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A Population Pharmacokinetic-Pharmacodynamic Model of Pegfilgrastim
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Pharmetheus, Uppsala, Sweden. (Farmakometri)
Dr Reddys Labs, Basel, Switzerland.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Pharmetheus, Uppsala, Sweden;Uppsala Univ, Dept Pharmaceut Biosci, Pharmacometr Res Grp, Uppsala, Sweden. (Farmakometri)
Pharmetheus, Uppsala, Sweden.
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2018 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 5, article id 91Article in journal (Refereed) Published
Abstract [en]

Neutropenia and febrile neutropenia (FN) are serious side effects of cytotoxic chemotherapy which may be alleviated with the administration of recombinant granulocyte colony-stimulating factor (GCSF) derivatives, such as pegfilgrastim (PG) which increases absolute neutrophil count (ANC). In this work, a population pharmacokinetic-pharmacodynamic (PKPD) model was developed based on data obtained from healthy volunteers receiving multiple administrations of PG. The developed model was a bidirectional PKPD model, where PG stimulated the proliferation, maturation, and margination of neutrophils and where circulating neutrophils in turn increased the elimination of PG. Simulations from the developed model show disproportionate changes in response with changes in dose. A dose increase of 10% from the 6 mg therapeutic dose taken as a reference leads to area under the curve (AUC) increases of similar to 50 and similar to 5% for PK and PD, respectively. A full random effects covariate model showed that little of the parameter variability could be explained by sex, age, body size, and race. As a consequence, little of the secondary parameter variability (C-max and AUC of PG and ANC) could be explained by these covariates.

Place, publisher, year, edition, pages
SPRINGER , 2018. Vol. 20, no 5, article id 91
Keywords [en]
full random effects modeling, granulocyte colony-stimulating factor, pegfilgrastim, population pharmacokinetic-pharmacodynamic model
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-362482DOI: 10.1208/s12248-018-0249-yISI: 000441928900001PubMedID: 30112626OAI: oai:DiVA.org:uu-362482DiVA, id: diva2:1254926
Available from: 2018-10-10 Created: 2018-10-10 Last updated: 2019-04-11Bibliographically approved
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)
Opponent
Supervisors
Available from: 2019-05-13 Created: 2019-04-11 Last updated: 2019-06-17

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Brekkan, AriYngman, GunnarHooker, AndrewKarlsson, Mats O

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