Biologics 2 PDF

Biologics 2 ADME of MAbs Rob Thatcher, 2024 Based on lectures by Ana Abdala Sheikh ADME of MAbs Absorption - Intravenous Functional proteins seldom survive the GI tract - acidi cation, proteases etc. 2 principal routes of administration; Intravenous (IV) Rapid exposure and onset of e ects D...

Biologics 2 ADME of MAbs Rob Thatcher, 2024 Based on lectures by Ana Abdala Sheikh ADME of MAbs Absorption - Intravenous Functional proteins seldom survive the GI tract - acidi cation, proteases etc. 2 principal routes of administration; Intravenous (IV) Rapid exposure and onset of e ects Direct to circulatory system Controlled administration in clinical setting ff fi ADME of MAbs Absorption - Subcutaneous Functional proteins seldom survive the GI tract - acidi cation, proteases etc. 2 principal routes of administration; Subcutaneous Must be injected into skin - side e ects Limited to small volumes Self-administration ff fi ADME of MAbs Absorption - Subcutaneous, site of absorption The extracellular matrix is negatively charged and is less permeable to negatively charged IgG ADME of MAbs Absorption - Subcutaneous, E ect of MW on route of absorption IgG MW ~150 kDa ff ADME of MAbs Absorption - Subcutaneous, Factors that a ect absorption ff ADME of MAbs Absorption - Subcutaneous, Factors that a ect absorption ff ADME of MAbs Distribution - From blood vessels to interstitial space  ADME of MAbs Distribution - From blood vessels to interstitial space Blood Vessel Passive paracellular diffusion trancytotic vesicles Through Junction Endothelial Cell Transmembrane Transport Proteins (Passive) Diffusion Most MAbs distribute into tissues this way Interstitial Space ⬇︎⬇︎ ADME of MAbs Distribution - Paracellular di usion depends on the type of vasculature CNS is typically impermeable to most MAbs ff ADME of MAbs Distribution - MAbs can exhibit accumulation in diseased tissue ADME of MAbs Recycling - The neonatal Fc receptor (FcRn) ADME of MAbs Recycling - The neonatal Fc receptor (FcRn) ADME of MAbs FcRn recycling increases t1/2 of MAbs ADME of MAbs IgG trapped in kidneys are removed by FCRn ADME of MAbs Elimination by pinocytosis ADME of MAbs Elimination by receptor-mediated endocytosis Leucocytes Endothelial Cells ADME of MAbs Clearance via speci c binding is saturable Rituximab shows biphasic PKs fi ADME of MAbs Target-mediated drug deposition ADME of MAbs MAb fragments undergo renal excretion Renal ltration cut o in humans 50 kDa ff fi ADME of MAbs PEGylation increases t1/2 of Fab fragments  ADME of MAbs E ect of MAb conformation on PK pro le ff fi Therapeutic Antibodies can be Immunogenic The immune system can generate Antibodies that recognise MAbs Therapeutic Antibodies can be Immunogenic MAb aggregates are highly immunogenic Summary Factors a ecting ADME of MAbs Drug-speci c factors – Molecular weight/structure/charge – Glycosylation/PEGylation – FcRn and FcγR binding – Immunogenicity – Mode of action Patient-related parameters – Route/site of administration – Blood ow, interstitial volume pressure – Target tissue – Disease status (e.g. vascular permeability increased in in amed tissue) – Target expression and distribution (TNFα highly expressed in in amed tissue) fl ff fi fl fl