Abstract Background Personalized dosing is primarily used in anti-TNF-alpha agents, guided by therapeutic drug monitoring (TDM) and relying on trough-level measurements to inform treatment decisions. However, model-informed precision dosing (MIPD) allows greater flexibility by enabling drug-level assessments at any timepoint. Previously, our group identified Pharmacokinetic/Pharmacodynamic (PK/PD) targets for vedolizumab (VDZ) and ustekinumab (UST) to ensure endoscopic remission (ER). Here, we present time-based thresholds derived from PK-models fitted to literature PK/PD thresholds. Aim To put the literature PK/PD thresholds into clinical perspective by Probability of Target Attainment (PTA) analysis, and to bridge the gap between TDM and MIPD by introducing model-derived continuous PKPD threshold profiles which combine the flexibility of MIPD with TDM’s ease of clinical implementation. Methods Published PK-models (Rosario 2015 and Adedokun 2022) were used to stochastically simulate (n = 1000) the standard dosing regimens of VDZ and UST for virtual reference patients, corresponding to the respective medians of the model building populations. Their trough concentrations (Cmin) were compared to median PK/PD thresholds identified in prior literature to calculate the PTA. To derive continuous PK/PD threshold curves for any time-point, PK parameters (e.g. CL, V, etc.) that best-fit the median of literature PK/PD thresholds were estimated and used for subsequent deterministic simulations. Results PTA analysis showed that only ∼50% of UST-treated patients hit the treatment target during induction, dropping to ∼30% during maintenance. For VDZ ∼80% hit the treatment target during induction, decreasing to ∼42% in late induction and maintenance. Full concentration-time profiles were simulated for i) UST weight-based induction for different weights, ii) VDZ induction with doses at weeks 0, 2 and 6, and iii) UST subcutaneous- and VDZ intravenous maintenance dosing every 4-12 weeks. The generated PK/PD profiles are thus allowing to measure drug-concentrations at any given time point, and compare this to the corresponding thresholds derived from the respective concentration-time profile. Conclusion Our findings suggest a need for dose optimization, as current regimens may not ensure adequate target attainment for all patients. The proposed PK/PD threshold profiles allow for flexible, time-independent TDM. Further clinical validation is warranted before implementation. References: Adedokun OJ, Xu Z, Gasink C, Kowalski K, Sandborn WJ, Feagan B. Population Pharmacokinetics and Exposure-Response Analyses of Ustekinumab in Patients With Moderately to Severely Active Crohn’s Disease. Clin Ther. 2022;44(10):1336-1355. doi:10.1016/j.clinthera.2022.08.010 Rosario M, Dirks NL, Gastonguay MR, et al. Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn’s disease. Aliment Pharmacol Ther. 2015;42(2):188-202. doi:10.1111/apt.13243 Conflict of interest: Widigson, Ella: No conflict of interest Mrs. Frimor, Camilla: Duvnjak, Zrinka: No conflict of interest Steenholdt, Casper: No conflict of interest Kjeldsen, Jens: No conflict of interest Husinga, Wilhelm: Has received research grants from an industry consortium (AbbVie, AstraZeneca, Boehringer Ingelheim, F. Hoffmann-La Roche, Merck, Novo Nordisk and Sanofi) for the graduate research training program PharMetrX Weber, Franz: No conflict of interest Ainsworth, Mark Andrew: lectures/consulting for Abbvie, Celltrion, Eli Lilly, Janssen, MSD Kloft, Charlotte: Has received research grants from an industry consortium (AbbVie, AstraZeneca, Boehringer Ingelheim, F. Hoffmann-La Roche, Merck, Novo Nordisk and Sanofi) for the graduate research training program PharMetrX. As well as grants from the Innovative Medicines Initiative-Joint Undertaking (DDMoRe), from the European Commission within the Horizon 2020 framework programme (H2020-EU.3.1.3, ‘FAIR’)
Widigson et al. (Thu,) studied this question.