Preclinical Drug Development

Proof-of-Concept in the Force Field of Efficacy and Safety

  • Table 1: Initial set of drug transportersTable 1: Initial set of drug transporters
  • Table 1: Initial set of drug transporters
  • Table 2: Initial set of drug metabolizing enzymes
  • Table 3: Initial set of secondary and safety pharmacology targets
  • Dr. Klaus Syha MBA, Syha Consult

Drug development in the context of the respective disease is a risk/benefit process concerning efficacy and safety of an investigational candidate. It is estimated that ~70% of drug development projects do not lead to a marketed product. The risk of failure is perpetuated by lacking therapeutic efficacy or unexpected adverse drug reactions (ADRs) in the post marketing stage. Unanticipated safety and efficacy issues each account for ~30% of current attritions. An ADR profile is often becoming relevant only above a certain threshold trough interaction with unwanted targets. Consequences of these post approval failures are detrimental from the perspectives of the pharmaceutical industry and patients. Accordingly, there is high value in algorithms and methodologies that can identify potential failures and clinical liabilities at the earliest possible stage.

Investigational Gap

A drug is designed as an agent acting on a primary target: transporter, ion channel, receptor or enzyme, shaping its efficacy. In contrast, non-target effects on transporters (impaired fluxes), metabolizing enzymes (adverse metabolites) and receptors (ant/agonists), which are key to drug bioavailability, kinetics and toxicology, have strong implications for its safety. Both targeted and non-targeted molecular entities are subject to individual genetic expression, contributing to patient heterogeneity. Heterogeneity is further expressed by genetics of disease; by people being changed by disease and changing with age. These patient population differences are giving rise to drugs for personalized medicine, patient stratification, exclusion of non-responders, discovery and validation of biomarkers or establishing reliable surrogate/biomarker correlations. To address drug efficacy and safety issues the pharmaceutical industry has already successfully implemented physicochemical characterization (molecular mass, solubility, log P/D, pKa), intestinal permeability (Lipinski's rule of five) and pharmacokinetic early absorption, distribution, metabolism, excretion (ADME) and toxicological assays. On the other hand there exists a gap between primary pharmacodynamic studies, investigating the drug in relation to its "desired therapeutic (target) effect", and study of its toxic effects.

As the gap may only show its impact at the stage of first use in human (FIH) or even at the post marketing stage, investigating the diversity and novelty of molecular targets is forcefully addressed by the number, complexity, and stringency of regulatory requirements (to come).

Closing the Gap

This gap is indented to be closed by safety pharmacological studies, employed to "investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions (crucial cardiovascular, central nervous and respiratory functions) in relation to exposure in the therapeutic range and above". This still leaves the gap "to investigate the mechanisms of action and/or effects of a candidate not related to its desired therapeutic target", its off-target effects, demanding secondary pharmacodynamics. Such "secondary target" information, submitted as part of the pharmacology section of the Common Technical Document, can complement and inform primary pharmacodynamic, safety pharmacology and toxicological studies; it can support dose selection and inspire drug repositioning. Consequently, the armament of preclinical investigations should include in vitro studies with all molecular targets, including recombinant human targets, relevant to improve fail early (and cheap) decision-making and decreasing the probability that a flawed candidate fails only at the stage of proof of concept (FIH) or even at the post marketing stage. This is supported by a front-loading incremental and iterative approach based on existing primary pharmacodynamic and toxicological candidate information, employing an initial set of bridging bioavailability, metabolism, secondary and safety pharmacology targets (tables 1-3). The set includes targets that mediate vital functions of the cardiovascular, central nervous, respiratory and gastrointestinal systems (tables 1, 3). Screening of initially selected and emerging targets - also towards primary and toxicological targets - under physiology-relevant assay conditions is broadening the biological space for potentially undesirable effects. Initial methodologies employ in vitro radioligand binding and enzyme activity assays at the appropriate candidate concentration. Using (calculated) in vivo exposure (AUC, Cmax) the therapeutic margin - desired therapeutic activity versus occurrence of ADRs - can be determined. Based on the margin, the affinity of the candidate for non-primary targets can be explored. All targets showing clear response (hits) are further investigated in concentration-effect studies to provide quantitative analysis. Interesting effects and selectivity of the candidate concerning relevant secondary, safety and toxicological properties can be further explored by appropriate in vivo investigations and animal studies. Such selective shaping of the chemical space is significantly informing candidate efficacy and safety.

Exploring the Pharmacological Space

Because of their role in ADRs, non-targeted transporters (table 1), metabolizing enzymes (table 2) and bridging secondary and safety pharmacology targets must be considered in in vitro studies of pharmacological space (table 3).

Integrated View

The multiple target view of candidate efficacy and safety is further supported and also stressed by simulation and prediction based on computational and molecular systems biology. The non-primary chemical and biological space of the candidate is instrumental to consolidate its full pharmacological space, allowing comparison in the context of the pharmacological space of benchmark/relevant drugs. Pharmacological space is key to generate both individual candidate and drug class integrated views. Safety-relevant data retrieved from large in vitro and in vivo datasets can help to assess the risk associated with the target and off-target interactions of the candidate; revealing and filling existing gaps not captured by the individual assay pharmacology. The integrated view facilitates the correlation of in vitro candidate properties to clinical outcomes.


Pharmacological space - efficacy and safety - of a drug candidate is consolidated by in vitro studies using a relevant set of molecular targets - spanning secondary to safety pharmacology targets (biological space) followed by appropriate in-depth in vivo/animal dose-effect studies (chemical space). Comparison of candidate space with drug class pharmacological space - supported and stressed by an interactive algorithmic and methodological approach - can be instrumental for risk/benefit assessments with respect to fail early decision-making, proof of concept (FIH), patient stratification, exclusion of non-responders, and discovery and validation of/correlation with biomarkers, and failure at the post marketing stage.




Syha Consult
Im Rosengärtchen 11
61440 Oberursel
Phone: +49 6171 25160

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