L8: Safety pharmacology and toxicology part 3

Question 1

CV assessment

Answer 1

Blood pressure, heart rate and ECG intervals as a minimum, with inotropy a common extra

Drugs that increase blood pressure are not tolerated for most therapeutic indications

Even very small increases in blood pressure (5mmHg) over time cause increased incidence of stroke, coronary heart disease and heart failure

Only chemotherapeutic agents – e.g. Sutent (sunitinib) – are permitted to increase BP

CV assessment: Torsades de Pointes (TDP)
Big issue for pharmaceutical industry
Because TDP a rare but lethal ADR

QT prolongation in vivo a good biomarker
But this is slow and expensive
Dog telemetry done just before FIH

HTS sought (biomarkers)
IKr screen (hERG) done GLP
However IKr block does not always lead to TDP (ranolazine)

Question 2

CV assessment: types of method

Answer 2

In vivo
Whole animal, e.g. rat*, dog monkey
Anaesthetised or conscious
ECG, haemodynamics
Complex measures e.g. organ blood flow
*Never for TDP liability test
Tissue based
Whole heart, Purkinje fibre, ‘wedge’ prep
Measures action potential
Cell based
Cardiac ion chanels e.g. IKr (hERG)
Patch clamp (manual or automated)
Measure block or opening of individual ion channel

Question 3

cardiovascular assessment in conscious telemetered animals

Answer 3

Permanently implanted
Allows free roaming animals
Battery life 2 years continual use

Reliable signal for BP and LVP
Stable, consistent ECG

Standard in dogs just before FIH
Now available for small animals for early safety assessment

Question 4

possible CNS ADRs

Answer 4

• Lethargy
• Anorexia / weight gain
• Personality changes
• Sedation
• Dizziness
• Anxiety
• Drowsiness
• Nausea
• Disorientation
• Cognitive impairment
• Insomnia
• Sexual dysfunction
• Amnesia
• Involuntary movements
• Auditory dysfunction
• Motor in-coordination
• Depression
• Visual disturbance
• Tremor
• Autonomic effects
• Abuse potential
• Seizures
• Hallucinations
• Suicidal ideations
• etc…

Question 5

CNS ADRs

Answer 5

Most impact “quality of life” rather than “risk to life”

But some are life-threatening:
Decreased respiratory drive – respiratory arrest
Decreased sympathetic outflow – cardiovascular collapse
Loss of consciousness, seizures, convulsions

Some are indirectly life-threatening:
Drowsiness, cognitive impairment, motor inco-ordination, dizziness, visual disturbance – can affect e.g. driving performance

Question 6

approaches to studying ADRs in nervous system

Answer 6

Neuronal cultures
In vitro electrophysiology (ion channels; neurons; slices)

Behavioural/neurological assessment
Physiological recording (e.g. EEG; nerve conduction velocity)
Biochemical recording (e.g. in vivo microdialysis; biomarkers)
Imaging (e.g. MRI; MRS; PET; SPECT)

Core battery
Motor activity, behavioural changes, coordination, sensory/motor reflex responses and body temperature

Done as ‘Functional Observation Battery (FOB)’ aka the modified Irwin’s test (J Pharm Tox Methods 82:90-108, 2016)

Follow-up
Behavioural pharmacology, learning and memory, ligand-specific binding, neurochemistry, visual, auditory and/or electrophysiology examinations, etc.
Histopathology
(very much part of ‘toxicology’ …)

Question 7

PK properties influence ADR risk

Answer 7

e.g., The reason for the lack of sedation with second generation antihistamines is their low brain penetration