Jurij Zdovc (1), Jurij Hanžel (2,3), Erwin Dreesen (4), 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
Objectives: Crohn’s disease (CD) is a debilitating, relapsing-remitting, incurable inflammatory disease of the digestive tract. It is a global disease with the highest frequency in temperate climates and more industrialized regions, affecting around three million individuals in the westernized world, with rising incidence worldwide. Treatment is focused on achieving endoscopic and biochemical remission. The decreased disease activity is indicated by decreased Simple Endoscopic Score for CD (SES-CD) and decreased faecal calprotectin (FC) concentrations [1, 2].
Monoclonal antibodies targeting proinflammatory cytokines present a promising option for CD treatment. Ustekinumab is a IgG1κ monoclonal antibody against the p40 subunit, shared by IL-12 and IL-23 [3]. Its efficacy in inducing and maintaining remission of moderate-to-severe CD has recently been proven in the UNITI program [4]. However, the real-world studies with the current treatment regimen have reported that up to one half of the patients achieve clinical remission, and only up to 25% of patients achieve endoscopic remission [5–10]. Therefore, it seems that the treatment regimen could be optimized, but there is a lack of knowledge on how to individualize treatment, which is related to limited data on the exposure-response relationship.
In this work we characterized the exposure-response relationship of ustekinumab in CD by means of a population pharmacokinetic-pharmacodynamic (PK-PD) model.
Methods: This was a prospective observational study at a single tertiary referral center. The study received approval from the national ethics committee, was conducted in accordance with the 1975 Declaration of Helsinki, and all patients provided written informed consent.
All CD patients aged 18 years or older who started treatment with ustekinumab between October 2017 and June 2019 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, followed by a fixed maintenance dose of 90 mg, administered subcutaneously every 8 weeks.
Serum samples were prospectively collected at week 0 (baseline), 1 hour after the intravenous infusion, and subsequently at weeks 2, 4, 8, 9, 10, 12, 16, 20, 24 and 32. Free serum ustekinumab concentration was measured with a validated ELISA assay (lower limit of quantification (LLOQ), 0.4 μg/mL). Antidrug antibodies (ADA) were measured in serum samples with ustekinumab concentration < 1 μg/mL. Demographic characteristics (age, weight and sex), clinical data (co-morbidities, disease activity at baseline, disease history, concomitant and previous treatment) and biochemical markers (FC, CRP, serum albumin) were recorded. Additionally, polymorphisms in IL12B (rs3212227, rs3213094, rs6887695) were genotyped by real-time polymerase chain reaction using specific TaqMan SNP genotyping assays.
SES-CD was estimated based on colonoscopy between weeks 24 and 26 by a single endoscopist, blinded to the patients’ condition. The FC concentration was assessed at baseline, and at weeks 8, 16 and 24 (LLOQ, 15.6 mg/kg, ULOQ, 500 mg/kg).
Linear one- and two-compartment models and several target mediated drug disposition (TMDD) model approximations with first-order absorption were fitted to the serum concentrations [11, 12]. Additive, proportional and combination (additive + proportional) error models were tested for residual variability. The logit transformation was used to describe the interindividual variability (IIV) of ustekinumab bioavailability (F) and the exponential model was used to describe the IIV of other PK parameters.
Stepwise covariate modelling (pA sequential PD analysis was performed to model the relationship between ustekinumab exposure, and SES-CD and FC as disease activity markers.
Analyses were conducted in NONMEM 7.3 and the M3 method was used for data below or above the LOQ [13, 14]. Akaike information criterion was used for model comparison. The model was internally validated with a visual predictive check. Parameter uncertainty was assessed with bootstrap with replacement method.
Results: Data from 57 consecutive patients were available, including 573 serum ustekinumab concentration measurements and 222 FC measurements. SES-CD was estimated for 41 patients. None of the tested samples had detectable ADA. A TMDD approximation model comprising first-order absorption (Ka), two-compartment disposition and an exponential decrease of clearance over time (KD) best described the PK.
Typical linear CL (CLL), nonlinear CL (CLN) and the KD were estimated at 0.274 L/day (Relative Standard Error, 9%), 0.0648 L/day (33%) and 0.0144 day-1 (36%), respectively. The typical Ka, F, the intercompartmental clearance and the volumes of distribution in the central (VC) and peripheral compartment (VP) were estimated at 0.458 day-1 (16%), 0.674 (8%), 5.59 L/day (100%), 3.59 L (13%) and 3.87 L (16%), respectively. The residual variability was described by a combination of additive and proportional error, estimated at 0.676 μg/mL (25%) and 7.84 % (36%), respectively.
A power model described the positive relationship between body weight and CLL, VC, and VP. Decreasing serum albumin (linear model) and previous therapy with biologics (categorical) were related with increased CLL. The rs6887695 polymorphism was related with lower F. The IIV, expressed as coefficient of variation with respective shrinkages, for CLL, CLN, VC and VP were estimated at 19% (shrinkage, 24%), 141.6% (19%), 15% (13%) and 24% (27%), respectively. The correlation between the CLL and VC was estimated at 0.30. The IIV, expressed as a standard deviation, for bioavailability was 0.593 (shrinkage, 23%).
Both FC and SES-CD decreased with increasing ustekinumab exposure. A sigmoidal Emax model with an effect compartment best described the relationship between ustekinumab PK and FC. Presence of ulcerations at baseline was related with higher baseline FC and increased CRP was related with increased EC50. A linear model best described the negative relationship between cumulative exposure until week 24 (AUC0-24) and SES-CD. The PK-PD relationship was clinically informative and all patients (5/41) with the AUC0-24 > 2300 μg*day/mL had SES-CD ≤ 4.
Conclusions: We developed the first population PK-PD model for ustekinumab in CD. The decrease of CL over time might be related to the target removal due to the disease treatment. The model could be used to inform prospective treatment individualization and thus contribute to a more effective use of otherwise potentially inefficient and costly therapy with ustekinumab. It seems that patients with inadequate response could benefit from dose escalation or interval shortening, for example maintenance dose administration every 4 weeks.
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Reference: PAGE () Abstr 9531 [www.page-meeting.org/?abstract=9531]
Poster: Oral: Drug/Disease Modelling