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As the transition to model-based drug development continues, pharmacometric analysis will have an increasingly important role across the entire life cycle of drug discovery, development, regulatory approval, and commercialization. For this reason, pharmacometrics can—and should—have an integrating function in the transformation to model-based development. This essay describes an approach for formalizing the pharmacometrics process using the disciplines encompassed by enterprise engineering.Clinical Pharmacology & Therapeutics (2007) 82, 137–142. doi:10.1038/sj.clpt.6100270 [ABSTRACT FROM AUTHOR]

Presents abstract of the study "Model based development of a direct factor Xa inhibitor," by S. Rohatagi and colleagues.

The article discusses the problems faced by medical practitioners in determining the right dose of prescription medicine for patients. It reports that one out of five effective prescription drugs are removed from the market or relabeled. It informs that the development of clinical pharmacology has provided a blueprint for determining correct individualized dosage regimens.

Quantitative and systems pharmacology (QSP) is increasingly being applied in pharmaceutical research and development. One factor critical to the ultimate success of QSP is the establishment of commonly accepted language, technical criteria, and workflows. We propose an integrated workflow that bridges conceptual objectives with underlying technical detail to support the execution, communication, and evaluation of QSP projects. [ABSTRACT FROM AUTHOR]

The article focuses on the need of model-based drug development (MBDD) process for improving the productivity of the pharmaceutical industry. As reported, pharmaceutical industry is facing a crisis in research and development (R&D) and though several companies have moved toward a more proactive utilization of modeling and simulation (M&S) these efforts have been insufficient to improve productivity. Thus there is a need to develop a new R&D enterprise that fully exploits the MBDD process.

Melphalan is associated with severe side effects such as mucositis, diarrhea, and myelosuppression. We investigated how much the individual severity of these side effects is predicted by pharmacokinetics. In addition, we studied glutathione S-transferase GSTM1, GSTT1, and GSTP1 polymorphisms in relation to adverse events. A high interindividual pharmacokinetic variability was observed in 84 patients. There was a linear correlation between creatinine and melphalan clearance (P=0.0004). Patients treated with a dose 70 mg/m2 had a 23-fold increased risk to develop mucositis (P<0.001) and a 12-fold increased risk to develop diarrhea (P<0.001) compared with lower doses. The GSTP1 codon 105 polymorphism may be relevant for development of mucositis and the GSTT1 deletion may predict diarrhea, but these findings require confirmation. Melphalan-induced side effects were significantly dependent only on dose. Therapeutic drug monitoring or genotyping for GST does not appear to be very helpful in optimizing therapy with melphalan.Clinical Pharmacology & Therapeutics (2008); 83, 5, 749–757. doi:10.1038/sj.clpt.6100336 [ABSTRACT FROM AUTHOR]

Pharmacology is considered a core course for virtually every medical school in the world. Although the study and teaching of the properties of drug-like substances dates from at least ancient Greece and Egypt,1 Oswald Schmiedeberg (1838–1921) at the University of Strassburg in Germany is generally recognized as the founder of modern pharmacology.2,3 Schmiedeberg himself trained many of the first generation of modern academic pharmacologists, including the first chair of pharmacology in North America, John Jacob Abel at the University of Michigan.1 Furthermore, the discovery, development, and use of morphine during the U.S. Civil War bolstered the desire for future physicians to be taught about the properties of drugs, and by the 1890s almost every medical school had a course on drugs.1Clinical Pharmacology & Therapeutics (2007) 82, 134–137. doi:10.1038/sj.clpt.6100266 [ABSTRACT FROM AUTHOR]

The low productivity and escalating costs of drug development have been well documented over the past several years. Less than 10% of new compounds that enter clinical trials ultimately make it to the market, and many more fail in the preclinical stages of development. These challenges in the “critical path” of drug development are discussed in a 2004 publication by the US Food and Drug Administration. The document emphasizes new tools and various opportunities to improve drug development. One of the opportunities recommended is the application of “model-based drug development (MBDD).” This paper discusses what constitutes the key elements of MBDD and how these elements should fit together to inform drug development strategy and decision-making.Clinical Pharmacology & Therapeutics (2007) 82, 21–32. doi:10.1038/sj.clpt.6100235; published online 23 May 2007 [ABSTRACT FROM AUTHOR]

Systematic implementation of model-based drug development (MBDD) to drug discovery and development has the potential to significantly increase the rate of medical breakthroughs and make available new and better treatments to patients. An analysis of the strengths, weaknesses, opportunities, and threats (ie, SWOT) was conducted through focus group discussions that included 24 members representing 8 pharmaceutical companies to systematically assess the challenges to implementing MBDD into the drug development decision-making process. The application of the SWOT analysis to the successful implementation of MBDD yielded 19 strengths, 27 weaknesses, 34 opportunities, and 22 threats, which support the following conclusions. The shift from empirical drug development to MBDD requires a question-based mentality; early, proactive planning; dynamic access to multisource data; quantitative knowledge integration; multidisciplinary collaboration; effective communication and leadership skills; and innovative, impactful application of pharmacometrics focused on enhancing quantitative decision making. The ultimate goal of MBDD is to streamline discovery and development of innovative medicines to benefit patients. [ABSTRACT FROM PUBLISHER]

A keyword index for the February 2009 issue of "Clinical Pharmacology & Therapeutics" is presented.