EXPERT REVIEW Gene Therapy: A Pharmacokinetic/Pharmacodynamic Modelling Overview Zinnia P. Parra-Guillén & Gloria González-Aseguinolaza & Pedro Berraondo & Iñaki F. Trocóniz Received: 9 February 2010 / Accepted: 24 March 2010 / Published online: 13 April 2010 # Springer Science+Business Media, LLC 2010 ABSTRACT Since gene therapy started over 20 years ago, more than one-thousand clinical trials have been carried out. Nonviral vectors present interesting properties for their clinical application, but their efficiency in vivo is relatively low, and further improvements in these vectors are needed. Elucidating how nonviral vectors behave at the intracellular level is enlightening for vector improvement and optimization. Model-based approach is a powerful tool to understand and describe the different pro- cesses that gene transfer systems should overcome inside the body. Model-based approach allows for proposing and predicting the effect of parameter changes on the overall gene therapy response, as well as the known application of the pharmacokinetic/ pharmacodynamic modelling in conventional therapies. The objective of this paper is to critically review the works in which the time-course of naked or formulated DNA have been quantitatively studied or modelled. KEY WORDS computational modelling . gene therapy . pharmacokinetic/pharmacodynamic modelling INTRODUCTION During the last two decades, pharmacokinetic/pharmaco- dynamic (PK/PD) models for both efficacy and safety have been developed in almost all therapeutic areas (1–3), showing a clear benefit in the drug development process (4). There are areas, however, where PK/PD modelling is still an exception. One of those areas is gene therapy (5). Gene therapy can be defined as the transfer of genetic material (DNA or RNA) to somatic cells in order to obtain a therapeutic effect, by either (i) correcting genetic defects, (ii) over-expressing proteins that are therapeutically useful, or (iii) inhibiting the production of harmful proteins (6). Since 1989, when the first clinical trial was approved for advanced melanoma (7), over 1500 clinical trials have been carried out or approved (8). The major percentage (89.1%) of these trials focuses on cancer therapies, cardiovascular diseases, infectious diseases (acquired immune deficiency syndrome (AIDS)) and inherited monogenic diseases (cystic fibrosis). However, although there are two gene therapy drugs commercialized for cancer disease in China, no human gene therapy product has been approved by the Food and Drug Administration (FDA) or European Medicines Agency (EMEA) to date (9). The concept of drug is continuously evolving, from pills to intelligent drug delivery systems and from natural products to biotechnology (proteins, DNA, RNA or even cells). Yet, it can be expected that if models have been proved to be beneficial in understanding and predicting the effects of “traditional” drugs, the same would be the case for modern therapies such gene therapy (10). (Semi-)mechanistic PK/PD models have to take into consideration the following: (i) formulation characteristics, (ii) biopharmaceutic aspects, (iii) pharmacokinetic and pharmacodynamic properties, and (iv) system behaviour. All those aspects can be represented by processes that can be quantified by estimating specific parameters through a model-building process using experimental and/or simu- lated data. Z. P. Parra-Guillén : I. F. Trocóniz(*) Department of Pharmacy and Pharmaceutical Technology School of Pharmacy, University of Navarra Pamplona, Spain e-mail: itroconiz@unav.es G. González-Aseguinolaza : P. Berraondo Division of Hepatology and Gene Therapy Center for Investigation in Applied Medicine (CIMA) Pamplona, Spain Pharm Res (2010) 27:1487–1497 DOI 10.1007/s11095-010-0136-4