Antibody drug conjugates (ADCs) are complex molecules in which monoclonal antibodies and cytotoxic drugs (small molecule payloads) are linked by linkers to form conjugates. In 2000, the FDA approved the first ADC Gemtuzumab ozogamicin (Mylotarg) for the treatment of CD33-positive acute myeloid leukemia. Mylotarg was withdrawn from the market in 2010 due to adverse events, particularly liver side effects, and was subsequently approved in 2017. Since the approval of Mylotarg in 2000, pharmaceutical companies have been very focused on the development of ADCs.
ADCs combine the selectivity of antibodies with the efficacy of small-molecule drugs, enabling more precise and targeted therapeutic applications. ADC has three components: monoclonal antibody, payload and linker. All three components are very important when designing an ADC. In modern drug development, pharmacokinetics (PK) plays an important role in designing safe and effective doses to treat diseases. Several factors can alter the PK of a drug, including “intrinsic” and “extrinsic” factors. For small molecules, the influence of both internal and external factors is well established. It is well known that age, gender, disease state (eg, kidney and liver damage), drug-drug interactions, etc. all have an impact on small molecule PK. For macromolecules, the influence of these factors has not been well established. Since ADCs are combined products of monoclonal antibodies linked to small molecules, the small molecules and monoclonal antibodies of ADCs may be affected by many intrinsic and extrinsic factors.
Intrinsic Factors Affecting ADC PK
Intrinsic factors are factors related to the individual. For example, age, gender, genetics, and disease status are all intrinsic factors. External factors are external influences. For example, drug-drug interactions, food or drink, smoking, malnutrition, and other environmental factors.
Based on the 10 FDA-approved ADCs, the overall conclusion on age differences between older adults and younger adults is that there are insufficient data to determine PK differences between these two age groups, and population pharmacokinetics (POPPK) cannot Differences in PK were detected, with no clinically meaningful PK differences between the two age groups.
Gender and race
Gender did not have any clinical effect on PK, and POPPK could not detect differences in PK, or no information was available. EMA noted that “an adult population model showed no significant effect of race on Mylotarg’s PK”. Furthermore, it should be noted that the sample size based on race was not sufficient to determine the effect of race on Mylotarg PK in the POPPK study.
For all 10 ADCs, the FDA’s drug label did not provide any pediatric PK information. To date, only two PK studies of ADCS have been conducted in pediatrics.
Buckwalter et al studied the PK of Mylotarg in children with relapsed or refractory AML. Plasma samples were analyzed for antibody fractions and small molecule payloads using a validated enzyme-linked immunosorbent assay (ELISA) method. Children aged 1 to 16 years, the dose is 9mg/m2. There were two infants (ages 0-2), five children (ages 3-11) and seven adolescents (ages 12-16). PK parameters were assessed by non-compartmental analysis: Mylotarg clearance was 30 mL/h, 60 mL/h, and 260 mL/h in infants, children, and adolescents, respectively, and 270 mL/h in adults. Steady-state volumes of distribution (Vss) were 2.9 L, 3.9 L, and 9.4 L for infants, children, and adolescents, respectively, while the adult Vss was 20 L. Despite the small sample size, studies have shown that the PK of Mylotarg varies with age in the pediatric population.
In addition, Flerlage et al conducted a POPPK study of Adcetris in 16 children (6-18 years) with Hodgkin lymphoma. Compared with adults, the AUC and Cmax of pediatric Adcetris were 25% and 11% lower, respectively. The greatest effect of age on drug PK generally occurs in younger age groups (≤5 years).
The payload of an ADC is usually a small molecule, and from experience with small molecules, small molecules excreted through the kidney can have an impact on PK (higher exposure or lower clearance) upon kidney injury. With the exception of Adcetris, the effects of severe renal impairment were not studied for the other nine ADCs.
In one study, subjects with normal renal function (n=8), mild (n=4), moderate (n=3) and severe (n=3) were treated with Adcetris at a dose of 1.2 mg/kg. n=3) PK assessment of small molecule MMAE was performed in patients with renal impairment. The results showed that the AUC of ADC was 7%, 22% and 71% lower in subjects with mild, moderate and severe renal impairment, respectively, compared to subjects with normal renal function. MMAEAUC in patients with mild and moderate renal impairment was comparable to that in patients with normal renal function. In subjects with severe renal impairment, the AUC of MMAE was almost twice that in subjects with normal renal function.
Currently, most studies have been conducted on patients with mild hepatic impairment, and no differences have been found between subjects with normal liver function and those with mild hepatic impairment. With the exception of Adcetris, there are no data on subjects with severe hepatic impairment.
In one study, subjects with normal liver function (n=8), mild (n=1), moderate (n=5) and severe (n=5) were treated at a dose of 1.2 mg/kg 10) A PK study of Adcetris was performed in patients with liver injury. The results showed that the AUC of ADC was reduced in patients with hepatic impairment. Compared with subjects with normal liver function, the AUC of subjects with mild, moderate and severe hepatic impairment was 57%, 65% and 71%, respectively. The AUC of MMAE was 3.5, 2.2 and 1.77 times higher in patients with mild, moderate and severe liver injury, respectively.
As with renal impairment, if substantial exposure of the ADC payload is found in patients with hepatic impairment, the drug should not be completely avoided in patients with moderate or severe hepatic impairment, thereby depriving the patient of the therapeutic benefit of the ADC, and dose adjustment of the ADC should be considered .
External factors affecting ADC PK
Drug Interaction Studies
With the exception of TRODELVY, drug interaction studies with ADCs have been performed reasonably well and are described in the drug labeling. For TRODELVY, no drug interaction studies have been conducted.
As can be seen from the FDA drug labeling, at least nine ADCs have undergone immunogenicity studies (except Mylotarg). For Mylotarg, the European Medicines Agency’s assessment report indicated that the incidence of anti-antibodies (ADA) following Mylotarg treatment was <1% in four clinical studies. Overall, the immunogenicity rate of approved ADCs does not appear to be high. The effect of anti-antibodies on PK, efficacy, and safety remains unknown.
The effect of pregnancy on the PK, efficacy and safety of ADCs was not specifically assessed. The drug label for the ADC provides a general statement: “Based on its mechanism of action, ADC may cause embryo-fetal damage when administered to a pregnant woman because it contains a genotoxic compound and affects the active division of cells”. There are no data on the use of ADCs in pregnant women to assess drug-related risks.
There are no specific studies on ADCs or their metabolites in breast milk. For some ADCs, a time frame is prescribed that the child should not be breastfed for at least weeks or months after the mother’s last dose of the ADC. The FDA also emphasized that “the decision to discontinue nursing or to discontinue medication should take into account the importance of the drug to the mother.”
It is well known that intrinsic and extrinsic factors often have a significant impact on the PK of small molecules, but the impact of these factors on macromolecules has not been comprehensively studied. Since ADCs are the combined products of macromolecules (monoclonal antibodies) and small molecules (payloads), it is important to study the effects of internal and external factors on the PK of these two molecules.
Attempts have been made to determine the effect of intrinsic and extrinsic factors on ADC PK through population pharmacokinetics. It is recognized, however, that in order to detect the effect of covariates on PK parameters from POPPK, the sample size should be sufficient. Currently in many cases, such as age, gender, severe liver and kidney impairment, and drug-drug interaction studies, the sample size is insufficient to examine the effects of intrinsic and extrinsic factors on the PK of these ADCs. Therefore, more rigorous research is needed in these areas.
Some ADCs (blenrep, adcetris, padcev, trodelvy, enhertu, and zynlonta) received conditional approval from the FDA with a statement that “accelerated approval for this indication is based on tumor response rate and duration of response. Continued approval for this indication may depend on Validation and description of clinical benefit in confirmatory trials”. This can be a risky approach, and only time will tell if this approach to approving marketed drugs (conditional approval) is appropriate.
In short, ADCs are effective drugs for the treatment of cancer. However, the development and approval of ADCs requires a more rigorous approach. The influence of intrinsic and extrinsic factors should be rigorously evaluated in order to select the optimal dose for a patient or patient population with a specific background.
1. Effect of Intrinsic and Extrinsic Factorson the Pharmacokinetics of Antibody–Drug Conjugates (ADCs). Antibodies (Basel). 2021Dec; 10(4): 40.