European Journal of Pharmaceutical Sciences 13 (2001) 115–122 www.elsevier.nl / locate / ejps Commentary q Role of modelling and simulation in Phase I drug development a b, c d e * ´ Leon Aarons , Mats O. Karlsson , France Mentre , Ferdinand Rombout , Jean-Louis Steimer , f Achiel van Peer and invited COST B15 Experts a School of Pharmacy, University of Manchester, Manchester, UK b Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden c INSERM U436, Mathematical and Statistical Modeling in Biology and Medicine, Paris, France d Institute for Clinical Pharmacology, Bayer AG, Wuppertal, Germany e Biostatistics, Hoffman-La Roche, Basel, Switzerland f Clinical Pharmacokinetics, Janssen Research Foundation, Beerse, Belgium Received 22 September 2000; received in revised form 21 December 2000; accepted 29 December 2000 Abstract Although the use of pharmacokinetic / pharmacodynamic modelling and simulation (M&S) in drug development has increased during the last decade, this has most notably occurred in patient studies using the population approach. The role of M&S in Phase I, although of longer history, does not presently have the same impact on drug development. However, trends such as the increased use of biomarkers and clinical trial simulation as well as adoption of the learn / confirm concept can be expected to increase the importance of modelling in Phase I. To help identify the role of M&S, its main advantages and the obstacles to its rational use, an expert meeting was organised by COST B15 in Brussels, January 10–11, 2000. This article presents the views expressed at that meeting. Although it is clear that M&S occurs in only a minority of Phase I clinical trials, it is used for a large number of different purposes. In particular, M&S is considered valuable in the following situations: censoring because of assay limitation, characterisation of non-linearity, estimating exposure–response relationship, combined analyses, sparse sampling studies, special population studies, integrating PK / PD knowledge for decision making, simulation of Phase II trials, predicting multiple dose profile from single dose, bridging studies and formulation development. One or more of the following characteristics of M&S activities are often present and severely impede its successful integration into clinical drug development: lack of trained personnel, lack of protocol and / or analysis plan, absence of pre-specified objectives, no timelines or budget, low priority, inadequate reporting, no quality assurance of the modelling process and no evaluation of cost–benefit. The early clinical drug development phase is changing and if these implementation aspects can be appropriately addressed, M&S can fulfill an important role in reshaping the early trials by more effective extraction of information from studies, better integration of knowledge across studies and more precise predictions of trial outcome, thereby allowing more informed decision making.  2001 Elsevier Science B.V. All rights reserved. Keywords: Drug development; Pharmacokinetic and pharmacodynamic modelling; Phase I clinical trials 1. Introduction main objective is to improve the predictive potential of scientific information gathered within the framework of COST B15 is an action sponsored by the European development of new, efficacious and safe drugs, as well as Community entitled ‘Modelling in drug development’. Its sustainable industrial chemicals. To do this the action has been divided into three working groups: q Based on a COST B15 meeting held in Brussels, 10–11 January • In vitro approaches to predicting kinetics and dynamics 2000. The expert panel members, all of whom approved this publication in vivo. as an appropriate representation of the meeting, were: K. Bol (Belgium), ´ M. Danhof (The Netherlands), T. Goggin (Switzerland), A. Grahnen • Markers of pharmacological and toxicological action. (Sweden), A. Khan (UK), S. Marshall (UK), P. Milligan (UK), V. • Modelling and simulation in clinical drug development. Piotrovskij (Belgium), H. Schaefer (UK), T. Shepard (UK), E. Snoeck (Belgium), J. Taubel (UK). This commentary summarises the opinions and ex- *Corresponding author. Tel.: 146-18-471-4105; fax: 146-18-471- periences expressed at an expert meeting in Brussels 4003. E-mail address: mats.karlsson@biof.uu.se (M.O. Karlsson). organised by the third workgroup, 10–11 January 2000. 0928-0987 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0928-0987(01)00096-3