The Association Between 6-Thioguanine Nucleotide Levels, Adalimumab Exposure, Immune Response, and Drug Clearance

Background Thiopurines are associated with improved infliximab pharmacokinetics (PK), but their impact on adalimumab PK and immunogenicity is not well defined. This study examined associations between 6-thioguanine (6-TGN) levels and antibodies to adalimumab (ATA), adalimumab drug levels (ADL), and adalimumab clearance (CL). Methods Using a large clinical laboratory database, we included adults with Crohn’s disease or ulcerative colitis treated with thiopurines and adalimumab who had RBC 6-TGN and adalimumab concentrations measured within 30 days. ATA, ADL, and CL were assessed using drug-tolerant assays and nonlinear mixed-effects modeling. A 6-TGN threshold of ≥ 125 pmol/8 × 108 RBCs was used. Logistic regression was performed to calculate odds ratios (ORs). Results We analyzed 1,194 specimens from 1,100 patients; ATA positivity was 3.7%. Compared with 6-TGN ≥125 pmol/8 × 108 RBCs, lower 6-TGN was associated with higher odds of ATA formation (>1.7 U/mL; OR = 2.55), lower odds of ADL ≥10 µg/mL (OR = 0.58), and lower odds of low CL (< 0.318 L/day; OR = 0.55). Compared with every-other-week dosing, weekly dosing produced higher ADL (13.1 vs 8.9 µg/mL; p < 0.01) but also higher CL (0.425 vs 0.302 L/day; p < 0.01). Within each dosing interval, higher 6-TGN levels were associated with lower prevalence of ATA (p < 0.05) and a higher chance of achieving ADL ≥10 µg/mL (p < 0.01) and CL < 0.318 L/day (p < 0.01). Conclusion Higher 6-TGN levels are associated with reduced immunogenicity, higher adalimumab drug levels, and lower clearance. Thiopurine may enhance adalimumab PK and support more favorable therapeutic response.