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* = Presenting author

P637 Pharmacokinetics of golimumab in patients with moderate-to-severe ulcerative colitis

S. Berends*1, A. Strik2, P. van Egmond1, H. Brandse2, R. Mathôt1, G. D’Haens2, M. Löwenberg2

1Academic Medical Centre (AMC), Hospital Pharmacy, Amsterdam, Netherlands, 2Academic Medical Centre (AMC), Gastroenterology, Amsterdam, Netherlands

Background

Golimumab is a new treatment option for patients with moderate-to-severe ulcerative colitis (UC). However, after an initial response a substantial proportion of patients loses response over time. This may be due to the development of antibodies to golimumab (ATG) or insufficient target engagement. Moreover, therapeutic antibodies are lost via degradation by metalloproteinases and enteric protein shedding. Therefore, we investigated the pharmacokinetics (PK) of golimumab in UC patients to further understand the dose–response relationship of this treatment.

Methods

In this ongoing prospective observational trial, patients with moderate-to-severe UC received induction treatment of subcutaneous golimumab (200 mg [day 1] and 100 mg [day 14]), followed by maintenance treatment with 50 or 100 mg every 4 weeks, in patients with a body weight of less or more than 80 kg, respectively. Serum golimumab concentrations, CRP, albumin, and ATG levels were measured and SCCAI was scored at standard time points. Endoscopy was performed at baseline and after induction treatment at week 8 using the Mayo endoscopic sub-score. PK analysis was performed using nonlinear mixed effects modelling (NONMEM).

Results

Preliminary data from 6 patients during induction treatment were available. Median age at start was 44 (interquartile range [IQR], 35–57 years), and median baseline parameters were CRP 2.7 mg/L [0.48–17 mg/L], albumin 45 g/L [43–47 g/L], SCCAI 10 [6.5–12], and endoscopic Mayo score 2.0 [2.0–2.3]. Concentration-versus-time profiles were best described by a 1-compartment PK model with first-order absorption and elimination. Mean values (plus between subject variability) for clearance, volume of distribution and absorption rate constant for a patient with CRP of 2.7 mg/L were 0.74 L/day (42%), 13.8 L (35%), and 0.511 L/day, respectively. CRP was significantly correlated with clearance, which increased with 5.2% (95% CI 1.4–9.0%) per mg/L CRP rise (p < 0.05). Median outcome patient parameters after induction treatment at week 8 were CRP 2.2 mg/L (1.1–15 mg/L), SCCAI 8.0 (4.5–12) and Mayo score 2.0 (1.0–2.5). None of the patients developed ATG.

Conclusion

This study demonstrates an association between inflammation (CRP) and clearance of golimumab. This may indicate that clearance is dependent on the severity of inflammation. Upon inclusion of more patients, the developed population PK model will be extended to determine the factors influencing PK. Further, faecal concentrations and the relationship between exposure and clinical/endoscopic outcome will be determined.