Review Khot, Sharma & Shah


A B Dose mAb/ADC


mAb/ADC peripheral


Kdeg


mAb/ADC plasma


Kdis Time units


Parent antibody Total antibody (TmAb) Conjugated antibody (CmAb)


C Dose ADC T-DM1 ADC peripheral ADCClearance Drug peripheral DrugClearance


Figure 2. Plasma PK of antibody–drug conjugates. (A) Profile of all the different formats in which the PK of ADC in plasma is measured and reported. (B) PK model capable of simultaneously characterizing in vivo plasma PK of TmAb and CmAb. (C) PK model capable of simultaneously characterizing in vivo plasma PK of TmAb, CmAb and unconjugated drug. (D) PK model developed by Lu et al. to simultaneously characterize the clinical PK of T-DM1 and trastuzumab. Q is the distributional clearance; CL1 is the deconjugation clearance and CL2 and CL3 are proteolytic degradation clearances. ADC: Antibody–drug conjugate; CmAb: Conjugated antibody; DAR: Drug–antibody ratio; mAb: Antibody; TmAb: Total antibody. (C) Adapted from [8,9]. (D) Adapted from [10].


model shown in Figure 2B, which provides an estimate of in vivo dissociation rate of the drug from ADC (kdis


ADC in vivo. As mentioned earlier, the estimated value of in vivo kdis


Higher the estimates of kdis


establish an in vitro-in vivo correlation for ADC stabil- ity. The PK of released drug in plasma is reported as unconjugated drug concentrations, and it is routinely measured using LC–MS-based methods. The PK of TmAb, CmAb and unconjugated drug can be char- acterized simultaneously using the models similar to the one shown in Figure 2C. Fitting of similar datas- ets using different variations of the model shown in Figure 2C can provide distinct insights into the disposi-


can also be compared with in vitro kdis 1636 Bioanalysis (2015) 7(13) ).


lower the stability of the to


tion of ADC and its components. For example, by fit- ting the model shown in Figure 2C to preclinical plasma PK data for A1mcMMAF and its unconjugated drug cys-mcMMAF, it was demonstrated that the nonspe- cific degradation of ADC contributes significantly more toward the appearance of unconjugated drug in the systemic circulation compared with the dissocia- tion of the drug from intact ADC [9]. The same work also demonstrated that distribution/binding of the unconjugated drug in the peripheral compartment can lead to prolonged exposure of the unconjugated drug in the systemic circulation. Lu et al. [10] employed a similar model (shown in Figure 2D) to simultaneously characterize the clinical PK of T-DM1 and trastu-


future science group ADC plasma DAR kdis Drug plasma CL2 CL3


peripheral (Vp, T-DM1


) QT-DM1 T-DM1 central (Vc ) CL1


Trastuzumab peripheral


(Vp, Trastuzumab ) QTrastuzumab


Trastuzumab central (Vc


) Total trastuzumab Conjugated drug


Drug antibody ratio (DAR) Unconjugated drug


D (used only for ADC)


Molar conc. units


DAR


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