Model-based individualization of ustekinumab dosing in Crohn's disease
Jurij Aguiar Zdovc (1), Jurij Hanžel (2,3), Erwin Dreesen (4,5), Debby Thomas (4), Barbara Ostanek (1), Tomaž Vovk (1), David Drobne (2,3), Iztok Grabnar (1)
(1) University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia, (2) Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia, (3) University of Ljubljana, Medical Faculty, Ljubljana, Slovenia, (4) Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium, (5) Department of Pharmacy, Uppsala University, Uppsala, Sweden
Objectives Crohn’s disease (CD) is a relapsing-remitting incurable inflammatory disease of the digestive tract. The decreased biochemical disease activity is indicated by decreased faecal calprotectin (FC) concentrations [1, 2].
Ustekinumab is a monoclonal antibody used in moderate-to-severe CD [3]. Based on the reported proportions of patients achieving remission, it seems there is an unmet need for the optimization of the standard treatment [4–9]. However, the identification of patients best suited for dose optimization and the optimal dosing strategy remain unresolved dilemmas in clinical practice. In this work we developed a population pharmacokinetic-pharmacodynamic (PK-PD) model for ustekinumab and FC in CD to compare the efficacy of various clinically relevant treatment regimens.
Methods CD patients, aged 18 years or older who started treatment with ustekinumab between October 2017 and June 2019 in a single tertiary referral center, were included. Patients received a weight-based intravenous induction dose (≤55 kg: 260 mg; 55–85 kg: 390 mg; >85 kg: 520 mg) infused over one hour at week 0 (baseline), followed by a fixed maintenance dose of 90 mg, administered subcutaneously every 8 weeks (standard treatment).
Unbound serum ustekinumab concentration was prospectively measured at baseline, 1 hour after the intravenous infusion, and subsequently at weeks 2, 4, 8, 9, 10, 12, 16, 20, 24 and 32. Demographic characteristics, clinical data and biochemical markers were recorded. Polymorphisms in IL12B (rs3212227, rs3213094, rs6887695), FCGR2A (rs1801274), and FCGR3A (rs396991) were genotyped. The FC concentration was assessed at baseline, and at weeks 8, 16 and 24.
Target mediated drug disposition (TMDD) model and its approximations were fitted to the unbound serum concentrations [10, 11]. After subcutaneous administration, first-order absorption was assumed. Scm was used for covariate modelling and a sequential PD analysis was performed to model the relationship between ustekinumab, latent target and FC.
The final PK-PD model was used for simulation of a virtual patient population receiving various treatment regimens, and the proportion of patients achieving biochemical remission (FC <100 mg/kg) at weeks 8, 16, 24 and 32 was calculated to compare the efficacy.
Results Data from 57 patients were available, including 574 serum ustekinumab concentration measurements and 224 FC measurements. A quasi-equilibrium (QE) approximation of the TMDD model, extended with distribution of the unbound ustekinumab and unbound target into a peripheral compartment, best described the PK of the ustekinumab.
After the induction dose, the terminal half-life of ustekinumab in a typical patient was estimated at 17 days. Ustekinumab clearance was higher with decreasing serum albumin, increasing FFM, and in patients with previous exposure to biologics. A power model described the increase of volumes of the central and peripheral compartment of ustekinumab with increasing FFM. The fraction of absorbed ustekinumab was higher in V/V patients of rs396991 FCGR3A polymorphism (88.8%), compared to F/F and V/F combined (71.0%). Ksyn increased with increasing baseline CRP.
The indirect response model best described the stimulating effect of the unbound target on the FC production. The simulation demonstrated that proportions of patients in remission at week 32 receiving standard treatment, treatment with initial induction and subsequent maintenance dosing every 4 weeks or treatment with induction dosing every 8 weeks were 41.9%, 52.2% and 56.0%, respectively.
Conclusions We developed a novel semi-mechanistic extended QE TMDD model for ustekinumab in CD. Our population PK-PD model could be used to guide future attempts to stratify treatment with ustekinumab in CD.
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