E.S.K. Widigson (1,2), C. Steenholdt (3), C. Frimor (4), M.A. Ainsworth (4), W. Huisinga (5), C. Kloft (1)
(1) Freie Universitaet Berlin, Institute of Pharmacy, Dept. of Clinical Pharmacy & Biochemistry - Berlin (Germany), (2) Graduate Research Training program PharMetrX, Berlin/Potsdam (Germany), (3) Herlev and Gentofte Hospital, Dept. of Gastroenterology, Herlev (Denmark), (4) Odense University Hospital, Dept. of Gastroenterology, Odense (Denmark), (5) Institute of Mathematics, University of Potsdam (Germany).
Objectives: Inflammatory bowel diseases (IBD) are a group of chronic immune-mediated diseases affecting the gastrointestinal tract, causing debilitating symptoms such as persistent abdominal pain, diarrhoea, and fatigue and with negative influence on quality of life [1]. Ustekinumab (UST) is a monoclonal antibody (mAb) drug used to treat IBD. Since UST has demonstrated an exposure-response relationship, the lack of response in some patients might be due to suboptimal drug concentrations. Subsequently, Therapeutic Drug Monitoring (TDM) has been proposed [2]. TDM is performed by measuring the drug serum concentration (typically trough levels) at a specific timepoint and comparing to a pre-defined pharmacokinetic (PK) concentration threshold linking drug concentration to beneficial pharmacodynamic (PD) treatment outcome. Given the long dosing intervals of mAb drugs, this means that there is usually a time lag of approximately eight to twelve weeks between TDM measurements and subsequent individual treatment optimisation. This work aimed to provide the framework for a more rapid UST treatment individualisation, leveraging the knowledge from nonlinear mixed-effects (NLME) modelling to account for and average PK/PD targets from several studies at different timepoints.
Methods: PK/PD targets for reaching endoscopic remission with UST treatment for IBD were collected from literature. Using a two-compartment NLME model with 1st-order absorption and elimination with parameters in the log-domain and logit transformed-constrained bioavailability, published by O. J. Adedokun et al. (2022), the maximum a posteriori (MAP) parameter value for CL was estimated representing the thresholds in NONMEM® with the setting MAXEVAL=0 [3]. Threshold concentration values were weighted based on the number of patients involved in deriving them (19 – 960 patients), with PK/PD targets derived from the same patient population but representing different timepoints treated as independent of each other. Based on the MAP estimated clearance parameter and the published model, a weighted averaged concentration-time profile was deterministically simulated for an UST clinical praxis dosing regimen of an intravenous weight-based induction loading dose (~6 mg per kg) followed by 90 mg subcutaneously every 8 weeks.
Results: A total of 10 concentration thresholds from 8 studies were collected from literature [4,5,6,7,8,9,10,11]. The MAP weighted model clearance, accounting for the 10 therapeutic thresholds, were estimated to 0.182 L/day, with the remaining model parameters used for deterministic simulation of the UST clinical praxis dosing regimen being fixed to that of the model publication (i.e., central of distribution = 2.75 L, peripheral volume of distribution = 1.88 L, intercompartmental flow = 0.287 L/day, absorption rate constant = 0.181 1/day and subcutaneous dosing bioavailability = 78.2%). From the simulated concentration-time profile, a model-informed concentration threshold table was created for weeks 1-16 during induction and weeks 1-8 after dosing during maintenance therapy, for increased availability to physicians without modelling experience. Some of the model-derived concentration thresholds include induction weeks 4, 8 (pre‑dose), 12 and 16 (pre-dose) at 21.2, 7.37, 7.70 and 2.69 mg/L, respectively, and weeks since the last dose during maintenance therapy 2, 4, 6 and 8 (pre-dose) at 9.56, 5.87, 3.47 and 2.06 mg/L, respectively.
Conclusions: A complete concentration-time profile was derived from 10 published PK/PD targets and a published NLME model. This work provides the framework for more rapid treatment individualisation by enabling TDM sampling of UST treatment against IBD at any point during the dosing interval.
References:
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Reference: PAGE 32 (2024) Abstr 11139 [www.page-meeting.org/?abstract=11139]
Poster: Clinical Applications