Challenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm

AIM: Despite an improved understanding of the molecular mechanisms of nociception, existing analgesic drugs remain limited in terms of efficacy in chronic conditions, such as neuropathic pain. Here we explore the underlying pathophysiological mechanisms of neuropathic and inflammatory pain, and discuss the prerequisites and opportunities to reduce attrition and high failure rate in the development of analgesic drugs. MEHTODS: A literature search was performed on preclinical and clinical publications aimed at the evaluation of analgesic compounds using MESH terms in PubMed. Publications were selected, which focused on 1) disease mechanisms leading to chronic/neuropathic pain and 2) drugable targets which are currently under evaluation in drug development. Attention was also given to biomarkers and pharmacokinetic-pharmacodynamic modelling. RESULTS: Multiple mechanisms act concurrently to produce pain, which is a non-specific manifestation of underlying nociceptive pathways. Whereas these manifestations can be divided into neuropathic and inflammatory pain, it is now clear that inflammatory mechanisms are a common trigger for both types of pain. This has implications for drug development, as the assessment of drug effects in experimental models of neuropathic and chronic pain is driven by overt behavioural measures. By contrast, the use of mechanistic biomarkers in inflammatory pain has provided the pharmacological basis for dose selection and evaluation of non-steroidal anti- inflammatory drugs (NSAIDs). CONCLUSION: A paradigm is required for the identification of relevant targets and candidate molecules whereby pain is coupled to the cause of sensorial signal processing dysfunction rather than to clinical symptoms. Biomarkers need to be identified that enable characterisation of drug binding and target activity, providing the basis for a more robust dose rationale in early clinical development. Such an approach may be facilitated by quantitative clinical pharmacology and evolving technologies in brain imaging, allowing accurate characterisation of target engagement, and prediction of treatment effects before embarking into large clinical trials

Individualised dosing algorithms and therapeutic monitoring for antiepileptic drugs

Pharmacokinetic (PK) models exist for most antiepileptic drugs (AEDs). Yet, their use in clinical practice to assess inter-individual differences and derive individualised doses has been limited. Here we show how model-based dosing algorithms can be used to ensure attainment of target exposure and improve treatment response in patients. Using simulations, different treatment scenarios were explored for 11 commonly used AEDs. For each drug, five scenarios were considered: i. all patients receive the same dose. ii. individual clearance (CL), as predicted by population PK models is used to personalize treatment. iii-v. individual CL, obtained by therapeutic drug monitoring (TDM) according to different sampling schemes is used to personalise treatment. Attainment of steady-state target exposure was used as performance criterion to rank each scenario. In contrast to current clinical guidelines, our results show that patient demographic and clinical characteristics should be used in conjunction with TDM to personalize the treatment of seizures

Establishing in Vitro to Clinical Correlations in the Evaluation of Cardiovascular Safety Pharmacology.

Preclinical studies are vital in establishing the efficacy and safety of a new chemical entity (NCE) in humans. To deliver meaningful information, experiments have to be well defined and provide outcome that is relevant and translatable to humans. This review briefly surveys the various preclinical experiments that are frequently conducted to assess drug effects on cardiac conductivity in early drug development. We examine the different approaches used to establish correlations between non-clinical and clinical settings and discuss their value in the evaluation of cardiovascular risk