Pharmacometrics: a Multidisciplinary Field to Facilitate Critical Thinking in Drug Development and Translational Research Settings

FORUM Pharmacometrics: A Multidisciplinary Field to Facilitate Critical Thinking in Drug Development and Translational Research Settings Jeffrey S. Barrett, PhD, FCP, Michael J. Fossler, PharmD, PhD, FCP, K. David Cadieu, BS, and Marc R. Gastonguay, PhD Pharmacometrics has evolved beyond quantitative analy- without such backgrounds. Given the paucity of existing sis methods used to facilitate decision making in drug training programs, available training materials, and acad- development, although the application of the discipline in emic champions, a virtual faculty and online curriculum this arena continues to represent the primary emphasis of would allow students to matriculate into one of several scientists calling themselves pharmacometricians. While programs associated with their advisor but take instruc- related fields populate and interface with pharmacomet- tion from faculty at multiple institutions, including rics, there is a natural synergy with clinical pharmacology instructors in both industrial and regulatory settings. due to common areas of research and the decision-making Flexibility in both the curriculum and the governance of expectation with respect to evolving conventional and the degree would provide the greatest hope of addressing translational research paradigms. Innovative and adapt- the short supply of trained pharmacometricians. able training programs and resources are essential in this regard as both disciplines promise to be key elements of the clinical research workplace of the future. The demand Keywords: Pharmacometrics; critical path; NIH roadmap; for scientists with pharmacometrics skills has risen sub- education; clinical pharmacology stantially. Likewise, the salary garnered by those with Journal of Clinical Pharmacology, 2008;48:632-649 these skills appears to be surpassing their counterparts © 2008 the American College of Clinical Pharmacology he history of pharmacometrics is relatively foreshadowed the paths that the field would later Trecent, with the first citations appearing in arti- traverse covering physiologic characterization of the cles by Lee in 19711 and 1976.2 This early research guinea pig gallbladder in vitro using various probe agents such as atropine and acetylcholine1 and the quantitative characterization of neuromuscular block From the Laboratory for Applied PK/PD, Clinical Pharmacology & by tubocurarine.2 Of course, the disciplines with Therapeutics Division, The Children’s Hospital of Philadelphia, Philadelphia, which pharmacometrics can be associated, includ- Pennsylvania (Dr Barrett); the Pediatrics Department, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (Dr Barrett); the ing basic and clinical pharmacology, biostatistics, Department of Clinical Pharmacokinetics, Modeling, and Simulation, and medicine, have much longer histories. Ette and GlaxoSmithKline, King of Prussia, Pennsylvania (Dr Fossler); KDC Group Williams3 have provided a historical context from Inc, Lawrenceville, New Jersey (Mr Cadieu); and the Metrum Institute, which the evolution of pharmacometrics can be Tariffville, Connecticut (Dr Gastonguay). Submitted for publication appreciated. More important than its history is the December 6, 2007; revised version accepted January 20, 2008. Address definition of the field itself and the rationale for why for correspondence: Dr Jeffrey S. Barrett, The University of Pennsylvania Medical School, Pediatrics Department, Abramson Research Center, Rm this discipline merits study and is likely to have 916H, 3615 Civic Center Boulevard, Philadelphia, PA 19104; e-mail: impact on medical and pharmaceutical research [email protected]. now and in the future. Several definitions for phar- DOI: 10.1177/0091270008315318 macometrics have been proposed. Early definitions 632 • J Clin Pharmacol 2008;48:632-649 THE DISCIPLINE OF PHARMACOMETRICS tended to focus on population-based methodologies, specifically population pharmacokinetics (pop-PK), Health Economics incorporating assessment of uncertainty as a unify- Regulatory ing topic. More recently, pharmacometrics has been Clinical Science described as the science of developing and applying Pharmacology mathematical and statistical models to characterize, Computer understand, and predict a drug’s PK, pharmacody- Science Statistics namic (PD), and biomarker-outcome behavior.3 This, Medicine too, is likely limiting given the scope of the disci- Pharmacology pline’s recent applications. A still broader definition Ethics Computational will be proposed in this treatise. Methods The salient point of the discussion on pharmacometrics is the explicit recognition of this field as a Engineering bridging discipline that facilitates translation of com- Pharmaceutics plex biologic processes and communicates them in a Marketing quantitative manner. Figure 1 illustrates the relation- ship between pharmacometrics and related disciplines (inner circle) as well as other fields (outside Figure 1. Multidisciplinary influence on the field of the circle) that may often interface with those pharmacometrics. engaged in pharmacometrics research, particularly within the confines of a drug development setting. very much in keeping with the intention of the While some of these external disciplines will never National Institutes of Health (NIH) Roadmap,5 which come into play for many pharmacometricians, exam- seeks to address the need to advance the under- ples of pharmacometric interface with each of these standing of the complexity of biological systems: disciplines can be shown and are easy to appreciate “Future progress in medicine will require a quanti- given the public perception of postmarket surveillance, tative understanding of the many interconnected the cost of drugs in general, and late-recognized tox- networks of molecules that comprise our cells and icity associated with marketed drugs that sometimes tissues, their interactions, and their regulation. We results in their removal from the market. As with need to more precisely know the combination of many relatively new fields, there is a temptation to molecular events that lead to disease if we hope to nest them as subspecialties within a broader defini- truly revolutionize medicine.” tion of the more established disciplines. This indeed Likewise, the discipline was specifically cited by may be a reasonable strategy to both nurture and the US Food and Drug Administration (FDA), along mentor those engaged in the research and fund or with advances in clinical pharmacology, as essential otherwise financially support the actual research. If elements for innovative drug development in its pharmacometrics research is to warrant sustained Critical Path Initiative.6 interest from scientists investing in these skills and We provide herein a critique of the pharmacomet- the institutions seeking to benefit from the actual rics discipline, including its scope, the interplay of research, it must be viewed as a complete discipline related disciplines, diversity of the career paths and not a subfield of clinical pharmacology. More defined by pharmacometrics expertise, and avail- importantly, the rapidly expanding complexity of the able training courses, programs, and materials. We underlying science mandates practitioners to focus also explore hiring data collected during the past 10 on this as a unique field in order to maintain compe- years and examine the financial benefit of pharma- tency for this bridging discipline. cometrics skills via comparisons within and across While the demand for pharmacometrics scientists various “homes” for pharmacometricians. Finally, is currently high among industrial and regulatory we propose a curriculum that accommodates the communities, there is also a growing appreciation diversity of skill sets necessary to graduate scientists for pharmacometrics skills as part of academic med- with formal pharmacometrics training. ical and translational research environments.4 Bridging disciplines as a means to tie concepts and DISCIPLINE DEFINED research aims together are commonly identified as necessary to avoid gaps in grant submissions reliant Pharmacometrics can be defined as that branch of on quantitative assessment and forecasting. This is science concerned with mathematical models of FORUM 633 BARRETT ET AL biology, pharmacology, disease, and physiology used simulations to probe the design parameter space is to describe and quantify interactions between xeno- likewise inherently Bayesian. biotics and patients, including beneficial effects and Perhaps the easiest way to define the discipline is side effects resultant from such interfaces. This def- through examples. One of the most visible applica- inition more broadly frames the scope of the disci- tions of pharmacometrics is the integration of popu- pline than earlier versions and at the same time lation-based pharmacokinetics/pharmacodynamics illustrates the obvious connection with other disci- (PK/PD) models with a clinical trial simulation plines. As previously discussed, pharmacometrics is model from which trial design and execution can be indeed a bridging discipline. The nature of the explored relative to performance and outcomes. This bridges built is somewhat dependent on the setting. approach has the added benefit of exploring doses, Drug developers are naturally aligned with this con- regimens, and compliance patterns outside of histor- cept because of the similarity with the phases of ical patient experience as well as clinical assump- drug development and the milestones

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