P.H. van der Graaf

Advanced methods for dose and regimen finding during drug development: Summary of the EMA /EFPIA workshop on dose finding (London 4-5 December 2014)

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late‐stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well‐established and regulatory‐acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4–5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP‐Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)‐based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well‐designed dose‐finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale.

Mechanism-Based Modeling of Adaptive Changes in the Pharmacodynamics of Midazolam in the Kindling Model of Epilepsy

AbstractPurpose. A mechanism-based model is proposed for the analysis of adaptive changes in the pharmacodynamics of benzodiazepines in vivo. Methods. The pharmacodynamics of midazolam was studied in the kindling model of experimental epilepsy. Concentration-EEC effect data from kindled rats and their controls were fitted to the operational model of agonism. A stepwise procedure was used, allowing changes in the parameters efficacy (τ) and tissue maximum (Em) either separately or in combination. The results were compared to data obtainedin vitro in a brain synaptoneurosomal preparation. Results. The relationship between midazolam concentration and EEC effect was non-linear. In kindled rats the maximum EEC effect was reduced by 27± 8.3µV from the original value of 94± 4.4µV. Analysis on the basis of the operational model of agonism showed that this decrease could be explained by a difference in the parameter system maximum (Em) rather than efficacy (τ). In the in vitro receptor binding assay no changes in density, affinity or functionality of the benzodiazepine receptor were observed, consistent with the lack of a change in efficacy (τ). Conclusions. The operational model of agonism provides a mechanistic basis to characterise adaptive changes in the pharmacodynamics of midazolam.

Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis.

Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug‐induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans.

The influence of drug distribution and drug-target binding on target occupancy : The rate-limiting step approximation

Abstract The influence of drug‐target binding kinetics on target occupancy can be influenced by drug distribution and diffusion around the target, often referred to as “rebinding” or “diffusion‐limited binding”. This gives rise to a decreased decline of the drug‐target complex concentration as a result of a locally higher drug concentration that arises around the target, which leads to prolonged target exposure to the drug. This phenomenon has been approximated by the steady‐state approximation, assuming a steady‐state concentration around the target. Recently, a rate‐limiting step approximation of drug distribution and drug‐target binding has been published. However, a comparison between both approaches has not been made so far. In this study, the rate‐limiting step approximation has been rewritten into the same mathematical format as the steady‐state approximation in order to compare the performance of both approaches for the investigation of the influence of drug‐target binding kinetics on target occupancy. While both approximations clearly indicated the importance of kon and high target concentrations, it was shown that the rate‐limiting step approximation is more accurate than the steady‐state approximation, especially when dissociation is fast compared to association and distribution out of the binding compartment. It is therefore concluded that the new rate‐limiting step approximation is to be preferred for assessing the influence of binding kinetics on local target site concentrations and target occupancy. Graphical abstract No caption available.

Multivariate pharmacokinetic/pharmacodynamic (PKPD) analysis with metabolomics shows multiple effects of remoxipride in rats

&NA; The study of central nervous system (CNS) pharmacology is limited by a lack of drug effect biomarkers. Pharmacometabolomics is a promising new tool to identify multiple molecular responses upon drug treatment. However, the pharmacodynamics is typically not evaluated in metabolomics studies, although being important properties of biomarkers. In this study we integrated pharmacometabolomics with pharmacokinetic/pharmacodynamic (PKPD) modeling to identify and quantify the multiple endogenous metabolite dose‐response relations for the dopamine D2 antagonist remoxipride. Remoxipride (vehicle, 0.7 or 3.5 mg/kg) was administered to rats. Endogenous metabolites were analyzed in plasma using a biogenic amine platform and PKPD models were derived for each single metabolite. These models were clustered on basis of proximity between their PKPD parameter estimates, and PKPD models were subsequently fitted for the individual clusters. Finally, the metabolites were evaluated for being significantly affected by remoxipride. In total 44 metabolites were detected in plasma, many of them showing a dose dependent decrease from baseline. We identified 6 different clusters with different time and dose dependent responses and 18 metabolites were revealed as potential biomarker. The glycine, serine and threonine pathway was associated with remoxipride pharmacology, as well as the brain uptake of the dopamine and serotonin precursors. This is the first time that pharmacometabolomics and PKPD modeling were integrated. The resulting PKPD cluster model described diverse pharmacometabolomics responses and provided a further understanding of remoxipride pharmacodynamics. Future research should focus on the simultaneous pharmacometabolomics analysis in brain and plasma to increase the interpretability of these responses. Graphical abstract Figure. No caption available.

CPT: Pharmacometrics & Systems Pharmacology Publishes Its 100th Article

CPT: Pharmacometrics & Systems Pharmacology (PSP) was launched in September 2012 and, since then, has published at least one new article every week on average. As a result, the journal has now already reached the milestone of publishing its 100th manuscript,1 which is a rare achievement for a new Open Access journal to reach in such a short period of time. Clearly, the success of PSP demonstrates the tremendous growth of the disciplines of pharmacometrics and systems pharmacology and the need for a journal dedicated to these growing areas of science.

Pharmacometrics and Systems Pharmacology Software Tutorials and Use: Comments and Guidelines for PSP Contributions

In addition to methodological Tutorials, 1 CPT:PSP has recently started to publish software Tutorials. 2, 3 Our readership and authors may be wondering what kind of format or product is expected, and the review of submissions we have already received prompted several discussions within the PSP Editorial Team. This editorial reflects on these discussions and summarizes their salient points. It aims at providing some details about the current vision of CPT:PSP for software tutorial articles. In addition, it brings some clarity on the topic of what role commercial software tutorials can have in CPT:PSP and how CPT:PSP tutorials differ from publications which describe the software itself, as those which can be found in other computer science journals. Finally, the discussion includes reproducibility considerations and the general use of commercial and noncommercial software in CPT:PSP publications. We hope our thoughts, and especially a stated requirement to publish user input to the software to aid in reproducibility, will help in guiding our authors and will stimulate healthy debate among our readers about the evolving nature of our science, how it can be facilitated using software and associated databases as a conduit, and what role this journal can play in fostering both the best modeling and simulation practices and the best scientific approaches to computational modeling, to bring the advantages of modeling and simulation to all regular practitioners, and not to just a (self) selected few.

Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics

ABSTRACT Introduction: Diseases of the Central Nervous System (CNS) affect millions of people worldwide, with the number of people affected quickly growing. Unfortunately, the successful development of CNS-acting drugs is less than 10%, and this is attributed to the complexity of the CNS, unexpected side effects, difficulties in penetrating the blood-brain barrier and lack of biomarkers. Areas covered: Herein, the authors first review how pharmacokinetic/pharmacodynamic (PK/PD) models are designed to predict the dose-dependent time course of effect, and how they are used to translate drug effects from animal to man. Then, the authors discuss how pharmacometabolomics gives insight into system-wide pharmacological effects and why it is a promising method to study interspecies differences. Finally, the authors advocate the application of PK/PD-metabolomics modeling to advance translational CNS drug development by discussing its opportunities and challenges. Expert opinion: It is envisioned that PK/PD-metabolomics will increase our understanding of CNS drug effects and improve translational CNS drug development, thereby increasing success rates. The successful future development of this concept will require multi-level and longitudinal biomarker evaluation over a large dose range, multi-tissue biomarker evaluation, and the generation of a proof of principle by application to multiple CNS drugs in multiple species.