Next-Generation Model-Based Drug Discovery and Development: Quantitative and Systems Pharmacology

Allerheiligen, S R B

doi:10.1038/clpt.2010.81

Cited by 56Statistical Methods in Clinical TrialsPharmaceutical studies and practicesComputational Drug Discovery Methods

Next-Generation Model-Based Drug Discovery and Development: Quantitative and Systems Pharmacology

Allerheiligen, S R B·2010·Clinical Pharmacology & Therapeutics

DOI 10.1038/clpt.2010.81

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Abstract

Pharmaceutical researchers have undertaken many initiatives and technologies to stem the rising costs of drug discovery and development. Biomarkers, adaptive trial designs, modeling, trial simulations, predictive metabolism, data mining, and disease models have reshaped the way in which researchers approach discovery and development. Quantitative pharmacology (QP), which leverages model-based approaches, operates at both cultural and technical levels to integrate data and scientific disciplines so as to utilize existing knowledge while concomitantly enhancing the ability to make predictions about future experiments and results.

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QSP is gaining traction against the background of an exponential increase in the number of QSP publications in scientific journals since the release of two seminal papers.
“QSP is gaining traction against the background of the exponential increase in the number of QSP publications in scientific journals since the release of two seminal papers1, 2 (see Figure 1)”
From Best Practices to Maximize the Use and Reuse of Quantitative and Systems Pharmacology Models: Recommendations From the United Kingdom Quantitative and Systems Pharmacology Network (2019) · cites this paper as [1]

Learning versus confirming in clinical drug development*
Sheiner, L. B. (1997) · Clinical Pharmacology & Therapeutics · doi:10.1016/s0009-9236(97)90160-0 · Cited by 633 · see citing works
Model-based Drug Development
Lalonde, R. L., Kowalski, K., Hutmacher, M. M., Ewy, W., Nichols, D., Milligan, P. A., Corrigan, B., Lockwood, P. A., Marshall, S. A., Benincosa, L. J., et al. (2007) · Clinical Pharmacology & Therapeutics · doi:10.1038/sj.clpt.6100235 · Cited by 452 · see citing works
Quantitative Disease, Drug, and Trial Models
Gobburu, J. V. S., & Lesko, L. J. (2008) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.011008.145613 · Cited by 122 · see citing works
Model-Based Drug Development: The Road to Quantitative Pharmacology
Zhang, L., Sinha, V. P., Forgue, S. T., Callies, S., Ni, L., Peck, R., & Allerheiligen, S. R. B. (2006) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-006-9010-8 · Cited by 110 · see citing works
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Zhang, L., Pfister, M., & Meibohm, B. (2008) · The AAPS Journal · doi:10.1208/s12248-008-9062-3 · Cited by 93 · see citing works
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Gobburu, J. (2009) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2009.57 · Cited by 30 · see citing works
The heart is already working
Noble, D. (2005) · Biochemical Society Transactions · doi:10.1042/bst0330539 · Cited by 14 · see citing works

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Authors: Allerheiligen, S. R. B.
Affiliations: Eli Lilly (United States) (US)
Corresponding author: Allerheiligen, S R B
Venue: Clinical Pharmacology & Therapeutics
Publisher: Wiley
Published: 2010-06-09
Volume: 88
Issue: 1
Pages: 135-137
ISSN: 0009-9236 (ISSN-L)
1532-6535
DOI: 10.1038/clpt.2010.81
OpenAlex: W2145053176
Cited by: 56
References: 7
Citations by year: 2026: 1 · 2025: 4 · 2024: 1 · 2023: 3 · 2021: 2 · 2020: 1 · 2019: 5 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 6 · 2014: 3 · 2013: 9 · 2012: 7
FWCI: 6.26
Type: journal article
Language: en
Open access: closed
Locations: Clinical Pharmacology & Therapeutics (publishedVersion)
PubMed (publishedVersion)
Topics: Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords: quantitative pharmacology, systems pharmacology, drug development, biomarkers, adaptive trial design, clinical trial simulation, data mining, disease models
MeSH terms: Animals, Clinical Trials as Topic, Drug Industry, Humans, Pharmacology, Clinical, Research Design, Models, Statistical, Biomarkers, Clinical Trials, Phase I as Topic, Systems Biology, Drug Discovery

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Next-Generation Model-Based Drug Discovery and Development: Quantitative and Systems Pharmacology

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