Pharmacokinetics and Exposure-response Relationship of Golimumab in Patients with Moderately-to-Severely Active Ulcerative Colitis: Results from Phase 2/3 PURSUIT Induction and Maintenance Studies

Abstract

Background and aims: To assess golimumab pharmacokinetics [PK] and exposure-response [ER] in adults with moderate-to-severe ulcerative colitis [UC] from the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment [PURSUIT] studies.

Methods: We analysed golimumab PK and ER data of patients with moderate-to-severe UC from the PURSUIT-subcutaneous induction [N = 1064] and maintenance [N = 464] studies. Induction analyses evaluated serum golimumab concentration [SGC] and efficacy data through Week [wk] 6 following subcutaneous doses at wk0 and wk2; maintenance analyses assessed data through wk54 following 4-weekly dosing. ER relationships were assessed using trend, logistic regression, and receiver-operating-characteristic curve analyses.

Results: Median SGCs peaked at induction wk2 for golimumab 100/50mg, 200/100mg, and 400/200mg. Wk6 median SGCs were 0.78, 1.78, and 4.01 μg/ml, respectively. SGCs were sustained, reaching steady state approximately 8wks after golimumab maintenance commenced [wk14 of golimumab] regardless of induction dose. Median trough SGCs from maintenance wks8-44 ranged from 0.69 to 0.83 µg/ml [50 mg] and 1.33-1.58 µg/ml [100 mg]. SGCs were approximately dose proportional, and higher SGCs were associated with higher efficacy response rates during induction and maintenance. Factors associated with golimumab exposure were body weight, antibody-to-golimumab status, serum albumin, alkaline phosphatase, faecal markers, C-reactive protein, and pancolitis. SGCs of 2.5 µg/ml [induction wk6] and 1.4 µg/ml [maintenance steady-state trough] are potential target concentrations. Immunomodulators had no apparent impact on SGC with golimumab 100mg, whereas drug levels were slightly higher with golimumab 50mg with vs without immunomodulators.

Conclusions: SGCs are approximately dose proportional, and a positive SGC-efficacy relationship exists during induction/maintenance golimumab treatment of adult UC patients. Optimal SGC targets require validation in prospective studies.

Keywords: Ulcerative colitis; anti-tumour necrosis factor; pharmacokinetics.

© European Crohn’s and Colitis Organisation (ECCO) 2016.

Figures

Figure 1.

Patient disposition throughout the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment [PURSUIT] among 1064 patients who had serum golimumab concentration and efficacy outcome data suitable for analysis. IV, intravenous; M, maintenance; PK, pharmacokinetic; SC, subcutaneous.

Figure 2.

Median serum golimumab concentrations illustrating dose proportionality over time during the induction phase of PURSUIT. IQR, interquartile range; PURSUIT, the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment.

Figure 3.

Proportions of patients achieving clinical response, mucosal healing, and clinical remission during induction by SGC quartile at Week 6 [A], and during maintenance by SGC quartile at Week 44 [B], in PURSUIT. PURSUIT, Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment; SGC, serum golimumab concentration.

Figure 4.

Receiver-operating-characteristic curve analysis of optimal SGC thresholds associated with clinical response at Week 6 [A] and clinical remission at Weeks 30 and 54 [B] of the PURSUIT studies. CPW2/4/6/28/30/44/54, concentration at Week 2/4/6/28/30/44/54; PURSUIT, Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment; SGC, serum golimumab concentration.