Pharmacokinetics‐Based Dosing Strategies for Therapeutic Proteins in Inflammatory Bowel Disease

Mould, Diane R.; Upton, Richard N.; Wojciechowski, Jessica

doi:10.1002/9781119289234.ch12

Cited by 1 publication

(4 citation statements)

References 75 publications

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“…When patients initiate treatment for CD, therapy is individualized based on clinical presentation, medical history, prior treatments, severity of disease, etc 4–6 . Either “bottom up” (step up) or “top down” approaches may be used.…”

Section: Introductionmentioning

confidence: 99%

“…Either “bottom up” (step up) or “top down” approaches may be used. In bottom‐up therapy, when patients fail to respond or are intolerant to the chemical agents, they switch to the alternative treatment option of biologics 4–6 . However, there can be 10%–30% of primary nonresponders and about 30%–40% of secondary nonresponders that fail to achieve sustained clinical response to biologics 7 .…”

Section: Introductionmentioning

confidence: 99%

“…3 When patients initiate treatment for CD, therapy is individualized based on clinical presentation, medical history, prior treatments, severity of disease, etc. [4][5][6] Either "bottom up" (step up) or "top down" approaches may be used. In bottom-up therapy, when patients fail to respond or are intolerant to the chemical agents, they switch to the alternative treatment option of biologics.…”

Section: Introductionmentioning

confidence: 99%

“…In bottom‐up therapy, when patients fail to respond or are intolerant to the chemical agents, they switch to the alternative treatment option of biologics. 4 , 5 , 6 However, there can be 10%–30% of primary nonresponders and about 30%–40% of secondary nonresponders that fail to achieve sustained clinical response to biologics. 7 The cause of the nonresponse can be due to drug‐related factors, such as neutralizing antibodies, altered clearance of drug or possibly biological escape mechanisms, or factors unrelated to the drug, including absence of active inflammation, concurrent infection, or septic complications.…”

Section: Introductionmentioning

confidence: 99%

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Combining pharmacometric models with predictive and prognostic biomarkers for precision therapy in Crohn's disease: A case study of brazikumab

Zhang,

Chan,

et al. 2023

CPT Pharmacom & Syst Pharma

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Pharmacometric models were used to investigate the utility of biomarkers in predicting the efficacy (Crohn's Disease Activity Index [CDAI]) of brazikumab and provide a data‐driven framework for precision therapy for Crohn's disease (CD). In a phase IIa trial in patients with moderate to severe CD, treatment with brazikumab, an anti‐interleukin 23 monoclonal antibody, was associated with clinical improvement. Brazikumab treatment effect was determined to be dependent on the baseline IL‐22 (BIL22) or baseline C‐reactive protein (BCRP; predictive biomarkers), and placebo effect was found to be correlated with the baseline CDAI (a prognostic biomarker). A maximal total inhibition on CDAI input function of 50.6% and 42.4% was predicted for patients with extremely high BIL22 or BCRP, compared to a maximal total inhibition of 20.9% and 17.8% for patients with extremely low BIL22 or BCRP, respectively, which were mainly due to the placebo effect. We demonstrated that model‐derived baseline biomarker levels that achieve 50% of maximum unbound systemic concentration of 22.8 pg/mL and 8.03 mg/L for BIL22 and BCRP as the cutoffs to select subpopulations can effectively identify high‐response subgroup patients with improved separation of responders when compared to using the median values as the cutoff. This work exemplifies the utility of pharmacometrics to quantify biomarker‐driven responses in biologic therapies and distinguish between predictive and prognostic biomarkers, complementing clinical efforts of identifying subpopulations with higher likelihood of response to brazikumab.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%