Session Information
Date: Sunday, November 13, 2016
Title: Rheumatoid Arthritis – Small Molecules, Biologics and Gene Therapy - Poster I
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: ABT-122 is a novel dual-variable domain immunoglobulin (DVD-IgTM), which specifically neutralizes both TNF alpha (TNFα) and interleukin-17A (IL-17). Drugs individually neutralizing TNFα or IL-17 have demonstrated efficacy in patients with RA and PsA. The objective of this work was to characterize the pharmacokinetics of ABT-122 and the effect of patient-specific covariates on ABT-122 exposures using available Phase 1 and 2 data in healthy volunteers (HV) and subjects with RA and PsA.
Methods: ABT-122 serum concentrations (approximately 4400 samples) from two Phase 1 single-dose studies in HV (N=72 subjects; ABT-122 doses: 0.1 to 10 mg/kg administered intravenously [IV] and 0.3 to 3 mg/kg administered subcutaneously [SC]), two Phase 1 multiple-dose studies in subjects with RA (N=31 subjects; ABT-122 doses: 1 mg/kg SC every other week [EOW] and 0.5 to 3 mg/kg SC every week [EW] for 8 weeks) and two Phase 2 studies, one each in subjects with RA (N=165 subjects; ABT-122 doses: 60 mg SC EOW to 120 mg SC EW for 12 weeks) and PsA (N=144 subjects; ABT-122 doses: 120 mg SC EW to 240 mg SC EW for 12 weeks) were included in this analysis. The effect of clinically relevant covariates on ABT-122 exposures were evaluated. Data were analyzed using non-linear mixed-effects modeling.
Results: ABT-122 serum concentrations were characterized using a two-compartment pharmacokinetic model with a combination of first-order (linear) and saturable (non-linear) eliminations. For reference intravenous administration, ABT-122 linear clearance and steady-state volume of distribution were 0.419 L/day and 6.0 L, respectively. The contribution of saturable elimination was negligible in the dose range evaluated in Phase 2 studies (range of 60 mg EOW to 240 mg EW SC). ABT-122 absolute SC bioavailability ranged from about 35% to 55% for different formulations and studies. ABT-122 terminal elimination half-life was approximately 9 days. Subjects with bodyweights of 42 and 137 Kg (lowest and highest in the dataset) were estimated to have about 30% lower and 60% higher ABT-122 clearance, respectively, relative to a 70 kg individual. ABT-122 clearance increased with the increase in ABT-122 anti-drug antibody titers, with an anti-drug antibody titer of 100 units estimated to result in 5-fold increase in ABT-122 clearance. In Phase 2 studies, incidence and titers of ABT-122 anti-drug antibodies decreased as the dose increased.
Conclusion: ABT-122 clearance is estimated to be approximately 3-fold faster than the well characterized values for adalimumab, leading to 3-fold higher ABT-122 dose needed to provide equivalent serum exposures to adalimumab. The developed pharmacokinetic and covariate models for ABT-122 enabled integrated exposure-response analyses across ABT-122 development program, allowing better understanding of the responses to dual TNF and IL-17 inhibition with this novel DVD.
To cite this abstract in AMA style:
Khatri A, Othman AA. Population Pharmacokinetics of ABT-122, an Immunoglobulin Targeting Both TNF-α and IL-17A: Analyses Across Phase 1 Studies in Healthy Volunteers and Phase 2 Studies in Subjects with Rheumatoid or Psoriatic Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/population-pharmacokinetics-of-abt-122-an-immunoglobulin-targeting-both-tnf-%ce%b1-and-il-17a-analyses-across-phase-1-studies-in-healthy-volunteers-and-phase-2-studies-in-subjects-with-rheumatoid-or/. Accessed .« Back to 2016 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/population-pharmacokinetics-of-abt-122-an-immunoglobulin-targeting-both-tnf-%ce%b1-and-il-17a-analyses-across-phase-1-studies-in-healthy-volunteers-and-phase-2-studies-in-subjects-with-rheumatoid-or/