In this blog on preclinical drug evaluation redefinitions (Preclinical safety pharmacology in a new era; Drug Discovery Today Volume 27, # 1 Jan. 2022) we discuss the core battery (CB) tests that pharmaceutical companies used the last 20 years to obtain authorization for the use in humans (Baldrick, P. J of Pharma. & Toxicological methods 109 (2021) 107055).
CB is revisited to evaluate potential unnecessary studies and comply with the (3R Replacement, Reduction and Refinement perspective) on CB resources. CB so far, intends to proactively determine cardiovascular (CV), central nervous system (CNS) and respiratory effects of the studied drugs to avoid safety issues.
The author reviews 105 small molecules developments that supported phase I studies in the last decade.
Summary of observations on the CV functional testing:
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Summary of observations on the CNS functional testing:
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Summary of observations on the respiratory functional assessment:
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Reevaluating CB – CV functional testing:
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- This suggests hERG assay as the “only tool to predict clinical arrythmias”.
- To complement these studies, Comprehensive in vitro pro-arrhythmic assay (CiPA paradigm) suggests use of In silico reconstructions with ventricular cardiomyocytes (VC) to identify effects and verifying them in human stem cells derived VC for potential electrophysiological effects.
In general, there is high confidence in functional changes absence and no CV pathology but low confidence on prediction value of CV changes & pathology.
Because double negative non-clinical findings is underappreciated in clinical strategy, an ICH working group prepared a guide to non-clinical evaluations of QT/QTc intervals effects and pro-arrhythmic potentials. The document final form is as ICH E14S7B, August 2022.
Reevaluating CB – CNS functional testing:
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- FOB AEs were mild but did not impact Go/no Go decision for clinical phase.
- Author revised approach for CNS testing needs and suggests adjusting CB based on whether drug penetrates CNS.
- This approach for FOB testing could reduce animal needs up to 24 rats/study.
Reevaluating CB – Respiratory functional testing:
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- Animal needs based on this little concordance could represent 30 rats less for study.
- Even though it is suggested to scale down plethysmography studies, running them can be useful if studied drug pharmacology suggests it.
Conclusions
After reviewing 105 small molecule development’ scientific brochures, the author made apparent, relevant limitations to predict AEs in the clinical phase: 21% of rodent CNS evaluations and 28% of plethysmography data, failed to alert moving to FIH.
The phase I dose escalation includes a safety/tolerability/PK before going to the next dose. The drug’s pharmacology could determine case-by-case decisions.
Low IC50 in hERG assay had little correlation with animal data. The suggestion step forward is to include multiple channels assessment also called CiPA paradigm.
The key challenges in preclinical assessments were described (Avila et al, 2020) as
- Improve pro-arrhythmic risks identification while avoiding dismiss potentially useful drugs.
- Make CB CNS screens more quantitative and objective measures.
- Standardize CB protocols/statistical approaches to allow comparisons.
- Improve higher cognitive function and sensory specificity testing.
- Replace tests with detailed clinical observations and appropriate measurement in non-rodents.
CNS and respiratory tests with rodents have limited use and their re-evaluation would contribute to 3R perspective.
In summary, we need to revisit the CB to look for better and more predictable tests to gain common objectives from both developers and regulatory Agencies.