs: Integration into Clinical Dose Optimization and Toxicity Management

On the use of juvenile animal studies to support oncology medicine development in children

Binding Kinetics Survey of the Drugged Kinome

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