Week 3 Flashcards
(23 cards)
Non-Clinical (NCL) Studies
Use at Early and/or Late Stages of Product Development.
in vitro, in vivo, ex vivo safety studies
For in vivo (animal) models use SAME route of administration as
intended for clinical use, where possible
NCL studies inhalation formulation
animal inhalation chambers delivered in spray for continuous exposure. Nose only chambers.
Can calculate - Purity level, flow rate, body weights, duration of exposure
Animal Testing design
Chose relevant species/strain.
Select age, route of administration, lab conditions, formulation research
controls, duration, ethic approval
Animal dosing methods (liquid oral)
For Rat & Mouse: Gavage dosing with tube or catheter
– For Dog: Gavage dosing with stomach tube
– For NH Primate: Gavage dosing with stomach tube under restraint
Animal dosing methods (solid oral)
– For Rat & Mouse: powder in diet
– For Dog: Several tablets in larger capsule
– For Dog: Several small capsules in larger capsule
Animal dosing methods (IV)
For Rat & Mouse: May be high concentration liquid; careful iv injection into tail
vein; also can use jugular vein
– Dog & NH Primate: Cephalic vein or saphenous vein for iv delivery
Major Milestones in Pharmaceutical Product Development - stage 1
Stage 1 Development:
* Process Development & Manufacturing scale-up
* Product Formulation Research
* Nonclinical (NCL) Studies to support first-in-human clinical trial
* Phase 1 Clinical Trial (usually in healthy volunteers, PK, Safety
Major Milestones in Pharmaceutical Product Development - stage 2
Stage 2 Development:
* Further Process Refinement & Manufacturing Scale-up
* Refining Product Formulation
* NCL Studies to support early efficacy & dose ranging clinical trials
* Preparation of Technical Dossiers, Regulatory Applications, Evaluation & Regulatory Approvals
* Phase 2 (a/b) clinical Trials (dose ranging, PK, Efficacy, Safety assessments
Major Milestones in Pharmaceutical Product Development - stage 3
Large Scale manufacture of API/DS & Drug Product
– Completion of NCL programme for Phase 3 Clinical Trials & Product Registration
– Updates to Technical Dossiers, Regulatory Applications, Evaluations & Regulatory Approvals for Pivotal Clinical Trials
– Phase 3 Clinical Trials to confirm Dose, Efficacy & Safety of NCE/NME
standard set of respiration and associated parameters that
can be measured in experimental studies
- tidal volume
- rate of respiration
- minute volume
- inspiratory time
- expiratory time
- peak inspiratory flow
- peak expiratory flow
- airway resistance
- pulmonary arterial pressure
- blood gases
- blood pH
- These are ‘ventilatory’ parameters
Experimental methods for investigating drugs on
ventilatory parameters
WHOLE BODY PLETHYSMOGRAPHY (equipment marketed by EMMS)
Recording of essential data in treated and comparator/placebo animals
Advantages are:
- whole animal sits in chamber (rat or mouse)
- conduct of studies in conscious & unrestrained animals
- minimum stress to animals
- no influence of immobilization
PLETHYSMOGRAPHY procedure
Testing process:
- inspiration phase pulls air from within chamber into lung of animal
- this reduces chamber pressure
- simultaneously, as lungs expand with increased air the chamber
pressure is increased
- WBP technique measures the signals created by the differences
between these two processes (flow caused by nasal flow & thoracic movement)
- signal is picked up through electrical amplification and digital
acquisition systems to produce a wave form
- For routine assays after drug/compound administration readings are collected over defined time periods (e.g. 15 min intervals and over 6 hours); calculations are made from tracings
RESTRAINED BODY “HEAD OUT” PLETHYSMOGRAPHY
- uses conscious rats
- head out of the chamber and free but body restrained within a
sealed chamber - pressure differences during inspiration/breathing are monitored
and recorded for calculations of derived parameters
Central Nervous System testing
Different dose levels of the drug/compound are employed in the testing cascade
* Several types of tests & study designs are now available for
assessment of such potential:
- Tests based on the Irwin Protocol (Modified Irwin Test)
- Functional Observational Battery (FOB)
- Other behavioural assessment studies
Modified Irwin Test
- a comprehensive experimental method for a systematic observational assessment of behavioural & physiological responses to drugs
- uses the rodent as the subject model
- and a detailed examination method that also requires training of personnel making the observations (‘observer’)
- integral to the testing design are the physical arrangement of the
observational areas and use of specific equipment and animal cages - uses a scoring system starting from “zero-time” (baseline) and a
direct observation procedure for assessing state/condition of animal
over time after drug administration (behavioural, neurological, autonomic)
Attributes used in the Irwin Protocol
Behavioural:
- spontaneous activity
- motor-affective responses
- sensori-motor responses
Neurological:
- posture
- muscle tone
- equilibrium & gait
- CNS excitation
Autonomic:
- eyes
- secretions & excretions
- respiration rate / arrhythmia
Mortality
Functional Observational Battery (FOB)
- using single dose exposure or multidose exposures
- includes motor activity tests
- a systematic evaluation of nervous system function in the rat
- non human primates may also be used
- variety of clinical observations & measurements for detecting the
functional effects of a
drug/compound on:
general activity
neuromuscular
autonomic
sensorimotor
behavioural
body weight gain - through a series of subjective & quantitative measures
- can address a broad range of neurological functions
- a compendium of CNS tests that operates at the level of hazard
identification
Renal/urinary system
Assessment of urinary enzymes
GRF assessment
blood urine samples (pH, specific gravity, volume, glucose)
Gastro-Intestinal System
gastric secretion, bile secretion, pH, mucosal damage, emptying and motility
Autonomic Nervous System
heart rate variability, baroreflex, automonic nerve stimulation
Effects on Skeletal Muscle
myopathy/myotoxicity.
ultrastructural pathology, electromyography, plasma CK profiling
Endocrine System
gynecomastia, thyroid test, fasting glucose, urine examination, plasma levels, check organ weights and histology of animals
Dependency Potential
A two-tiered approach to nonclinical testing recommended. Trigger for the second tier arising out of any suggestive finding from evaluation of relevant data from initial studies
Tier 1:Any indication from pharmaceutical, pharmacodynamic,
CNS receptor-binding activity, or other CNS-based tests such as FOB, Modified Irwin test for behavioural,
autonomic and neurological assessments data that may
suggest such a potential may exist
Tier 2:Self administration tests, Drug discrimination tests & Physical dependence assays
