The association between 6-thioguanine nucleotide levels, adalimumab exposure, immune response, and drug clearance.

Abstract

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 1194 specimens from 1100 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/d; OR = 0.55). Compared with every-other-week dosing, weekly dosing produced higher ADL (13.1 vs 8.9 µg/mL; P < .01) but also higher CL (0.425 vs 0.302 L/d; P < .01). Within each dosing interval, higher 6-TGN levels were associated with lower prevalence of ATA (P < .05) and a higher chance of achieving ADL ≥10 µg/mL (P < .01) and CL < 0.318 L/d (P < .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 a more favorable therapeutic response.