Letter to Dreesen et al. on their article “Modelling of the Relationship Between Infliximab Exposure, Faecal Calprotectin, and Endoscopic Remission in Patients With Crohn's Disease”—A comprehensive review of infliximab population pharmacokinetic modelling publications

Sir, In their article, Dreesen et al. have reanalysed data from TAILORIX trial and investigated the concentration–response relationship of infliximab in ulcerative colitis (UC). The authors used an elegant population model that linked infliximab concentration, faecal calprotectin, and endoscopic remission data over time and showed the relevance of faecal calprotectin as a monitoring biomarker. We have already published extensive reviews of publications reporting population pharmacokinetic modelling of monoclonal antibodies. With 26 publications including the article by Dreesen et al., infliximab was the subject of the largest number of publications, followed by rituximab and adalimumab for which pharmacokinetics was described in 19 and 11 publications, respectively. Infliximab pharmacokinetics was mostly described using twocompartment models with first-order transfer and elimination rate constants (18 and 8 publications, for twoand one-compartment models, respectively). Linear two-compartment pharmacokinetic system leads to a biexponential decay of concentrations. This decay is made of an early (“distribution” or “alpha”) and a late (“elimination” or “beta”) phase, respectively, quantified by α and β slope parameters, from whichT1⁄2-α and T1⁄2-β half-lives are derived. Infliximab estimated pharmacokinetic parameters varied markedly between studies, notably those T1⁄2-α and T1⁄2-β (Table S1). Part of this variability may be explained not only statistical variability related to the number of patients and/or covariate coding, but also to the influence of antigen mass on infliximab pharmacokinetics. Indeed, infliximab clearance was found to increase with CRP levels in 6 publications. Since CRP and TNF-α are correlated, this influence was suggested to be due to target-mediated drug disposition (TMDD) of infliximab. In addition, target-mediated elimination of infliximab was recently quantified using aTMDD model in UC patients. The majority of publications reported a T1⁄2-β of approximately 14 days, except 4 which reported T1⁄2-β values of more than 20 days. By contrast, inter-publication variability of T1⁄2-α was large: reported values were below 1 day (8 publications), between 1 and 4 days (8 publications), or approximately 11 days (2 publications). Indeed, if the inter-publication variability (median; [interquartile range]) of central (VC) and peripheral (VP) volumes of distribution and systemic clearance (CL) were moderate (3.4 L [3.1–5.1], 2.0 L [1.5–3.1], and 0.32 L/day [0.27–0.38], respectively), the distribution of inter-compartment clearance (Q) was much larger (0.74 L/day [0.15–2.2]). This disparity may be due to data paucity, since most pharmacokinetic analyses were based on “trough and peak” concentrations, which lead to poor identifiability of parameters describing infliximab transfers between central and peripheral compartments. In their study, Dreesen et al. have described infliximab pharmacokinetics using a two-compartment model and reported their population estimates in table 2 of their article. Estimates CL (0.299 L/day) and VC (5.23 L) were comparable and superior, respectively, to those from literature. They also reported the lowest values for VP (0.785 L) and Q (0.0216 L/day). As a consequence, calculated values of T1⁄2-α and T1⁄2-β were 10.8 and 28.4 days, respectively. In TAILORIX trial, infliximab was infused at weeks 0, 2, 6, 14 and every 8 weeks thereafter, while samples were collected at weeks 2, 6, 12, 14 and every 4 weeks thereafter. Therefore, no blood sample seem to have been collected sooner than 2 weeks after an infusion. Limited information from the sampling strategy may have hampered identifying a peripheral compartment and could explain differences between Dreesen et al. and literature pharmacokinetic parameters estimates. We think that three possible solutions would have been (i) to use a one compartment model, as in a previous study of our group which presented a similar sampling strategy; if using a twocompartment model was necessary, it is still possible (ii) to fix VP to the same value than VC, as previously done for nivolumab, an antiPD-1 monoclonal antibody, or (iii) to fix VP and/or Q values to their average (2.5 L and 1.2 L/day, respectively) calculated from the 11 infliximab pharmacokinetic studies in inflammatory bowel diseases that used a two-compartment model. This would have allowed the authors to report parameter values compatible with that of the literature. Of note, it should be kept in mind that fixing one parameter to a given assumed value may cause estimation bias for other parameters, which should therefore be accompanied with an analysis of sensitivity. Received: 2 June 2020 Revised: 31 July 2020 Accepted: 2 September 2020