Module 9 2024
03/09/2024
Nonclinical testing of biologics Repeat dose toxicology study design
Study parameters :
• Clinical signs, body weight, food consumption
Ophthalmoscopy
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• Safety Pharmacology - ECG, Blood pressure, heart rate, respiration, FOB
• Haematology & clinical chemistry
• Pathology including injection site (local tolerance) & other selected organs (e.g. lymphoid organs)
Immunotoxicology • Minor to comprehensive depending on target and mechanism of action • Endpoints include haematology, flow cytometry and immune function tests
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• Case-by-case assessments eg cytokines, complement, acute phase protein
ECG = Electrocardiogram; FOB = Functional observation battery, assessing neurological effects
The Organisation for Professionals in Regulatory Affairs
Preclinical Testing of Biologicals – Sept 2024
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Nonclinical testing of biologics Repeat dose toxicology study design
Pharmacokinetics (PK) and Pharmacodynamics (PD) :
• Relationship between PK and PD is essential component of biologics tox
• Essential to interpret toxicity and/or exaggerated pharmacology
• Used to determine safe human starting dose and likely efficacious dose
• Exposure may have different time course to PD effect (e.g. Rituximab; Diagram from Hausler et al, 2018 shows prolonged PD in mice → Significantly longer in human) • For mAbs, long half-life provides prolonged exposure and thus less frequent dosing than small molecules • Human T½ approx. 18-22 days → Typically only need to dose once every 4 weeks • Primate 7-14 days • Rat 3 - 5 days
The Organisation for Professionals in Regulatory Affairs
Preclinical Testing of Biologicals – Sept 2024
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