Pharmacometabolomics in Early‐Phase Clinical Development

Burt, Tal; Nandal, Savita

doi:10.1111/cts.12396

Cited by 33 publications

(28 citation statements)

References 52 publications

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“…Knowledge of these metabolic differences could also be highly valuable for the design of clinical trials in which patients would be enrolled and stratified based on their pretreatment metabolic profiles. Use of metabolomics as an inclusion criterion could result in reduced study patient heterogeneity and improve the likelihood of clinical trial success …”

Section: Precision Medicine and Drug Targets For Sepsismentioning

confidence: 99%

Metabolomics as a Driver in Advancing Precision Medicine in Sepsis

et al. 2017

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Objective The objective of this review is to explain the science of metabolomics—a science of systems biology that measures and studies endogenous small molecules (metabolites) that are present in a single biological sample—and its application to the diagnosis and treatment of sepsis. In addition, we discuss how discovery through metabolomics can contribute to the development of precision medicine targets for this complex disease state and the potential avenues for those new discoveries to be applied in the clinical environment. Methods A nonsystematic literature review was performed focusing on metabolomics, pharmacometabolomics, and sepsis. Human (adult and pediatric) and animal studies were included. Main Results Metabolomics has been investigated in the diagnosis, prognosis, and risk stratification of sepsis, as well as for the identification of drug target opportunities. Metabolomics elucidates a new level of detail, when compared with other systems biology sciences, with regard to the metabolites that are most relevant in the pathophysiology of sepsis, as well as highlighting specific biochemical pathways at work in sepsis. Metabolomics also highlights biochemical differences between sepsis survivors and nonsurvivors at a level of detail greater than that demonstrated by genomics, transcriptomics, or proteomics, potentially leading to actionable targets for new therapies. The application of pharmacometabolomics and its integration with other systems pharmacology to sepsis therapeutics could be particularly helpful in differentiating drug responders and nonresponders and furthering knowledge of mechanisms of drug action and response. Conclusion The accumulated literature on metabolomics suggest that it is a viable tool for continued discovery around the pathophysiology, diagnosis and prognosis, and treatment of sepsis in both adults and children, and provides a greater level of biochemical detail and insight than other systems biology approaches. However, the clinical application of metabolomics in sepsis has not yet been fully realized. For this to be achieved, prospective validation studies are needed to translate metabolites from the discovery phase into the clinical utility phase.

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Section: Precision Medicine and Drug Targets For Sepsismentioning

confidence: 99%

Metabolomics as a Driver in Advancing Precision Medicine in Sepsis

et al. 2017

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“…One area of use for these strategies is cancer, and several reviews have been written that provide comprehensive background on the area (113–117). As the life-time risk of developing CRC in the US is 1 in 21 (4.7%) for men and 1 in 23 (4.4%) for women (118) it is no surprise that concerted efforts have been made to apply these methodologies to this disease.…”

Section: Therapeutics and Pharmacometabolomics In Colorectal Cancermentioning

confidence: 99%

Environmental Influences in the Etiology of Colorectal Cancer: the Premise of Metabolomics

et al. 2017

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Purpose of Review In this review we discuss how environmental exposures predominate the etiology of colorectal cancer (CRC). With CRC being a personalized disease influenced by genes and environment, our goal was to explore the role metabolomics can play in identifying exposures, assessing the interplay between co-exposures, and the development of personalized therapeutic interventions. Recent Findings Approximately 10 % of CRC cases can be explained by germ-line mutations, whereas the prevailing majority are caused by an initiating exposure event occurring decades prior to diagnosis. Recent research has shown that dietary metabolites are linked to a procarcinogenic or protective environment in the colon which is modulated by the microbiome. In addition, excessive alcohol has been shown to increase the risk of CRC and is dependent on diet (folate), the response of microbiome, and genetic polymorphisms within the folate and alcohol metabolic pathways. Metabolomics can not only be used to identify this modulation of host metabolism, which could affect the progression of the tumors but also response to targeted therapeutics. Summary This review highlights the current understanding of the multifaceted etiology and mechanisms of CRC development but also highlights where the field of metabolomics can contribute to a greater understanding of environmental exposure in CRC.

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“…To address uncertainties regarding the dose–effect relationship in phase II studies and inform optimal dose selection in confirmatory phase III trials, the MCP‐Mod (Multiple Comparison Procedures Modeling) was developed and endorsed by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) . In addition, identifying and validating biomarkers that narrow the optimal dose range and target populations as early as possible in clinical development could optimize exposure–response profiles and increase the implied power of the studies . Likewise, using enriched populations, more likely to respond to treatment, can increase the implied effect size.…”

Section: Preventative Minimizing and Mitigating Approachesmentioning

confidence: 99%

“…31 In addition, identifying and validating biomarkers that narrow the optimal dose range and target populations as early as possible in clinical development could optimize exposureresponse profiles and increase the implied power of the studies. [32][33][34][35] Likewise, using enriched populations, more likely to respond to treatment, can increase the implied effect size. However, this may come at the expense of generalizability to the intended target therapeutic population.…”

Section: Preventative Minimizing and Mitigating Approachesmentioning

confidence: 99%

The Burden of the “False‐Negatives” in Clinical Development: Analyses of Current and Alternative Scenarios and Corrective Measures

Burt¹,

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Thom

et al. 2017

Clinical Translational Sci

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The "false-negatives" of clinical development are the effective treatments wrongly determined ineffective. Statistical errors leading to "false-negatives" are larger than those leading to "false-positives," especially in typically underpowered early-phase trials. In addition, "false-negatives" are usually eliminated from further testing, thereby limiting the information available on them. We simulated the impact of early-phase power on economic productivity in three developmental scenarios. Scenario 1, representing the current status quo, assumed 50% statistical power at phase II and 90% at phase III. Scenario 2 assumed increased power (80%), and Scenario 3, increased stringency of alpha (1%) at phase II. Scenario 2 led, on average, to a 60.4% increase in productivity and 52.4% increase in profit. Scenario 3 had no meaningful advantages. Our results suggest that additional costs incurred by increasing the power of phase II studies are offset by the increase in productivity. We discuss the implications of our results and propose corrective measures. Clin Transl Sci (2017) 10, 470-479; doi:10.1111/cts.12478; published online on 4 July 2017. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?✔ Early-phase clinical development studies are usually underpowered, with little knowledge about the extent, magnitude, and economic impact of the consequent "falsenegatives." Only one brief previous report, using different methodology, has studied the topic. 48 WHAT QUESTION DID THIS STUDY ADDRESS?✔ Our simulations aimed to study the impact of statistical error thresholds on clinical development productivity. WHAT THIS STUDY ADDS TO OUR KNOWLEDGE ✔ Underpowered phase II studies result in unacceptably high rates of "false-negatives." The burden of "falsenegatives" on clinical development productivity is potentially enormous, leading to loss of effective treatments and associated commercial profits. Increasing the power of early-phase trials is worth the investment in larger sample sizes. HOW THIS MIGHT CHANGE CLINICAL PHARMACOL-OGY OR TRANSLATIONAL SCIENCE ✔ Increasing power of early-phase clinical trials could improve productivity of drug development with increased profits due to reduction in frequency of "false-negatives" compensating the costs of larger sample-sized studies.Clinical development is increasingly a complex, risky, lengthy, failure-prone, and costly process with considerable healthcare benefits and commercial profits at stake.1-4 Contributing to the costs and delays are statistical errors that lead to "false-positive" and "false-negative" results. The "falsepositives" are the treatments that appear promising but in fact are not. These errors can lead to expensive followup testing, exposure to unnecessary risks and ineffective treatments, and potentially costly delays in development of promising back-up treatments. The "false-negatives" are the effective treatments wrongly eliminated, leading to missed healthcare and economic opportunities and are the subject of our investigation. While the "falseness" o...

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Pharmacometabolomics in Early‐Phase Clinical Development

Cited by 33 publications

References 52 publications

Metabolomics as a Driver in Advancing Precision Medicine in Sepsis

Metabolomics as a Driver in Advancing Precision Medicine in Sepsis

Environmental Influences in the Etiology of Colorectal Cancer: the Premise of Metabolomics

The Burden of the “False‐Negatives” in Clinical Development: Analyses of Current and Alternative Scenarios and Corrective Measures

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