Through an in-depth literature review, study of pharmacokinetic information obtained from approved ADC medications, and a comprehensive summary of research knowledge, we have established four distinct prerequisites for ADC pk study:
- Proficiency in conducting pharmacokinetic (PK) studies of both small and big substances is necessary.
- ADME and bioanalysis necessitate extensive capabilities and facilities, encompassing the capacity to conduct studies on both large and small animals, analyze big and tiny compounds, do in vitro drug-drug interaction studies, identify metabolites through in vitro and in vivo methods, and handle radiolabeled ADME.
- It is imperative to tailor the overall strategy for pharmacokinetic (PK) investigations and the individual protocols based on the composition of the antibody-drug conjugate (ADC) and the requirements for the efficacy and safety of novel medications.
- The ADC PK study necessitates exceptional project administration proficiency, together with the aptitude to synchronize and cooperate across various departments.
The ADC PK study have been classified into four primary domains: in vitro DDI, ADME, PK, and bioanalysis. Each of these factors is of great importance in the process of drug exploration, pre-clinical advancement, and clinical phases.
Correlation between the ADC payload discharge and the toxicity of ADC, along with DDI:
The relationship between the discharge, metabolism, and disposal of ADC payloads in non-targeted host-tissues and ADC toxicity and drug-drug interactions(DDI) is significant. ADCs can be categorized into two structural types: cleavable ADCs, which discharge payloads through the action of lysosomal enzymes or under an acidic environment, and the liberated payloads have a distinct structure. Another type of ADCs is non-cleavable, which means they do not break down. These ADCs discharge payloads that are attached to incomplete sequences of peptides or amino acids. However, the specific structures of the metabolites connected to these payloads are yet unclear.
Exposing the liberated ADCs payloads to non-targeted tissues may result in toxicity. If the digestion or disposal of such ADC payloads is influenced by inhibitors of metabolic enzymes, their overall exposure in the body would rise, leading to hazardous effects.
In the case of cleavable ADCs, the metabolic mechanism of ADCs under in vitro conditions is employed to assess if the payloads are liberated in accordance with the design of the ADC. In the case of non-cleavable ADCs, proteolysis is employed by the metabolic system to detect metabolites associated with the payload.
Final Thoughts:
If the detection of liberated tiny molecules is achieved and there is existing PK study or data for those molecules, conducting DDI and ADME studies for the payloads is superfluous. Nevertheless, a novel payload is required to carry out a sequence of investigations. These studies mostly concentrate on two things. The 1st objective is to identify the metabolites of ADC payloads, which involves comparing in vitro metabolites in various species, conducting animal ADME studies, and identifying small molecule metabolites in plasma of human beings. The 2nd objective is to conduct in vitro drug-drug interaction (DDI) studies, which include assessing the activation and suppression of CYP450 enzymes, phenotyping metabolic enzymes, and evaluating the suppression or substrate properties of drug transporters. The findings of such investigations establish a solid foundation for the advancement and approval of ADCs, including recommendations for the identification of harmful species, investigation of genetic variations in metabolic enzymes, design of clinical drug-drug interaction studies, and research on specific demographic groups.
