Background: A subcutaneous formulation of infliximab was recently approved for maintenance therapy of inflammatory bowel disease (IBD). However, limited clinical experience, particularly with escalated intravenous infliximab regimens, poses challenges for transitioning to subcutaneous therapy.

Aims: To investigate the pharmacokinetics and pharmacodynamics of subcutaneous infliximab to identify early predictors of relapse upon switching.

Methods: We repurposed data from a prospective, multicenter trial involving patients switching from intravenous to subcutaneous infliximab. We estimated each patient’s infliximab clearance using Bayesian forecasting from a pre-switch sample and a population pharmacokinetics model. We performed pharmacodynamics modeling to evaluate pre-switch predictors of post-switch relapse. Relapse was defined as clinical recurrence (partial Mayo score >2 or Harvey–Bradshaw Index >4 leading to therapeutic escalation) or an increase in fecal calprotectin (fCal) ≥150 μg/g upon switching.

Results: Using data from 98 patients with IBD, we identified infliximab clearance and fCal as independent predictors of relapse. A two-item risk score stratified patients into low-risk (<19% probability of relapse; 75/98; 77%) and high-risk (≥19% probability of relapse; 23/98; 23%) groups (sensitivity 0.52 [95%CI 0.31−0.73], specificity 0.95 [95%CI 0.87−0.99], positive predictive value 75% [95%CI 48−93%], negative predictive value 87% [95%CI 77−93%]). Our pharmacokinetics–pharmacodynamics model classified patients with and without relapse (p <0.0001), with area under the receiver operating characteristic curve of 0.83 (95%CI 0.71−0.93).

Conclusions: Pre-switch infliximab clearance and fCal are accurate predictors of relapse after switching to subcutaneous infliximab. An interactive risk stratification tool facilitates confirmation of a stratified medicine approach to improve infliximab therapy in IBD.

Keywords: Infliximab, TDM, Risk-stratification

Background: Extending the infliximab infusion interval has been attempted in patients with Crohn’s disease (CD) and ulcerative colitis (UC) who sustained treatment response after an earlier interval shortening.

Aims: To compare therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) for de-acceleration of infliximab dosage.

Methods: In this prospective, historically controlled Phase 4 trial, patients with steroid-free clinical and biological remission on accelerated infliximab dosing underwent interval extension guided either by TDM (historical control) or MIPD (prospective intervention), targeting an infliximab trough concentration (TC) of 5 mg/L. The primary endpoint was sustained steroid-free clinical and biological remission over one year. Infliximab concentrations were measured at each study visit. Bayesian forecasting was performed using the TDMx Infliximab module (www.tdmx.eu).

Results: The study enrolled 52 patients: 21 patients (11 CD, 10 UC) in the TDM arm and 31 patients (19 CD, 12 UC) in the MIPD arm. MIPD achieved a numerically higher rate of sustained steroid-free clinical and biological remission (52% vs. 29%, p=0.17) and a significantly higher rate of sustained steroid-free clinical remission (81% vs. 38%, p<0.01) over one year compared to TDM. The infliximab dose per infusion over the one-year period was comparable between the TDM arm (7.5 [7.4–8.2] mg/kg) and the MIPD arm (8.8 [6.6–10.9] mg/kg).

Conclusions: MIPD-guided dosage de-acceleration of infliximab resulted in similar rates of sustained steroid-free clinical and biological remission compared to TDM. ClincialTrials.gov, number NCT04982172.

Keywords: anti-TNF therapy; biologics; inflammatory bowel disease; model-informed precision dosing; pharmacometrics; therapeutic drug monitoring

Backgrounds: A multitude of factors can play a role in the observed interindividual variability in pharmacokinetics of therapeutic antibodies including bevacizumab (BV). In our previous case series, some patients with proteinuria had decreased trough serum BV concentrations (Masuda T, Cancer Chemother Pharmacol, 2024). This study aimed to develop a population pharmacokinetic (PopPK) model and to evaluate the effect of proteinuria on BV pharmacokinetics.
Methods: Seventy Japanese cancer patients newly starting BV were enrolled in this study. Serum BV concentrations in 368 samples were measured using an LCMS-8060 quadrupole mass spectrometer. PopPK analysis was conducted using a nonlinear mixed-effects modeling program (NONMEM version 7.5.1) employing the first-order conditional estimation method with interaction. This study was approved by the Ethics Committee (No. R2643).
Results: Serum albumin concentration, body weight, and urinary protein to creatinine ratio (UPCR) were identified as significant covariates on BV clearance. BV clearance increased with decreasing serum albumin concentration or increasing UPCR. The simulated median trough concentrations of BV decreased by 12, 21, and 32 % in patients with proteinuria CTCAE Grade 1, Grade 2, and Grade 3, respectively, compared to those with no proteinuria.
Conclusion: We successfully established a PopPK model to predict serum BV concentrations in Japanese cancer patients with proteinuria. PopPK analysis revealed that proteinuria as well as serum albumin concentration and body weight were factors associated with BV clearance.

Background: TDM have been employed in the use of anti-TNFα drugs with the aim of optimizing their use. However, use of TDM in clinical practice is variable, possibly due to conflicting results in the literature
Aims: We aimed to evaluate whether the use of TDM in inflammatory bowel disease (IBD) patients on biologic therapy results in improved clinical outcomes.
Methods: A systematic search strategy was developed and conducted across PubMed, EMBASE, Web of Science, and Cochrane Library from database inception to December 12, 2023. Articles which matched the inclusion criteria were included. For controlled study data conforming to a normal distribution, meta-analysis was performed using RevMan 5.3 software
Results: We included eight RCTs and fifteen cohort studies with regard to infliximab and adalimumab. RCT results demonstrated comparable efficacy between the TDM group and conventional clinical management in clinical remission rates, clinical response rates, endoscopic remission, and mucosal healing rates. In contrast, cohort studies revealed opposing trends. RCT evidence indicated significantly lower levels of C-reactive protein and fecal calprotectin in the TDM group. Cohort study findings further showed reduced surgical intervention rates and hospitalization rates in TDM-managed patients. No controlled studies comparing TDM with standard/conventional therapy were identified for ustekinumab, vedolizumab, golimumab, or certolizumab pegol.
Conclusions: Current evidence supporting TDM for biologics in IBD remains limited and inconclusive, which maybe a barrier for implement. More studies with larger RCTs and standardized assays are needed to substantiate these results and validate the cost-effectiveness of TDM.
Keywords: Biologics, TDM, IBD

Background: Infliximab is a safe and effective rescue therapy for patients with steroid-refractory acute severe ulcerative colitis (ASUC). There is no evidence that intensified/accelerated infliximab regimens are superior to standard induction dosing.

Aims: To develop a risk stratification algorithm that assigns patients with ASUC into risk groups of colectomy within 90 days after the start of infliximab therapy and inform personalized infliximab rescue dosing.

Methods: We performed a multicenter, retrospective population pharmacokinetics (popPK) and exposure–response study using pooled data from ASUC patients. Time-to-event modeling was used to describe colectomy within 90 days. Patient characteristics and pharmacokinetics projections were evaluated as predictors of colectomy. The popPK model and regression coefficients of the time-to-event model were used to develop an algorithm for risk stratification and personalized infliximab rescue dosing.

Results: Eight medical centers contributed data from 74 ASUC patients, providing 157 infliximab concentrations. Eleven patients (15%) underwent colectomy within 90 days. The log-transformed ratio of the posterior, Bayesian forecasted area under the infliximab concentration–time curve between weeks 2 and 4 (AUCw2–w4; modifiable risk factor) over the estimated infliximab clearance (unmodifiable risk factor) was the best predictor of colectomy (AUROC, 0.79 [95%CI 0.53–1.00]). Patients with an AUCw2-w4/CL below 5.81 were defined as at high risk for colectomy (sensitivity 83%, specificity 85%). Classification accuracy was 84% [95%CI 73%–92%].

Conclusions: Personalized dosing of infliximab may achieve lower colectomy rates in patients with ASUC. An interactive tool is provided to facilitate decision-making based on therapeutic drug monitoring.

Keywords: Infliximab, Personalized dosing, Pharmacometrics, Therapeutic drug monitoring