Table 1.

Comparison from kinetic and clinical pharmacology aspects of small molecules, monoclonal antibodies, and T cell therapies

	Small molecule	Monoclonal antibody	T cell therapy
Pharmacokinetic/cellular kinetic aspect
Absorption	Intestinal absorption if p.o.	Injection site absorption if s.c. or i.m.	Only relevant if regional delivery
Distribution	Various tissues/organs Many distribute intracellularly	Mainly limited to plasma, interstitial fluid, lymphatic system, and endothelial system TMDD Liver and reticuloendothelial system	T cells may traffic to secondary lymphoid tissues, general tissues, and tumor sites
Metabolism/catabolism	CYP enzyme‐mediated metabolism Transporter‐mediated uptake/efflux can be the rate‐determining step	Catabolism No CYP enzyme‐mediated metabolism	No enzyme‐mediated metabolism or proteasome/lysosome‐based catabolism
Excretion	Renal and biliary	Not applicable	Not applicable
CL	Dose/AUC	Dose/AUC	Not applicable T cells actively proliferate T cells may die through natural or contact‐induced apoptosis
t1/2	Hours	Days to weeks	Months, can be up to years Difficult to determine accurately with sparse sampling in terminal phase Difficult to interpret with potentially ongoing re‐activation
Clinical pharmacology consideration
Route of administration	Oral, i.v.	i.v., s.c., i.m.	i.v., regional
Dose frequency	Hourly to daily	Weekly to monthly	Often once in a lifetime
Dose proportionality	Mostly linear Nonlinear if complicated absorption or enzyme/transporter saturation	Mostly linear at high dose Usually nonlinear at low concentration (TMDD)	Not well established
Bioanalysis	Analyte: drug and metabolite Method: LC‐MS	Analyte: antibody and anti‐drug antibody Method: ELISA	Analyte: transgene, cell count, anti‐drug antibody Method: qPCR, flow cytometry, cell‐based and non‐cell‐based assays
Food/ARA effect	Yes	Not applicable	Not applicable
Formulation/excipient effect	Yes	May affect ka and F for s.c. or i.m.	Not applicable
DDI	CYP enzyme/transporter‐mediated inhibition and induction	Reversal of inflammatory disease state may indirectly cause DDI	Cytokine release may indirectly cause DDI
hERG and cardiotoxicity	Yes	Unlikely	Elevated cytokine; Cross‐reactivity with epitope derived from protein expressed by cardiac tissue
Organ impairment	Yes	No	Unlikely
Immunogenicity	No	Yes	Yes
PK/PD relationship	Drug exposure at the site of action (plasma, interstitium, and intracellular space) drives PD PD typically does not affect PK	Drug exposure at the site of action (mainly plasma and interstitium) drives PD Target may also affect PK via TMDD	Cell exposure at the tumor site (blood, interstitium, lymph, and lymphoid tissues) drives PD Target also affects T cell proliferation via antigen stimulation

ARA, acid reducing agent; AUC, area under the curve; CL, clearance; DDI, drug‐drug interaction; ELISA, enzyme‐linked immunosorbent assay; F, bioavailability; hERG, human ether‐à‐go‐go‐related gene; k_a, absorption rate constant; LC‐MS, liquid chromatography mass spectrometry; PD, pharmacodynamics; PK, pharmacokinetics; qPCR, quantitative polymerase chain reaction; t_1/2, terminal half‐life; TMDD, target‐mediated drug disposition.