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.

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; Vmax and Km 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.