Infliximab and Ustekinumab Clearance Better Predict Endoscopic Outcomes Than Trough Concentrations in Crohn's Disease
Zhigang Wang1, Yannick Hoffert1, Wei Zhang1
1Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
Insights
Drug clearance, not just drug levels, effectively predicts endoscopic outcomes in Crohn's disease (CD) patients treated with infliximab and ustekinumab. Monitoring clearance offers a reliable method for assessing treatment response in CD.
Area of Science:
- Gastroenterology
- Pharmacology
- Immunology
Background:
- Infliximab and ustekinumab clearance are potential biomarkers for disease activity in inflammatory bowel diseases.
- Predicting endoscopic outcomes is crucial for managing Crohn's disease (CD).
Purpose of the Study:
- To evaluate the utility of infliximab and ustekinumab clearance monitoring for predicting endoscopic outcomes in CD patients.
- To compare the predictive value of drug clearance versus drug concentration (Ctrough) for treatment response.
Main Methods:
- Repurposed data from moderate-to-severe CD patients on infliximab (n=108) and ustekinumab (n=80) therapy.
- Assessed endoscopic remission/response at various time points using validated scores.
- Employed Bayesian forecasting with population pharmacokinetic models to estimate time-varying drug clearance from drug concentrations and covariates.
Main Results:
- Lower infliximab clearance and higher Ctrough at week 2 predicted endoscopic remission at week 12 during induction.
- During maintenance, lower infliximab clearance predicted endoscopic remission at week 54, while Ctrough did not.
- Infliximab clearance showed similar predictive ability to fecal calprotectin for endoscopic outcomes during maintenance.
- Ustekinumab clearance, but not Ctrough, differentiated between endoscopic responders and nonresponders.
Conclusions:
- Drug clearance, specifically for infliximab and ustekinumab, is a reliable predictor of endoscopic outcomes in CD.
- Drug trough concentrations (Ctrough) may lose predictive power with dose optimization or non-weight-based dosing.
- Clearance monitoring offers a valuable tool for assessing treatment efficacy in CD patients, complementing or surpassing traditional biomarkers.
Background & Aims:
Infliximab and ustekinumab clearance have been suggested as predictors of disease activity in patients with inflammatory bowel diseases. We aimed to investigate the benefits of clearance monitoring for predicting endoscopic outcomes in patients with Crohn's disease (CD).
Methods:
Data from patients with moderate-to-severe CD starting infliximab (n = 108) and ustekinumab (n = 80) therapy were repurposed. Endoscopic remission (CD Endoscopic Index of Severity <3) was assessed at week (w)12 and w54 of infliximab therapy. Endoscopic response (>50% reduction in Simple Endoscopic Score for CD) was assessed at w24 of ustekinumab therapy. We performed Bayesian forecasting to estimate time-varying mAb clearance using drug concentrations, covariates, and in-house developed population pharmacokinetics models.
Results:
Patients achieving endoscopic remission at w12 had significantly lower infliximab clearance and higher infliximab serum trough concentrations (Ctrough) at w2 of standard 5 mg/kg infliximab induction therapy, than patients without endoscopic remission (P < .05). During infliximab maintenance therapy (with eventual dose optimizations), patients achieving endoscopic remission at w54 had significantly lower infliximab clearance (P < .001) but not higher infliximab Ctrough (P = .92) than those without remission. Moreover, infliximab clearance during maintenance had similar discriminative ability as fecal calprotectin (area under the receiver operating characteristics curve 0.63; 95% confidence interval, 0.56-0.69 vs 0.67; 95% confidence interval, 0.61-0.73, respectively). Ustekinumab clearance, but not Ctrough, was significantly different between endoscopic responders and nonresponders during standard ustekinumab induction and maintenance therapy (P < .05).
Conclusions:
Although Ctrough loses its ability to predict treatment response when doses are optimized or not administered by bodyweight, infliximab and ustekinumab clearance remains a reliable predictor for endoscopic outcomes.
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