Review Khot, Sharma & Shah A ADC sub-model p.o. Qpv Liver CL Hepatic clearance B Plasma B cells Lymph Node
Lung Heart Kidney Muscle Skin
Liver Brain
Adipose Thymus Bone Other Tumor
Plasma/blood flow Lymph flow
Other = stomach + bladder + gallbladder + thyroid...
Figure 5. Tissue PK models of antibody–drug conjugates. (A) Minimal PBPK model developed by Chen et al. to characterize the plasma PK of MMAE containing ADCs (anti-CD22-vc-MMAE and brentuximab-vedotin). The PBPK model has two submodels. The ADC submodel is for characterizing the systemic PK of ADC that is represented as antibody conjugated MMAE (acMMAE) concentrations. The payload submodel is for characterizing the systemic PK of unconjugated MMAE. (B) Representative structure of mAb PBPK model employed by Zhao et al. to characterize the systemic PK of anti-CD70 ADC. (C) Tissue level schematic of the PBPK model developed by Zhao et al. to characterize the disposition of anti-CD70 ADC SGN-75 and its released drug cys-mcMMAF in tissues and the tumor of a xenograft bearing mice. ADC: Antibody–drug conjugate; CL: Clearance; k: Transfer rate constant to a particular compartment; MMAE: Monomethyl auristatin-E; PBPK: Physiologically based PK; p.o.: Per-oral route of administration; PV: Portal vein; Q: Blood flow to a particular compartment. (A) Adapted from [21]. (B) Adapted from [23]. (C) Adapted from [22].
the released drug in the clinic, the model needs to be build and validated using the preclinical data. Therefore, the tissue concentrations data for the intact ADC and the released drug is required to build such models. It is technically challenging to employ ELISA or LC–MS-based methods to quantify ADC and unconjugated drug PK in tissues, and hence these studies are mostly performed using radiolabeled materials [15]. One such elegant study has been per- formed by Alley et al. [15] who investigated the tissue disposition of anti-CD70-mcMMAF ADC in tumor bearing mice, by labeling the mAb with 3
H and the 1640 Bioanalysis (2015) 7(13) drug with 14 C. They administered the dual radiola-
beled ADC to mice and analyzed the samples using a dual channel liquid scintillation counter to obtain total antibody and total MMAF concentrations. Zhao et al. [22] characterized the data using the PBPK model shown in Figure 5B & C. They employed an established PBPK model developed for mAb to char- acterize the PK of ADC [23,24], and then developed a separate small molecule PBPK model for the uncon- jugated drug cys-mcMMAF. Partition coefficients of cys-mcMMAF between plasma and different tissues were estimated, and cys-mcMMAF was assumed to
future science group Renal clearance C ADC Drug release ADC
S.I.=Du+Je+lle L.I.=Ce+Co Spleen
Pancreas Tumor Clearance
Clearance (tumor)
Tumor
Clearance (liver)
Convection
Lymph flow ADC + CD70
ADC–CD70 complex
Drug release Blood flow
Drug Diffusion
Drug + tubulin Blood flow Unconjugated drug
Qha Qh
Portal vein Qpv kout Central compartment kin IV Hepatic clearance (CYP3A metabolic CL + biliary CL) Liver Qh
Peripheral compartment
Qh kout Payload sub-model
Peripheral compartment
kin
Unconjugated MMAE in central compartment
CL acMMAE
Drug– tubulin complex
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