Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at Novartis Institute of Biomedical Research

Abstract

Characterizing the relationship between the pharmacokinetics (PK, concentration vs. time) and pharmacodynamics (PD, effect vs. time) is an important tool in the discovery and development of new drugs in the pharmaceutical industry. The purpose of this publication is to serve as a guide for drug discovery scientists toward optimal design and conduct of PK/PD studies in the research phase. This review is a result of the collaborative efforts of DMPK scientists from various Metabolism and Pharmacokinetic (MAP) departments of the global organization Novartis Institute of Biomedical Research (NIBR). We recommend that PK/PD strategies be implemented in early research phases of drug discovery projects to enable successful transition to drug development. Effective PK/PD study design, analysis, and interpretation can help scientists elucidate the relationship between PK and PD, understand the mechanism of drug action, and identify PK properties for further improvement and optimal compound design. Additionally, PK/PD modeling can help increase the translation of in vitro compound potency to the in vivo setting, reduce the number of in vivo animal studies, and improve translation of findings from preclinical species into the clinical setting. This review focuses on three important elements of successful PK/PD studies, namely partnership among key scientists involved in the study execution; parameters that influence study designs; and data analysis and interpretation. Specific examples and case studies are highlighted to help demonstrate key points for consideration. The intent is to provide a broad PK/PD foundation for colleagues in the pharmaceutical industry and serve as a tool to promote appropriate discussions on early research project teams with key scientists involved in PK/PD studies.

Using Chemical Reaction Kinetics to Predict Optimal Antibiotic Treatment Strategies

“…For example, we note that the effects of the physiological fluctuations of drug concentration are also poorly understood in the treatment of cancer [65], HIV [66] and malaria [67] and similar questions arise regarding the effects of exposure to harmful substances in toxicology [68]. …”

Mathematical modeling of receptor occupancy data: A valuable technology for biotherapeutic drug development

“…Furthermore, it can be appreciated that under certain scenarios, different time points are more informative than others, suggesting that attention be given to the design of PK-RO studies. Design of experiments is one area where modeling methods can be particularly valuable (14,15).…”

Advances and Future Directions for Tuberous Sclerosis Complex Research: Recommendations From the 2015 Strategic Planning Conference

“…Consequently, the NIH and leading scientific journals recognize the urgent need to submit preclinical studies to the same standards of rigor (e.g., blinding, randomization) and transparency that are expected of human clinical trials 60,61 ; also see recent NIH guidelines: http://grants.nih.gov/reproducibility/index.htm. In addition, when testing the efficacy of pharmacological interventions in preclinical models, it is imperative to obtain pharmacokinetic (PK) endpoints in plasma and/or the tissue in which the drug target is expressed 62–64 , and directly compare PK with pharmacodynamics (PD) endpoint(s). Finally, the most promising treatments should undergo replication, ideally in an independent laboratory and/or using another TSC model, prior to advancement to late-stage translational or clinical testing.…”