Ustekinumab dosing individualization in Crohn's disease guided by a population pharmacokinetic-pharmacodynamic model

Zdovc, Jurij (author), Hanžel, Jurij (author), Štabuc, Borut (author), Vovk, Tomaž (author), Ostanek, Barbara (author), Drobne, David (author), Grabnar, Iztok (author)

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.

• Language: English
• Keywords: ustekinumab, inflammatory bowel disease, fecal calprotectin, pharmacokinetics-pharmacodynamics, therapeutic drug monitoring
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 16 str.
• Numbering: Vol. 13, iss. 10, art. 1587
• PID: 20.500.12556/RUL-136291
• UDC: 615.277.3:616.344-002
• ISSN on article: 1999-4923
• DOI: 10.3390/pharmaceutics13101587
• COBISS.SI-ID: 78625027
• Publication date in RUL: 22.04.2022

Record is a part of a journal

• Title: Pharmaceutics
• Shortened title: Pharmaceutics
• Publisher: MDPI
• ISSN: 1999-4923
• COBISS.SI-ID: 517949977

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 01.10.2021

Secondary language

• Language: Slovenian
• Keywords: vnetje črevesja, terapevtsko spremljanje zdravil, fekalni kalprotektin, Crohnova bolezen, tarčna zdravila

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0189
• Name: Farmacevtska tehnologija: od dostavnih sistemov učinkovin do terapijskih izidov zdravil pri otrocih in starostnikih