Clinical Utility and Factors Associated with Certolizumab Pegol Drug Levels and Anti-Drug Antibodies in the Long-Term Treatment of Rheumatoid Arthritis

Meghna Jani¹, Hector Chinoy^1,2, John Isaacs³, Ann W. Morgan⁴, Anthony Wilson⁵, Kimme L. Hyrich⁶, Darren Plant^1,2 and Anne Barton^1,7, ¹Centre for Musculoskeletal Research, University of Manchester, Manchester, United Kingdom, ²NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academy of Health Sciences, Manchester, United Kingdom, ³National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle, United Kingdom, ⁴NIHR-Leeds Musculoskeletal Biomedical Research Unit, Leeds & Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom, ⁵Infection & Immunity, University of Sheffield, Sheffield, United Kingdom, ⁶Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, United Kingdom, ⁷NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust and University of Manchester, Manchester Academy of Health Sciences, Manchester, United Kingdom

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: anti-TNF therapy, certolizumab pegol, Compliance, drug treatment and pharmacokinetics

Session Information

Date: Tuesday, November 10, 2015

Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy Poster III

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:

Up to 40% of RA patients on anti-TNF agents fail to respond either due to primary or secondary inefficacy. One explanation is immunogenicity leading to the development of anti-drug antibodies (ADAb) and low drug levels, observed with monoclonal antibodies (adalimumab and infliximab). Data from prospective studies on the value of pharmacological testing in certolizumab-treated RA patients is lacking. An additional challenge is the practicality of obtaining trough drug levels and impact on service delivery. Our aims were to evaluate (i) the association between random certolizumab drug levels, ADAbs and treatment response in patients with RA; (ii) factors associated with ADAbs and certolizumab drug levels.

Methods:

115 patients on certolizumab were selected from the Biologics in RA Genetics and Genomics Study Syndicate prospective cohort. Serum samples were collected at 3, 6 and 12 months following initiation of therapy. ADAbs were measured using RIA and drug levels using ELISA assays at 3, 6 and 12 months. Disease activity (DAS28) scores were measured at each visit and 12 month EULAR response was calculated. Patient self-reported adherence was collected longitudinally. Ordinal logistic regression and generalised estimating equation (GEE) were used to test the association between random drug levels on treatment response, between ADAbs and drug levels, and factors associated with drug levels.

Results:

253 serial samples were tested for certolizumab drug levels (n=230 suitable for ADAb measurement). Mean age: 56 ± 13 years; 75% female; baseline DAS28 score: 5.9 ± 0.8; median BMI 27.5 (IQR 23.6-32.3). 87% were on a DMARD (58% MTX). ADAbs were detected in 37% (cut off ≥20 AU/ml; 42/112 patients at ≥1 time points by 12 months). The presence of ADAbs were significantly associated with lower drug levels over 12 months using GEE (β=-0.037, 95% confidence interval [CI]-0.055 to -0.018, p<0.0001) but not independently with 12 month EULAR response (β=0.0013 [95% CI:-0.0032, 0.00061], p=0.18). Drug level was associated with 12 month EULAR response (β=0.035 [95% CI: 0.0018-0.069], p=0.039). Patients who developed ADAbs had longer disease duration (8.3 years [5.7-15.3]) vs. patients who did not (6.0 years [3.3-12.4], p=0.01). Factors associated with certolizumab drug level in the univariate GEE analysis were gender, adherence, BMI, CRP and ADAb level (Table). In the multivariate model after adjustment of confounders, ADAb level and adherence remained significant (Table).

Table: Predictors of drug levels in certolizumab treated RA patients using generalised estimating equation
Variable	β Coefficient (95% confidence intervals)	P value
Univariate analysis
Age	0.14 (-0.017, -0.29)	0.08
Gender*	4.76 (0.21, 9.29)	0.040
BMI*	-0.46 (-0.89, -0.041)	0.032
CRP *	-0.099 (-0.17, -0.029)	0.005
Methotrexate use	-0.11 (-0.47, 4.47)	0.96
Anti-drug antibody level*	-0.037 (-0.055, -0.018)	<0.0001
Adherence* Multivariate model †	10.43 (4.76, 16.11)	<0.0001
Anti-drug antibody level*	-0.044 (-0.059 to -0.028)	<0.0001
Adherence*	7.08 (0.71, 13.45)	0.029
Gender	1.77 (-4.21, 7.76)	0.56
BMI	-0.13 (0.66, 0.43)	0.65
CRP	-0.065 (-0.14, 0.013)	0.102
*p <0.05; †Adjusted for variables significant in the univariate analysis

Conclusion:

Drug levels in certolizumab-initiated patients may be clinically useful even in the absence of trough levels to determine treatment response. Adherence and ADAb levels are associated with low certolizumab drug levels, whilst high disease duration prior to biologic initiation associated with ADAbs. ADAb measurement may help determine the aetiology of a low drug level, but were not associated with 12 month EULAR response.

Disclosure: M. Jani, Pfizer Inc, 8,Abbvie, UCB, 5; H. Chinoy, Novartis, Janssen, Pfizer, UCB, Abbvie, Celgene, Servier, Roche, MSD, and aTyr, 5,Novartis, Janssen, Pfizer, UCB, Abbvie, Celgene, Servier, Roche, MSD, and aTyr, 2; J. Isaacs, None; A. W. Morgan, None; A. Wilson, UCB, 2; K. L. Hyrich, None; D. Plant, None; A. Barton, Eli-Lilly, Pfizer, Abbvie, 2.

To cite this abstract in AMA style:

Jani M, Chinoy H, Isaacs J, Morgan AW, Wilson A, Hyrich KL, Plant D, Barton A. Clinical Utility and Factors Associated with Certolizumab Pegol Drug Levels and Anti-Drug Antibodies in the Long-Term Treatment of Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/clinical-utility-and-factors-associated-with-certolizumab-pegol-drug-levels-and-anti-drug-antibodies-in-the-long-term-treatment-of-rheumatoid-arthritis/. Accessed .

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