Ustekinumab and Vedolizumab Drug and Anti-Drug Antibody Monitoring: Analysis of 45,429 Patient Results Using Lab Developed Chemiluminescent Immunoassays
Background:
Therapeutic drug monitoring (TDM) assays are used to optimize therapy of vedolizumab (VDZ), an anti-α4b7 integrin monoclonal antibody, and ustekinumab (UST), the monoclonal interleukin-12 and -23 antagonist. Similar to TDM of TNF inhibitors, drug and anti-drug antibodies (ADAb) are measured in two separate assays that are provided in tandem. Exposure-response relationships have been demonstrated for VDZ and UST in both CD and UC with proposed target trough concentrations of >33-37 ug/mL for VDZ week 6, >15 for week 14 and >10 maintenance and >4 ug/mL for UST maintenance. Here, 23,825 vedolizumab (VDZ) and 21,604 ustekinumab (UST) patient samples were analyzed.
Methods:
Drug and ADAb levels are measured by drug-specific lab-developed chemiluminescent immunoassays. Lower limits of quantitation are 1.3 and 0.1 ug/mL for VDZ and UST, and 25 and 40 ng/mL for respective ADAb assays. Drug assays measure free (ADAb-unbound) drug while ADAb assays are drug tolerant and detect total antibodies (including IgM & IgG subtypes). All ADAb positive samples undergo a confirmatory step to confirm the drug specificity of antibodies.
Results:
Of 23,825 VDZ and 21,604 UST samples, 99% (23,643) and 98% (21,188) were ADAb-free, respectively. Immunogenicity rates were 0.8% for Anti-VDZ and 1.9% for Anti-UST. In the absence of ADAb, VDZ concentrations ranged from 0.6 to 463 ug/mL, with 25% < 10 ug/mL, 41% < 15 ug/mL, 31% between 15 -25 and 19% greater than 30. In the absence of Anti-UST, UST concentrations ranged from 0.1 to 135 ug/mL with 12% less than 1.0 ug/mL, 57% less than the proposed target of 4, 36% within the target of 4 – 10, and 7% >10. Even though immunogenicity rates were very low, among those samples with ADAb, an inverse relationship between drug and ADAb was evident where Anti-VDZ or Anti-UST in titers in excess of 500 ng/mL were associated with diminished free drug levels.
Conclusions:
Vedolizumab and ustekinumab had very low incidence of immunogenicity (0.8% and 1.9%, respectively) in contrast to ∼30% immunogenicity observed with infliximab and adalimumab. Nevertheless, when present, Anti-VDZ and Anti-UST do adversely affect free drug levels, especially in titers >500 ng/mL. Target trough concentration ranges for VDZ and UST have yet to be firmly established, but depending upon the timing of sample collection and the target cutoff, as many as 25 to 41% of patients on VDZ and 12 to 57% of patients on UST may benefit from dose optimization.
