Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival

Morgan, Paul; Graaf, Piet H. van der; Arrowsmith, John; Feltner, Doug E.; Drummond, Kira S.; Wegner, Craig D.; Street, Steve D.A.

doi:10.1016/j.drudis.2011.12.020

Cited by 617 publications

(473 citation statements)

References 23 publications

Supporting

Mentioning

469

Contrasting

Order By: Relevance

“…To that end, it is important to connect such data to information on drug distribution to target sites, target binding kinetics, signal trans- [ 88] duction, and homeostatic feedback mechanisms. Such insight is obtained by integration of data obtained from multilevel studies, that is, measurement of different biomarker types in a time-dependent manner [19,71,91,92,93]. In all cases, the experimental approach should be such that a distinction can be made between drug-specific and system-specific properties, to allow for scaling between drugs and/or scaling between species [61].…”

Section: Biomarkers Of Drug Effects and Diseasementioning

confidence: 99%

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

Lange

Brink

Yamamoto

et al. 2017

Expert Opinion on Drug Discovery

View full text Add to dashboard Cite

Introduction: CNS drug development has been hampered by inadequate consideration of CNS pharmacokinetic (PK), pharmacodynamics (PD) and disease complexity (reductionist approach). Improvement is required via integrative model-based approaches. Areas covered: The authors summarize factors that have played a role in the high attrition rate of CNS compounds. Recent advances in CNS research and drug discovery are presented, especially with regard to assessment of relevant neuro-PK parameters. Suggestions for further improvements are also discussed. Expert opinion: Understanding time-and condition dependent interrelationships between neuro-PK and neuro-PD processes is key to predictions in different conditions. As a first screen, it is suggested to use in silico/in vitro derived molecular properties of candidate compounds and predict concentrationtime profiles of compounds in multiple compartments of the human CNS, using time-course based physiology-based (PB) PK models. Then, for selected compounds, one can include in vitro drug-target binding kinetics to predict target occupancy (TO)-time profiles in humans. This will improve neuro-PD prediction. Furthermore, a pharmaco-omics approach is suggested, providing multilevel and paralleled data on systems processes from individuals in a systems-wide manner. Thus, clinical trials will be better informed, using fewer animals, while also, needing fewer individuals and samples per individual for proof of concept in humans. ARTICLE HISTORY

show abstract

Section: Biomarkers Of Drug Effects and Diseasementioning

confidence: 99%

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

Lange

Brink

Yamamoto

et al. 2017

Expert Opinion on Drug Discovery

View full text Add to dashboard Cite

show abstract

“…Scientists at Pfizer considered evidence of exposure at the site of action, target binding and expression of functional pharmacological activity for 44 Phase II programmes across several therapeutic areas 8 . In 43% of cases, it was reported that the target mechanism had not been adequately tested owing to the lack of evidence of target engagement.…”

Section: Target Engagementmentioning

confidence: 99%

Failed trials for central nervous system disorders do not necessarily invalidate preclinical models and drug targets

Bespalov

Steckler

Altevogt

et al. 2016

Nat Rev Drug Discov

View full text Add to dashboard Cite

A recent article identified five key technical determinants that make substantial contributions to the outcome of drug R&D projects (Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework. Nat. Rev. Drug Discov. 13, 419-431 (2014)) 1 . Careful consideration of such determinants might be particularly valuable in the fields of neurology and psychiatry, in which successful drug development has declined precipitously over the past decade. This decline has largely been fuelled by a high failure rate in the translation of preclinical efficacy findings, caused by multiple factors (see Supplementary information S1 (table)), including limited training and poor protocol design, inadequate animal models, insufficiently validated therapeutic targets and problems with data handling and reporting.Here, we focus on three factors that can be addressed immediately in order to re-evaluate the therapeutic potential of older drugs and targets and to increase the probability of success for future preclinical-to-clinical translation: data robustness, data generalizability and target engagement data, a factor that was also highlighted in the recent article 1 . We argue that the many failed clinical trials in neuropsychiatry do not necessarily invalidate the potential of a drug target or an animal model. Rather, these failures indicate a need for improved experimental designs and a robust translational strategy to better inform compound and dose selection for clinical trials. We conclude that many of the drugs and targets in neuropsychiatry that have been discarded because of negative clinical trial outcomes may deserve re-evaluation using contemporary knowledge, methodology and tools.

show abstract

“…These three pillars represent the hurdles that a candidate molecule must overcome to become a successful centrally acting drug. In a 2012 review of decision making for 44 of its drug programs in Phase II, Pfizer revealed that, in 43% of decisions, it was not able to conclude whether these three pillars had been met [2]. PET neuroimaging is unique in being able to provide a direct quantification of parameters central to the three pillars in the human brain in vivo, through the use of radiolabelled drugs or biomarkers [1,3].…”

Section: Introductionmentioning

confidence: 99%

“…These lack direct quantitative information on the levels of brain exposure to the drug, target engagement and pharmacological activity -the so-called three pillars of drug survival [2] (Figure 2). These three pillars represent the hurdles that a candidate molecule must overcome to become a successful centrally acting drug.…”

Section: Introductionmentioning

confidence: 99%

Imaging in Central Nervous System Drug Discovery

Gunn

Rabiner

2017

Seminars in Nuclear Medicine

View full text Add to dashboard Cite

Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival

Cited by 617 publications

References 23 publications

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

Failed trials for central nervous system disorders do not necessarily invalidate preclinical models and drug targets

Imaging in Central Nervous System Drug Discovery

Contact Info

Product

Resources

About