Erwin Dreesen(1), MSc, PharmD, Ruben Faelens(2), MEng, Gert Van Assche(3), MD, PhD, Marc Ferrante(3), MD, PhD, Séverine Vermeire(3), MD, PhD, Ann Gils(1), PharmD, PhD, Thomas Bouillon(2), MD, PhD
(1) Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven - University of Leuven, Leuven, Belgium; (2) Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven - University of Leuven, Leuven, Belgium; (3) Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
Objectives: Infliximab (IFX) is a chimeric monoclonal antibody that neutralizes the pro-inflammatory cytokine tumour necrosis factor alpha. Intravenous administration of IFX following an induction scheme of 5 mg/kg body weight at days 0, 14 and 42 has been shown to induce mucosal healing (MH) in 61% of patients with ulcerative colitis at day 56[1]. A positive association between IFX serum concentrations during induction therapy and post-induction MH (between day 56 and 98) has been reported[2,3].
In this study, we applied nonlinear mixed effects methodology to compare potential exposure targets for prediction of MH.
Methods: In this retrospective, single-centre cohort study, IFX was quantified in serum trough samples during induction therapy (2000-2013)[3,4]. An endoscopy was performed before start of IFX therapy (baseline) and after two to four induction doses (post-induction, between day 40 and 100). The Mayo endoscopic sub-score was assessed and simplified to three states: 3 (severe disease), 2 (moderate disease) and 1/0 (inactive disease). MH was defined as a post-induction sub-score being ≤1 in patients with ≥2 before IFX. We assumed that only ordered transitions can occur (i.e., patients going from 3 to 1/0 transitioned through state 2 and vice versa) and that the transition probabilities between states can be inversed (eg P32=1-P23). The pharmacokinetic (PK) and pharmacodynamic (PD) models were developed sequentially in NONMEM 7.3.
Results: A total of 204 patients was available for the PK analysis of IFX and 172 patients contributed to the PD analysis (fractions at baseline sub-score state 3, 2 and 1 were 49%, 47% and 4%, resp.). A one-compartment model described the concentration time course of IFX. Serum albumin concentration (SAC) and post-induction sub-score were identified as covariates. Volume of distribution (V) was 8.1/(SAC/43) L (CV=35%), elimination rate constant (Ke) was 0.045 day-1 in patients with post-induction sub-score ≤1 and 0.062 day-1 in patients with post-induction sub-score ≥2) (CV=23%). Body weight was not identified as a covariate in this adult cohort. Individual estimates from the base model without covariates and with between- and within-subject variability on Ke (CV = 39% and 22%, resp.) and V (CV = 42% and 15%, resp.) were used as an input for the PD model. A logistic regression model described the relation between exposure and probability of achieving MH. The three observed states and six transitions were described using four parameters: the baseline proportions of patients displaying sub-scores 2 and 3, P3(t0) and P2(t0), and the times or exposures corresponding to a 50% probability of going from state 3 to 2 and 2 to 1/0. Cumulative area under the curve (CAUC) up to time of endoscopy was identified as the most relevant predictor of MH (lowest Akaike information criterion, AIC), followed by the trough concentration at day 14 (Table 1). X50 refers to the value of the metric yielding a 50% probability of conversion from 3 to 2 and 2 to 1/0.
Table 1
|
Modelling hypothesis |
AIC |
X50 estimates ±SE |
|
Null model; no effect of dose, time or exposure |
639 |
– |
|
Cumulative dose (CD) to time of assessment drives response |
637 |
CD503->2 = 265 ±50 mg CD502->1/0 = 739 ±118 mg |
|
Time of assessment (T) drives response |
628 |
T503->2 = 16 ±3 day T502->1/0 = 47 ±8 day |
|
IFX concentration at day 14 (C14) drives response |
614 |
C14503->2 = 4.3 ±0.8 µg/mL C14502->1/0 = 13.7 ±2.3 µg/mL |
|
IFX CAUC drives response |
601 |
CAUC503->2 = 458 ±87 µg/mL*day CAUC502->1/0 = 1,460 ±234 µg/mL*day |
Conclusions: CAUC up to time of endoscopy is the best predictor of MH. Given the fixed induction time schedule, aiming at MH in 70% of patients and assuming time of assessment at day 84, we recommend a target CAUCday 84 of 4,380 µg/L*day. Dose optimization towards this PK target can improve effectiveness of IFX induction therapy in patients with ulcerative colitis (Faelens et al., submitted, PAGE 2018).
References
[1] Rutgeerts P, Sandborn WJ, Feagan BG, et al. Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005 Dec 8;353(23):2462-76.
[2] Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology. 2014 Dec;147(6):1296-1307.e5.
[3] Papamichael K, Van Stappen T, Vande Casteele N, et al. Infliximab concentration thresholds during induction therapy are associated with short-term mucosal healing in patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2016 Apr;14(4):543-9. [4] Arias MT, Vande Casteele N, Vermeire S, et al. A panel to predict long-term outcome of infliximab therapy for patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2015 Mar;13(3):531-8.
Reference: PAGE 27 (2018) Abstr 8591 [www.page-meeting.org/?abstract=8591]
Poster: Drug/Disease Modelling - Other Topics