A Population Pharmacokinetic and Exposure–Response Model of Golimumab for Targeting Endoscopic Remission in Patients With Ulcerative Colitis

Abstract

Background Unlike other anti–tumor necrosis factor alpha antibodies, golimumab does not deliver on its promise of effectiveness for treating patients with ulcerative colitis. We investigated the value of therapeutic drug monitoring for optimizing golimumab therapy. Methods We analyzed the golimumab pharmacokinetics data of 56 patients with moderate to severe ulcerative colitis. Induction and maintenance golimumab concentrations (296 venipuncture, 414 serum) were used to develop a population pharmacokinetic model. Exposure–response relationships were analyzed using the data of 40/56 patients with available endoscopy data. Receiver operating characteristic curve analysis was performed, and an exposure–response Markov model was developed, linking golimumab exposure to probabilities of transitioning between Mayo endoscopic subscore (MES) states from baseline to week (w)14. Results Golimumab pharmacokinetics was best described by a 2-compartment model with linear absorption and elimination. Antibodies to golimumab and previous biological therapy reduced golimumab exposure. Still, interindividual pharmacokinetic variability (IIVPK) remained largely unexplained. Endoscopic remission (ER; MESw14 ≤ 1) was achieved in 14/40 (35%) patients. Golimumab serum trough concentration thresholds of 7.4 mg/L (w6) and 3.2 mg/L (w14) predicted ER at w14 (positive predictive values [pv+] 83% and 91%, pv- 82% and 67%, respectively). The 3.2-mg/L target predicted 38% and 44% chances of achieving ER in patients with MESbaseline of 3 and 2, respectively. Conclusions Personalized, model-based induction dosing aiming at here-established target concentrations may account for IIVPK and thus provide patients with more equal chances of achieving ER. As <50% of patients attained the exposure targets, higher golimumab induction dosing requires investigation to secure its future in clinical practice.

Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases

“…The PANTS study, where anti-TNF naïve patients with luminal CD were enrolled at the time of anti-TNF initiation and prospectively observed until treatment discontinuation, reported that low TLs of infliximab (<7 mg/L) or adalimumab (<12 mg/L) at week 14 correlated with primary non-response at week 14 (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.20–0.62, p = 0.00038 for infliximab; OR 0.13, 95% CI 0.06–0.28, p < 0.0001 for adalimumab) and non-remission at week 54 (OR 0.29, 95% CI 0.16–0.52, p < 0.0001 for infliximab; OR 0.03, 95% CI 0.10–0.12, p < 0.0001 for adalimumab) [ 87 ]. Similar associations between TLs and therapeutic outcomes have also been observed for golimumab, both in the post-hoc analysis of the registration trial [ 88 ] and in some observational studies [ 89 , 90 , 91 , 92 ]. Some studies have suggested that specific disease phenotypes might need higher TLs to be adequately controlled.…”

Modelling of the relationship between infliximab exposure, faecal calprotectin and endoscopic remission in patients with Crohn's disease

“…For example, all patients in the analysis data set were biological‐naïve, received standard infliximab induction therapy (dose escalations were only performed from week 14 onwards), and had concomitant azathioprine therapy. Previous biological therapy and immunosuppressive comedication have been shown to affect exposure and response to biological therapies 24,44–46 . Therefore, the suitability of our models to inform precision dosing in these patients should be evaluated 47 .…”

Association of golimumab trough concentrations during maintenance with clinical, biological, endoscopic and histologic remission in patients with ulcerative colitis

“…Several realworld studies reported the relationship between golimumab exposure during induction therapy and mucosal healing. [25][26][27] Conversely, the association of SGC with mucosal healing during maintenance has only been evaluated in the real world in a retrospective study that included 19 patients with UC or IBD-unclassified. 28 Although there was a trend towards a higher trough golimumab level in patients with endoscopic remission (defined as an MES of 0 or 1), this difference was not statistically significant, which is most likely due to the small sample size.…”