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Pharmacometric models in the development of biological medicinal products
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
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 [en]
Pharmacometrics, model-based analysis, NONMEM, population modelling.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-381441ISBN: 978-91-513-0644-5 (print)OAI: oai:DiVA.org:uu-381441DiVA, id: diva2:1303944
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
List of papers
1. Reduced and optimized trial designs for drugs described by a target mediated drug disposition model
Open this publication in new window or tab >>Reduced and optimized trial designs for drugs described by a target mediated drug disposition model
2018 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 45, no 4, p. 637-647Article in journal (Refereed) Published
Abstract [en]

Monoclonal antibodies against soluble targets are often rich and include the sampling of multiple analytes over a lengthy period of time. Predictive models built on data obtained in such studies can be useful in all drug development phases. If adequate model predictions can be maintained with a reduced design (e.g. fewer samples or shorter duration) the use of such designs may be advocated. The effect of reducing and optimizing a rich design based on a published study for Omalizumab (OMA) was evaluated as an example. OMA pharmacokinetics were characterized using a target-mediated drug disposition model considering the binding of OMA to free IgE and the subsequent formation of an OMA-IgE complex. The performance of the reduced and optimized designs was evaluated with respect to: efficiency, parameter uncertainty and predictions of free target. It was possible to reduce the number of samples in the study by 30% while still maintaining an efficiency of almost 90%. A reduction in sampling duration by two-thirds resulted in an efficiency of 75%. Omission of any analyte measurement or a reduction of the number of dose levels was detrimental to the efficiency of the designs (efficiency ae<currency> 51%). However, other metrics were, in some cases, relatively unaffected, showing that multiple metrics may be needed to obtain balanced assessments of design performance.

Place, publisher, year, edition, pages
SPRINGER/PLENUM PUBLISHERS, 2018
Keywords
Optimal design, Target mediated drug disposition, Monoclonal antibodies, Sampling time optimization, Model-based
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-361677 (URN)10.1007/s10928-018-9594-9 (DOI)000438685100008 ()29948794 (PubMedID)
Available from: 2018-10-05 Created: 2018-10-05 Last updated: 2019-04-11Bibliographically approved
2. A Population Pharmacokinetic-Pharmacodynamic Model of Pegfilgrastim
Open this publication in new window or tab >>A Population Pharmacokinetic-Pharmacodynamic Model of Pegfilgrastim
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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
Keywords
full random effects modeling, granulocyte colony-stimulating factor, pegfilgrastim, population pharmacokinetic-pharmacodynamic model
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-362482 (URN)10.1208/s12248-018-0249-y (DOI)000441928900001 ()30112626 (PubMedID)
Available from: 2018-10-10 Created: 2018-10-10 Last updated: 2019-04-11Bibliographically approved
3. Pharmacokinetic and Pharmacodynamic Sensitivity of Pegfilgrastim
Open this publication in new window or tab >>Pharmacokinetic and Pharmacodynamic Sensitivity of Pegfilgrastim
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2019 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416Article in journal (Refereed) Submitted
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-381432 (URN)
Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-04-11
4. Handling Underlying Discrete Variables with Bivariate Mixed Hidden-Markov Models in NONMEM
Open this publication in new window or tab >>Handling Underlying Discrete Variables with Bivariate Mixed Hidden-Markov Models in NONMEM
(English)Manuscript (preprint) (Other academic)
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-381437 (URN)
Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-04-11
5. Characterization of Anti-Drug Antibody Dynamics Using a Bivariate Mixed Hidden-Markov Model
Open this publication in new window or tab >>Characterization of Anti-Drug Antibody Dynamics Using a Bivariate Mixed Hidden-Markov Model
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(English)Manuscript (preprint) (Other academic)
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-381438 (URN)
Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-04-11
6. Population Pharmacokinetics of Plasma-Derived Factor IX: Procedures for Dose Individualization
Open this publication in new window or tab >>Population Pharmacokinetics of Plasma-Derived Factor IX: Procedures for Dose Individualization
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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.

Keywords
Bayesian forecast; coagulation factor IX; hemophilia; patient-specific modeling; pharmacokinetics
National Category
Hematology
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-278160 (URN)10.1111/jth.13271 (DOI)000374979000012 ()26806557 (PubMedID)
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2019-04-11
7. Model-based evaluation of low dose factor VIII prophylaxis in haemophilia A
Open this publication in new window or tab >>Model-based evaluation of low dose factor VIII prophylaxis in haemophilia A
2019 (English)In: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 25, no 3, p. 408-415Article in journal (Refereed) Published
Abstract [en]

Introduction The optimal treatment modality for haemophilia A is lifelong prophylaxis which is expensive and may not be implementable everywhere where factor VIII (FVIII) availability is limited. A less costly alternative to prophylaxis is low-dose prophylaxis (LDP) which was compared to conventional prophylaxis in this model-based simulation study. Aim To explore whether LDP is motivated where standard prophylaxis is not implementable, including evaluating LDP efficacy compared to high-dose prophylaxis and investigating the potential economic benefit of individualized dosing. Methods For a virtual adult haemophilia A population, FVIII activity levels were simulated following alternative treatment regimens, based on a published population PK model. The regimens included very LDP, LDP and conventional prophylaxis twice and thrice weekly. The annual probability of bleeding was predicted based on the weekly time spent below 1 IU/dL, using a previously published relationship. Additionally, PK-based dose individualization was evaluated to determine FVIII savings using Bayesian forecasting. Results A treatment regimen of 10 IU/kg administered thrice weekly cost 75% less than a standard high-dose regimen and was predicted to have a 5% higher median probability of annual bleeds. PK-based dose individualization may result in further cost-savings, but implementation needs benefit versus feasibility consideration. Conclusion Based on simulations, a promising LDP regimen was identified that decreased treatment costs compared with standard high-dose prophylaxis at a small increase in bleeding risk. The results indicate that LDP is advocated where the standard-of-care is on-demand treatment; however, the results should be considered in the context of any limitations of the applied models.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
factor VIII prophylaxis, low‐dose prophylaxis, model simulations, population PK analysis
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-381430 (URN)10.1111/hae.13753 (DOI)000470929100026 ()31050134 (PubMedID)
Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-07-31Bibliographically approved

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