Models in a biological or physiological system at best are an approximation and the most simplistic form of describing the biological or physiological processes

Models in a biological or physiological system at best are an approximation and the most simplistic form of describing the biological or physiological processes. impact of both intrinsic and extrinsic factors is usually well established. The impact of age, gender, disease says such as renal and hepatic impairment, drugCdrug interaction, food, and in many cases alcohol around the PK of small molecules are well known. On the other hand, for macromolecules, the impact of these factors is not well established. Since the ADCs are a combination product of a monoclonal antibody linked to a small molecule, both the small molecule and the monoclonal antibody of the ADCs may be subjected to many intrinsic and extrinsic factors. This review summarizes the impact of intrinsic and extrinsic factors around the PK of ADCs and the payloads. Keywords: antibodyCdrug conjugates, pharmacokinetics, intrinsic and extrinsic factors, monoclonal antibodies, small molecule or payload 1. WT1 Introduction Monoclonal antibodies (mAbs) are widely used therapeutic agents to manage or cure a wide variety of diseases, especially in hematology and oncology. Although mAbs have shown therapeutic benefit in the field of oncology, these antibodies either do not have the optimal clinical efficacy or have to be co-administered with traditional chemotherapy. Therefore, in order to enhance the therapeutic benefit, there are efforts to enhance the efficacy of antibodies by forming a conjugate [1,2]. AntibodyCdrug conjugates (ADCs) are complex molecules wherein a monoclonal antibody is usually linked to Caudatin a biologically active drug (a small molecule), forming a conjugate [1]. In 2000, the US FDA approved the first ADC Gemtuzumab ozogamicin (trade name: Mylotarg) for the treatment of CD33-positive acute myelogenous leukemi [1]. MYLOTARG was withdrawn from the market in 2010 2010 due to adverse events, particularly hepatic side effects. It was then approved in 2017. Since the first approval of MYLOTARG Caudatin in 2000, there has been enormous focus by the pharmaceutical companies to develop ADCs to treat a wide variety of diseases. Initially, most of the ADCs were developed and are being developed for the treatment of malignancy; however, with time, it has been realized that ADCs can also be developed to manage or cure other diseases such as inflammatory diseases, Caudatin atherosclerosis, and bacteremia [2]. The main objective of an ADC as a cancer agent is to release the cytotoxic drug to kill the tumor cells without causing any harm to the normal or healthy cells. ADCs combine the selectivity of antibodies with the efficacy of small-molecule drugs, leading to more precise and targeted therapeutic applications. There are three components of ADCs: a mAb, a cytotoxic drug (small molecule drug also known as payload), and a specialized chemical linker which connects the mAb with the small molecule [3]. All these three components are very important in designing an ADC. The antibody portion of an ADC targets Caudatin a specific antigen only found on target cells. Once it binds to the cell, it delivers the payload with a very high specificity to the diseased cells, maximizing their efficacy and minimizing systemic exposure. Payload is the crucial part of an ADC with cytotoxic capability. Payloads for ADCs can be small molecules, protein toxins, and peptides [3]. Since the ADCs are complex compounds, several analytes or moieties are found in the blood which can be detected by the available analytical methods. The analytes that are generally measured are: the conjugated antibody or ADC (antibody with drug), the total antibody (conjugated, partially de-conjugated, and fully de-conjugated), the antibody-conjugated drug (the small molecule drug conjugated to antibody), the un-conjugated drug (small molecule drug not conjugated to antibody), and possibly metabolites of the small-molecule drug including or not part of the linker [3]. In modern day drug development, pharmacokinetics (PK) plays an important role in designing a safe and efficacious dose to treat a wide variety of diseases. PK is a quantita-tive analysis of how living systems handle a molecule after its administration into a living organism. Pharmacokinetics is the study and characterization of the time course of drug absorption, distribution, metabolism, and excretion (ADME) [4]. The main objective of a PK study is to obtain information regarding ADME of a molecule [4]. These pharmacoki-netic parameters can then be used to design an optimal dosing regimen to facilitate Phase II and Phase III clinical tests [4]. The PK parameters could be linked also.