Population Pharmacokinetics of the TNF‐α and IL‐17A Dual‐Variable Domain Antibody ABT‐122 in Healthy Volunteers and Subjects With Psoriatic or Rheumatoid Arthritis: Analysis of Phase 1 and 2 Clinical Trials

Abstract ABT‐122 is an IgG1 dual‐variable domain immunoglobulin that specifically blocks TNF‐α and IL‐17A. This work characterized ABT‐122 pharmacokinetics using nonlinear mixed‐effects modeling and ABT‐122 serum concentrations from 72 healthy subjects, 196 subjects with rheumatoid arthritis (RA), and 144 subjects with psoriatic arthritis (PsA) enrolled in 4 phase 1 and 2 phase 2 studies (0.1–10 mg/kg intravenously and 0.3–3 mg/kg subcutaneous single doses and 0.3–3.0 mg/kg subcutaneous and 60–240 mg subcutaneous doses weekly or every other week). A 2‐compartment model with a combination of linear clearance (0.419 L/day) and nonlinear clearance (relevant only at low doses; V max and K m of 0.155 mg/day and 0.0458 mg/L, respectively) described ABT‐122 pharmacokinetics. Subcutaneous bioavailability was 35%–58% across formulations and populations. Body weight was a significant covariate for ABT‐122 clearance, with subjects with body weight of 140 and 40 kg estimated to have 38% lower and 43% higher ABT‐122 AUC, respectively, compared with a 70‐kg reference subject. ABT‐122 antidrug antibody (ADA) titer (ADA incidence, 47%; 0 to 519 000 titer range in the data set) was a continuous covariate on ABT‐122 clearance. An ADA titer of 100 units resulted in a 5‐fold increase in clearance. Sex, age, and baseline serum albumin or baseline C‐reactive protein level did not impact ABT‐122 exposure. Fixed‐effects and random‐effects parameters were estimated with a relative standard error of ≤17% and ≤28%, respectively, and the model was qualified using bootstrap analysis and visual predictive checks. This analysis characterized ABT‐122 exposure across populations and supported exposure–response analyses of ABT‐122 efficacy in RA and PsA.