WG6 Nonclinical - Endpoint Predictivity
Vision
With the requirements for submission of nonclinical data in a standard electronic
format (SEND) contained in PDUFA V, we expect that the problem of compilation
and exploration of large sets of nonclinical data will become tractable in the near
future. We hope to utilize this data in a number of ways, including (but not
limited to):
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Enable better prediction (informing both drug development studies and
the clinical protocols and monitoring)
Build analysis panels for certain types of concerns
Enable better study design (endpoints, timing of collection, etc)
Reduce or streamline study endpoints or types based upon evidence
Identified Projects/Pilots/Activities
The current plan is to develop 3 scientific questions/use cases for piloting/further
work. Our high level questions currently are:
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Use Case 1: Do hERG changes in nonclinical models correlate with x, y or
z clinical effects?
o Refined: When a significant change in clinical BP (diastolic or
systolic) at the maximum effect time point is observed, what is the
mean BP change relative to the reference group in dog safety
pharmacology studies at the maximum effect time point?
Use Case 2: Do transaminase changes in rodents correlate with changes
in transaminases in humans?
Use Case 3: Are newer kidney biomarkers (e.g. KIM1) more predictive of
clinical effects than classic renal injury biomarkers (e.g. creatinine, BUN)?
Use Case 4: Do / Which CNS findings in nonclinical species translate to
clinical observations?
Draft project proposal Use Case 4: Do/Which CNS findings in nonclinical
species translate to clinical observations
The majority of marketed CNS compounds are basic (containing ionizable
nitrogen atom) or neutral. Those compounds are known to interfere with
the potassium (e.g.hERG and other ion channels). Quantitatively there
relationships between lipophilicity, amphiphilicity and ion channel affinities
described, allowing a rough estimate of potential of clinical side effects
and an optimization of drug safety profiles at the discovery stage in
parallel to biological activity (to be further supported by additional
studies).
Among others major side effects of CNS compounds include
convulsions/seizures[1] and tremors as well as blood pressure and heart
rate[2] modulations.
Therefore it’s especially of interest for CNS compounds, if CNS findings as
convulsion/seizures or tremors in animal studies translate to
seizures/convulsions in clinics:
Do convulsions/seizures seen in rodent (non -rodent) repeat-dose studies translate to
seizures in the clinic? If yes, what is the percentage of time that they translate? Do
convulsions in rodent repeat-dose studies translate to other observations in the clinic?”
and
if preclinical findings for CNS compounds regarding blood pressure (see
use case 1) and heart rate modulations translate to clinical findings and
are related to specific compound characteristics.
Do side effects on heart rate, ECG seen in rodent (non-rodent) repeat-dose studies for CNS
compounds can be confirmed in clinics? If yes, what is the percentage of time that they
translate? Are there relationships to their overall physicochemical, structural characteristics as
for hERG affinity.
Literature
[1] . Do preclinical seizure models preselect certain adverse effects of
antiepileptic drugs. Meldrum, Brian. Epilepsy Research (2002), 50(1-2),
33-40. | Language: English, Database: CAPLUS
[2] Effects of Paroxetine and Venlafaxine XR on Heart Rate Variability in
Depression. Davidson, Jonathan; Watkins, Lana; Owens, Michael;
Krulewicz, Stan; Connor, Kathryn; Carpenter, David; Krishnan, Ranga;
Nemeroff, Charles. Journal of Clinical Psychopharmacology (2005), 25(5),
480-484.