Ustekinumab Dosing Individualization in Crohn’s Disease Guided by a Population Pharmacokinetic–Pharmacodynamic Model

Abstract

Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.

Intensificación de Ustekinumab en enfermedad de Crohn: Revisión sistemática

“…También se debe destacar que ninguno de los estudios incluyó la monitorización de niveles de fármaco en sangre. Teniendo en cuenta que este aspecto actualmente es una herramienta fundamental a la hora de toma de decisiones terapéuticas, parece importante destacar la necesidad de incluir esta variable en futuros estudios (15,16) .…”

Drug Clearance in Patients with Inflammatory Bowel Disease Treated with Biologics

“…Several factors have been identified to accelerate the ustekinumab clearance in patients with IBD including increased body weight, lower albumin and immunogenicity (Figure 1) [41][42][43][44]. Other factors that can lead to a high clearance include prior exposure to biologics [42,43], increasing fat-free mass [43], male gender [42,44], Asian race [42] and higher CRP levels [42].…”

Optimizing Therapies Using Therapeutic Drug Monitoring: Current Strategies and Future Perspectives

“…71 This and other association studies have been supported in part by a population pharmacokinetic-pharmacodynamic model, which indicated that for patients not achieving remission by week 16 with standard dosing, intensifying the treatment to 4-weekly subcutaneous maintenance dosing could result in a 10% increment in remission rates by week 32. 72 However, for endoscopic response and remission, a similar model indicated only marginal benefit of treatment intensification. 73 Results from the ongoing RESCUE (Loss of RESponse to Ustekinumab Treated by Dose Escalation) study (NCT04245215), which is exploring the role of ustekinumab dose optimization in CD patients with secondary loss of response, will also contribute to our understanding of ustekinumab PK.…”