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. 2020 Nov;86(11):2274-2285.
doi: 10.1111/bcp.14330. Epub 2020 Jun 11.

Population pharmacokinetics of adalimumab biosimilar adalimumab-adbm and reference product in healthy subjects and patients with rheumatoid arthritis to assess pharmacokinetic similarity

Jia Kang  1 , Rena J Eudy-Byrne  1 , John Mondick  1 , William Knebel  1 , Girish Jayadeva  2 , Karl-Heinz Liesenfeld  3
Affiliations

Population pharmacokinetics of adalimumab biosimilar adalimumab-adbm and reference product in healthy subjects and patients with rheumatoid arthritis to assess pharmacokinetic similarity

Jia Kang et al. Br J Clin Pharmacol. 2020 Nov.

Abstract

Aims: Adalimumab-adbm is a monoclonal antibody developed as a biosimilar to adalimumab (Humira, AbbVie Inc.). The key objectives of this study were using a population pharmacokinetic (PPK) approach to assess pharmacokinetic (PK) similarity between adalimumab-adbm and Humira in patients with active rheumatoid arthritis (RA), to quantify the effects of potential covariates on adalimumab PK and to assess the impact of switching treatment from Humira to adalimumab-adbm on PK.

Methods: A PPK model was firstly developed using intensive PK data from the phase-1 study in healthy subjects (NCT02045979). PPK models were developed separately for phase-3 base study (NCT02137226) and its extension study (NCT02640612) in patients with active RA.

Results: PPK models were developed for adalimumab from adalimumab-adbm and Humira treatment in healthy subjects and RA patients. Weight and anti-drug antibodies were found to be important predictors of adalimumab clearance. Adalimumab PK was similar between adalimumab-adbm and Humira. The estimated effect of Humira on clearance, relative to the adalimumab-adbm, was 1.02 (i.e., Humira has 0.02 greater clearance). Similarly, the effect of treatment arms (switching) on clearance was estimated to be 1.00 and 0.997 for Humira:Humira:BI and Humira:BI:BI arms, respectively, relative to the BI:BI:BI arm (BI refers to adalimumab-adbm) in the phase-3 extension study.

Conclusion: PK similarity between adalimumab-adbm and Humira in patients with active RA was demonstrated using PPK approach. Adalimumab PK was also similar when switching treatment from Humira to adalimumab-adbm at either week 24 or 48.

Keywords: biosimilar; pharmacokinetics; rheumatoid arthritis.

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Conflict of interest statement

There are no competing interests to declare. G.J. and K.‐H.L. are employees of Boehringer Ingelheim. J.K., R.J.E.‐B., J.M. and W.K. are employees of Metrum Research Group, which was contracted by Boehringer Ingelheim to perform these analyses and support preparation of this manuscript.

Figures

FIGURE 1
FIGURE 1
Diagnostic plots of observed vs individual and population predicted concentrations from the final population pharmacokinetic models by treatment arm for the phase‐1 study (A), phase‐3 base study (B) and phase‐3 extension study (C). BI refers to adalimumab‐adbm. The black line of identity is included as reference. The blue dashed line represents a loess smooth line. In the phase‐3 base study, Humira:BI arm was for subjects who received Humira for 24 weeks and then switched to adalimumab‐adbm for the remaining 24 weeks. In the phase‐3 extension study, Humira:BI:BI arm was for subjects who received Humira for 24 weeks, then switched to adalimumab‐adbm during the base study and finally switched to open‐label adalimumab‐adbm during the extension, Humira:Humira:BI arm was for subjects who were treated with Humira for 48 weeks during the base study and switched to open‐label adalimumab‐adbm during the extension study
FIGURE 2
FIGURE 2
Changes in individual estimates of apparent clearance (CL/F) at week 50 and 98 are plotted vs treatment arm using boxplots. BI refers to adalimumab‐adbm
FIGURE 3
FIGURE 3
Plots of covariate effects on apparent clearance (CL/F) for the phase‐3 base study (A) and the phase‐3 extension study (B). CL/F relative to the typical patient with reference covariates (70 kg body weight [WT], anti‐drug antibody [ADA] titre value of 16, 3 mg/L C‐reactive protein [CRP], 43 g/L albumin [ALB], 47 IU/mL baseline rheumatoid factor [BRF]) is plotted by representative covariate value. Different cuts of WT, CRP, ALB, ADA and BRF represent the 5th, 25th, 75th and 95th percentiles of the observed covariate values during the treatment in the study. The black dot represents the clearance evaluated at the representative values of covariates and point estimates of the covariate parameter, compared to the CL/F in the typical patient. The blue line represents the clearance at the representative values of covariates and 95% CIs of the covariate parameter estimate relative to CL/F in the typical patient. The black solid line represents the CL/F in the typical patient with reference covariate values. The grey shaded region represents covariate effect size <±20% of the typical CL/F, which is considered not clinical meaningful
FIGURE 4
FIGURE 4
Plots of observed anti‐drug antibody [ADA] titre (in log 2 scale) vs time after the first dose by treatment arm and study. BI refers to adalimumab‐adbm. Black dots represent observed ADA titre value with blue loess smoothing trend line
See this image and copyright information in PMC

References

    1. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease modifying anti‐rheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Car Res (Hoboken). 2012;64(5):625‐639. - PMC - PubMed
    1. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease‐modifying antirheumatic drugs. Ann Rheum Dis. 2010;69(6):964‐975. - PMC - PubMed
    1. U.S. Food and Drug Administration . Guidance for Industry: Quality Considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. Available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformat...
    1. European Medicines Agency . Guideline on similar biological medicinal products containing monoclonal antibodies‐nonclinical and clinical issues. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidelin...
    1. Wynne C, Altendorfer M, Sonderegger I, et al. Bioequivalence, safety and immunogenicity of BI 695501, an adalimumab biosimilar candidate, compared with the reference biologic in a randomized, double‐blind, active comparator phase I clinical study (VOLTAIRE®‐PK) in healthy subjects. Expert Opion Investig Drugs. 2016;25:1361‐1370. - PubMed

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