Infliximab and Adalimumab Therapeutic Drug Monitoring (TDM): Analysis of >125,000 Patient Samples for Drug Levels and Designation of Anti-Drug Antibodies into Low, Intermediate and High Titers
Background:
Serum assays to measure biologic drugs, especially TNF inhibitors, and their anti-drug antibodies (ADAb) are utilized to manage suboptimal response including that caused by reversible immunogenicity and to proactively titrate doses and dosing intervals. Here, 72,819 infliximab (IFX) and 53,131 adalimumab (ADL) recent patient results were analyzed.
Methods:
Drug and ADAb levels are measured by drug-specific lab-developed chemiluminescent immunoassays. Lower limits of quantitation are 0.4 and 0.6 ug/mL for IFX and ADL, and 22 and 25 ng/mL for respective ADAb assays. Drug assays measure free (ADAb-unbound) biologic drug (validated for originator as well as biosimilars) while ADAb assays detect total antibodies (including IgM & IgG subtypes) and are drug-tolerant to the presence of up to >50 μg/mL drug. All ADAb positive samples undergo a confirmatory step to confirm the drug specificity of antibodies.
Results:
Of a total of 72,819 IFX and 53,131 ADL samples, 31% had Anti-IFX and 29% had Anti-ADL, respectively. In 50,325 samples without Anti-IFX, IFX concentrations ranged from 0.4 to 593 ug/mL, with 25% subtherapeutic at < 5.0 ug/mL; 27% were within the 5 to 10 target (potentially therapeutic, if trough); 27% were 11-20; one fifth (21.0%) were >20 (likely, non-trough samples). In the absence of Anti-ADL, ADL concentrations in 37,653 samples ranged from 0.6 to 74 ug/mL with 45% subtherapeutic at < 7.5 ug/mL; 37% were within the therapeutic target of 7.5 to 12; 14% were 13 to 20; 4% were >20. In the presence of ADAb, an inverse relationship between ADAb level and concomitant free (antibody-unbound) drug is clearly evident. When Anti-IFX and Anti-ADL are >1000 and >800 ng/mL, respectively, almost invariably the concomitant IFX or ADL is nil (< 0.4 and < 0.6 ug/mL).
Conclusions:
Of all ADAb-free samples, about one quarter (27%) were within the target range of 5-10 μg/mL for IFX and about one third (37%) within 7.5-12 μg/mL for ADL. Importantly, 25% and 45% were potentially subtherapeutic on IFX and ADL, respectively. Immunogenicity was 31% for Anti-IFX and 29% for Anti-ADL, respectively, showing a significant decrease from previous observations (ca. 2018) of 45% and 40%, respectively. Analyses led to the following cutpoints and designations: For Anti-IFX, 22-200 ng/mL is low titer, 201 to 1000 is intermediate, and >1000 is high titer. For Anti-ADL, 25 – 100 is low titer, 101 to 800 is intermediate, and >800 is high titer. “High titer” designation is given to ADAb when >1000 ng/mL for Anti-IFX and >800 for Anti-ADL because almost invariably, the concomitant free drug level is nil. In contrast, “low titer” antibodies do not appear to impact drug levels. These designations facilitate interpretation of ADAb numeric results. Sensitive, drug-tolerant ADAb assays enable the detection of early immunogenicity. High resolution ADAb assays help guide the reversal of immunogenicity since low-to-intermediate titer ADAbs (especially between 100 – 1000 ng/mL) have been successfully treated away with dose escalation +/- co-immunomodulator to restore clinical response and improve longevity.
