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Population pharmaco...
Population pharmacokinetic-pharmacodynamic model-based exploration of alternative ustekinumab dosage regimens for patients with Crohn's disease
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- Wang, Zhigang (författare)
- Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, O&N 2 Herestr 49 Bus 820, B-3000 Leuven, Belgium.
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- Verstockt, Bram (författare)
- Univ Hosp Leuven, Dept Gastroenterol & Hepatol, Leuven, Belgium.;Katholieke Univ Leuven, Dept Chron Dis & Metab, Leuven, Belgium.
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- Sabino, Joao (författare)
- Univ Hosp Leuven, Dept Gastroenterol & Hepatol, Leuven, Belgium.;Katholieke Univ Leuven, Dept Chron Dis & Metab, Leuven, Belgium.
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- Vermeire, Severine (författare)
- Univ Hosp Leuven, Dept Gastroenterol & Hepatol, Leuven, Belgium.;Katholieke Univ Leuven, Dept Chron Dis & Metab, Leuven, Belgium.
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- Ferrante, Marc (författare)
- Univ Hosp Leuven, Dept Gastroenterol & Hepatol, Leuven, Belgium.;Katholieke Univ Leuven, Dept Chron Dis & Metab, Leuven, Belgium.
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- Declerck, Paul (författare)
- Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, O&N 2 Herestr 49 Bus 820, B-3000 Leuven, Belgium.
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- Dreesen, Erwin (författare)
- Uppsala universitet,Institutionen för farmaci,Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, O&N 2 Herestr 49 Bus 820, B-3000 Leuven, Belgium.
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Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, O&N 2 Herestr 49 Bus 820, B-3000 Leuven, Belgium Univ Hosp Leuven, Dept Gastroenterol & Hepatol, Leuven, Belgium.;Katholieke Univ Leuven, Dept Chron Dis & Metab, Leuven, Belgium. (creator_code:org_t)
- 2021-07-19
- 2022
- Engelska.
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Ingår i: British Journal of Clinical Pharmacology. - : John Wiley & Sons. - 0306-5251 .- 1365-2125. ; 88:1, s. 323-335
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Aims: In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn's disease (CD) on ustekinumab achieved endoscopic response and 10.9% of patients achieved endoscopic remission at week (w)44. We aimed to evaluate the impact of alternative ustekinumab dosage regimens on endoscopic outcomes based on population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis.Methods: Real-world data were obtained from 83 patients with moderate-to-severe CD (95% biological-refractory) enrolled in a prospective cohort study receiving intravenous ustekinumab (similar to 6 mg/kg) followed by every eight-week (q8w) subcutaneous maintenance therapy (90 mg). Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fecal calprotectin (fCal), and a logistic regression outcome model linking fCal to endoscopic outcomes.Results: Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1800 mu g/g to 694 mu g/g (EC50). The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1800 mu g/g to 214 mu g/g (EC50). Simulation-based comparison of q8w and q4w maintenance dosing regimens predicted 16.7% and 22.2% endoscopic response rates, respectively. Endoscopic remission rates were estimated to be 4.2% on q8w dosing and 6.7% on q4w dosing.Conclusions: The developed models can guide clinical trial design and support model-informed dose optimization (stratified or individualized dosing) to improve endoscopic outcomes.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Gastroenterologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)
Nyckelord
- clinical trial simulation
- Crohn's disease
- pharmacometrics
- population pharmacokinetics-pharmacodynamics
- ustekinumab
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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