PKPD relationships and dose rationale in analgesic drug development : towards the prediction of target engagement

Taneja, A. (2013)

Doctoral Thesis

Chronic pain is a significant health problem that greatly impacts the quality of life of individual patients and imparts high costs to society. Despite intense research effort and progress in our understanding of the mechanistic and molecular basis of pain, chronic pain remains a significant clinical problem that has few effective therapies Throughout the various chapters we have highlighted some important conceptual and experimental flaws in the way that pain signalling and pharmacological activity are characterised and translated across species and disease conditions. The common denominator of the work presented here is the requirement for accurate characterisation of exposure-response relationships, without which the dose rationale for the progression of a molecule cannot justified, whether drugs are aimed at symptomatic relief, disease modification or prophylaxis. In addition to a comprehensive review of the mechanisms underlying pain signalling and symptoms, the work developed here focuses on three different aspects of research underpinning the use of pharmacokinetic-pharmacodynamic relationships. First, we have explored the requirements for the characterisation of behavioural measures of pain during the early screening of candidate molecules, shedding light onto the shortcomings of experimental protocols commonly used in preclinical research. Then we introduced the prerequisites for the parameterisation of pain behaviour to ensure accurate translation of the pharmacological properties across species as well as for bridging across different phases of development. Lastly, an attempt was made to model clinical response in chronic inflammatory pain and to establish correlations between symptom improvement and the underlying pharmacological effects using biomarkers. In addition our work showed how clinical trial simulations can be used as a design tool, enabling the evaluation of a variety of scenarios that disentangle the contribution of pharmacology from the confounding effects of placebo and disease dynamics.

• Translation
• Biomarkers
• Chronic pain
• Neuropathic pain
• Prediction
• Engagement
• Target
• Drug development
• Analgesic
• Relationships
• PKPD

• All authors: Taneja, A.
• Supervisor: Danhof, M.
• Co-supervisor: Della Pasqua, O.E.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Science, Leiden University
• Date: 2013-11-20
• ISBN (print): 9789053357385