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Population Pharmacokinetics of Plasma-Derived Factor IX: Procedures for Dose Individualization
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Skane Univ Hosp, Clin Coagulat Res Unit, Malmo, Sweden.
Skane Univ Hosp, Clin Coagulat Res Unit, Malmo, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
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2016 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 4, p. 724-732Article in journal (Refereed) Published
Abstract [en]

Background: Population pharmacokinetic (POPPK) models describing factor IX (FIX) activity levels in plasma, in combination with individual FIX measurements, may be used to individualize dosing in the treatment of hemophilia B. Objectives: The aim was to reevaluate a previously developed POPPK model for FIX activity and to explore the number and timing of FIX samples required in pharmacokinetic (PK) dose individualization. Methods: The POPPK model was reevaluated using an extended data set. Several sampling schedules, varying with respect to the timing and number of samples, were evaluated in a simulation study with relative dose errors compared between schedules. The performance of individually calculated doses was compared with commonly prescribed FIX doses with respect to the number of patients with a trough FIX activity > 0.01 U mL(-1). Results and conclusions: A three-compartment PK model best described the FIX activity levels. The number and timing of samples greatly influenced imprecision in dose prediction. Schedules with single samples taken on both day 2 and day 3 were identified as being convenient schedules with an acceptable performance level. Individually calculated doses performed better with respect to patient target attainment than a fixed 40 U kg(-1) dose regardless of how many samples were available to calculate individual doses. The results of this study suggest that PK dose tailoring with limited sampling may be applicable for plasma-derived FIX products.

Place, publisher, year, edition, pages
2016. Vol. 14, no 4, p. 724-732
Keywords [en]
Bayesian forecast; coagulation factor IX; hemophilia; patient-specific modeling; pharmacokinetics
National Category
Hematology
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-278160DOI: 10.1111/jth.13271ISI: 000374979000012PubMedID: 26806557OAI: oai:DiVA.org:uu-278160DiVA, id: diva2:906173
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2019-04-11
In thesis
1. Pharmacometric models in the development of biological medicinal products
Open this publication in new window or tab >>Pharmacometric models in the development of biological medicinal products
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Biological medicinal products (BMPs) are a successful class of drugs that are indicated in numerous diseases.  Common among them is that complexities associated with their manufacture and analysis lead to a high cost compared to small-molecular weight drugs.  If the development cost can be brought down and the use of BMPs optimized, these drugs may reach more patients at more affordable prices. Further, there are a number of knowledge gaps related to the characterization of their disposition, immunogenicity and use which can be filled through the development and application of novel methods for data analysis. In this thesis work, pharmacometric models and methods were developed and applied to aid BMP development and clinical use.

Model-based optimal design (OD) methodology was employed to reduce and optimize a published sampling schedule for a monoclonal antibody (mAb) displaying target-mediated drug disposition. Thus, illustrating that current sampling strategies for mAbs can be excessive from an economic and patient burden perspective.

A novel hidden-Markov model was developed to characterize anti-drug antibody (ADA) response which can plague many biologics throughout clinical development and post-approval. The developed model accounted for ADA assay inaccuracies by utilizing information from the assay and the pharmacokinetics (PK) of the therapeutic in question and allowed for an objective assessment of immunogenicity.

Model-based dose individualization and evaluation of low-dose prophylaxis (LDP) for coagulation factors were investigated in this work to improve treatment and lower costs. Individual doses were found to outperform standard-of-care while LDP was indicated as a viable treatment option in countries with limited coagulation factor access.

Biosimilar development is yet another method to reduce the costs of biologics. The development of a PKPD model for a pegylated granulocyte colony stimulating factor (GCSF) allowed for model simulations to demonstrate PK sensitivity to small differences in delivered dose between a reference and potential biosimilar product. The sensitivity of the system may be one of the reasons for difficulties associated with the development of biosimilar pegylated GCSFs.

In conclusion, the pharmacometric methods developed and applied in this thesis work can be used to improve BMP development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 80
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 271
Keywords
Pharmacometrics, model-based analysis, NONMEM, population modelling.
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-381441 (URN)978-91-513-0644-5 (ISBN)
Public defence
2019-06-05, B41, BMC, Husargatan, 75237, Uppsala, 09:15 (English)
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Available from: 2019-05-13 Created: 2019-04-11 Last updated: 2019-06-17

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Brekkan, AriNielsen, Elisabet IJönsson, Siv

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