Module 9 2024

03/09/2024

Nonclinical testing of biologics Repeat dose toxicology study design

Study parameters :

• Clinical signs, body weight, food consumption

Ophthalmoscopy

• 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

• 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

15

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

16

8

Made with FlippingBook Online newsletter creator