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Model-based analysis of change in kidney function over time in critically ill patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
2019 (English)Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Background: Colistin has been used as a last-resort treatment for infections caused by multi drug resistant pathogens. However, colistin is known to be nephrotoxic and the pharmacokinetic/toxicodynamic relationship is largely unknown.

Aim: To develop a model that best describes the change in kidney function (amount of creatinine elimination rate) over time, and can elucidate the influence of colistin on kidney function.

Methods: Data collected from 350 adult critically ill patients was analyzed. Model development was done using NONMEM 7.4.4 and PsN 4.9.1. Model evaluation was based on objective function value (p<0.05) and goodness-of-fit (visual predictive checks).

Results: A turn-over model describing change of creatinine best described the data. Adjustment for disease progression was modelled using an exponential change in kidney function with time. The delayed effect from daily colistin exposure was described with an effect compartment. Typical baseline creatinine was estimated to 450 mg, and typical elimination half-life of creatinine was estimated to 5.2 days.  It was estimated that 0.56 mg/L average total plasma concentration of colistin would lead to a reduction in kidney function with 37%, and that the maximum reduction in kidney function by colistin was 74%.

Conclusions: The model successfully described the data. The estimated toxicodynamic effects of colistin is lower to what has previously been described. The elimination half-life of creatinine was 31 times higher than expected.

Place, publisher, year, edition, pages
2019. , p. 32
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-404392OAI: oai:DiVA.org:uu-404392DiVA, id: diva2:1394435
Subject / course
Pharmacokinetics
Educational program
Master of Science Programme in Pharmacy
Supervisors
Examiners
Available from: 2020-02-20 Created: 2020-02-18 Last updated: 2020-02-20Bibliographically approved

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