Module 9 2021

22/03/2021

Preclinical testing of biologics Repeat dose toxicology study design

Study parameters : • Clinical signs, body weight/temperature • Ophthalmoscopy • ECG, Blood pressure, heart rate, respiration, FOB • Haematology & clinical chemistry • Pathology incl. injection site (local tolerance) & other organs of interest (e.g. lymphoid organs) • Immunotoxicology • Minor to comprehensive depending on target • Endpoints include haematology, flow cytometry and immune function tests • Case-by-case assessments eg cytokines, complement, acute phase protein

Preclinical testing of Biologics – March 22 nd 2021

The Organisation for Professionals in Regulatory Affairs

11

Preclinical testing of biologics Repeat dose toxicology study design

Pharmacokinetics and Pharmacodynamics : • Relationship between PK and PD is essential for NBEs

• Essential to interpret toxicity and/or exaggerated pharmacology • Used to determine human starting dose and efficacious dose

• Exposure may have different timecourse to PD effect (e.g. Rituximab; Diagram from Hausler et al, 2018 shows prolonged PD in mice) • For mAbs, long half-life provides long exposure with less frequent dosing than a small molecule • Human T½ approx. 18-22 days • Primate 7-14 days • Rat 3 - 5 days

Preclinical testing of Biologics – March 22 nd 2021

The Organisation for Professionals in Regulatory Affairs

12

6