P0531 - Adalimumab Serum Levels in Relation to World Health Organization Standardization and Immunization in Clinical Gastroenterology Practice

Judson McFarland, BS, Hong Law, BS, Michael Schwalbe, BS, Owen McLachlan, BS, Jessica Ho, PhD, Anjali Jain, PhD, Thierry Dervieux, PhD, PharmD
Prometheus Laboratories, Inc., San Diego, CA

Introduction: Proactive Therapeutic drug monitoring (TDM) of Adalimumab (ADA) is emerging as important to prevent the formation of Anti-Adalimumab antibodies (ATA) in inflammatory bowel diseases (IBD). Our objective was to evaluate the performance characteristics of the Homogenous Mobility Shift Assay (HMSA) against the World Health Organization (WHO) international standard and assess the impact of this drug tolerant assay on ADA immunization.

Methods: Data collection was conducted in a clinical laboratory accredited by the American College of Pathologists using liquid chromatography size exclusion HMSA. ADA WHO Standard (17/236) lyophilized powder was re-suspended in human serum. ADA concentrations measured by in-house and WHO calibration methods were compared using 31 de-identified specimens. ADA levels in relation to ATA formation were evaluated from a de-identified database of clinical specimens. Statistical analysis consisted of regression analysis and determination of interval likelihood ratio (ILR). Longitudinal changes in ATA titers (log normalized) were analyzed using linear mixed effect models.

Results: Between run precision was 6.2% (median CV; range 3.1-12.5%) and 4.2% (range: 0.9-10.4%) for measured ADA using in-house and WHO calibration, respectively. As presented in Figure 1, ADA levels measured using in-house calibration (mean [SD]: 16.0±9.7 µg/ mL) were comparable to those using WHO calibration (mean 15.9±9.9 µg/ml) (Deming’s slope 1.03 CI95%: 1.01-1.04). In a population of 84,540, ADA levels determined from 61,491 subjects (40±17 years, 53% female) recovered mean ADA of 10.0±8.0 µg/mL with 16.2% of the patients presenting detectable ATA ( >1.7 U/ml; mean titer 1.9±7.6 U/mL). ADA levels < 1.6 µg/mL associated with a 9.9-fold higher probability of ATA (ILR=9.85 CI 95%: 9.54-10.2) (Table 1). In contrast, ADA exposure >10 µg/mL resulted in negligible likelihood of ATA. Linear mixed effect models revealed that increasing ADA levels (log normal estimate=-0.79±0.01, p< 0.01), shorter interval dosing (weekly vs. every other week, estimate=-0.06±0.009, p< 0.001) and male gender (estimate= 0.05±0.009, p< 0.002) associated with lower ATA titers in the subset of patients (n=9,875) with two or more ATA determinations under a 40 mg dosing regimen (marginal R²=0.26).

Discussion: Calibration of the ADA-HMSA to WHO may facilitate harmonization of TDM in the clinical gastroenterology practice. Immunization to ADA appears to be mitigated by optimized exposure.


Figure: Deming’s Slope of Measured ADA by HMSA using In-house vs. WHO Calibration
31 specimens across the dynamic range were processed 6 consecutive times

ADA Interval	ATA Positive	ATA Negative	ILR [CI95%]
< 1.6 µg/mL	8221	4321	9.85 [9.54-10.2]
1.6 - 5.0 µg/mL	3047	7948	1.98 [1.91-2.06]
5.0 - 10.0 µg/ml	1734	22164	0.41 [0.39-0.42]
10.0 - 15.0 µg/ml	482	19050	0.13 [0.12-0.14]
15.0 - 20.0 µg/ml	139	9737	0.07 [0.06-0.09]
20.0 - 50.0 µg/ml	68	7630	0.05 [0.04-0.06]

Table: Interval Likelihood Ratio for ATA Formation in Relation to ADA Exposure


Disclosures:
Judson McFarland indicated no relevant financial relationships.
Hong Law indicated no relevant financial relationships.
Michael Schwalbe indicated no relevant financial relationships.
Owen McLachlan indicated no relevant financial relationships.
Jessica Ho indicated no relevant financial relationships.
Anjali Jain indicated no relevant financial relationships.
Thierry Dervieux indicated no relevant financial relationships.


Judson McFarland, BS, Hong Law, BS, Michael Schwalbe, BS, Owen McLachlan, BS, Jessica Ho, PhD, Anjali Jain, PhD, Thierry Dervieux, PhD, PharmD. P0531 - Adalimumab Serum Levels in Relation to World Health Organization Standardization and Immunization in Clinical Gastroenterology Practice, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.