uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Pharmacokinetic/pharmacodynamic models for the depletion of Vβ5.2/5.3 T cells by the monoclonal antibody ATM-027 in patients with multiple sclerosis, as measured by FACS
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (Farmakometri)
2004 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 58, no 4, 378-389 p.Article in journal (Refereed) Published
Abstract [en]

AIMS:

(i) To model the effects of the monoclonal antibody ATM-027 on the number of target cells and on the receptor density on the cell surface as measured by Fluorescence Activated Cell Sorter analysis, (ii) to investigate the effects of categorizing a continuous scale, and (iii) to simulate a phase II trial from phase I data in order to evaluate the predictive performance of the model by comparison with the actual trial results.

METHODS:

Based on the data from one phase I and one phase II study in multiple sclerosis (MS) patients, models were developed to characterize the pharmacokinetics and pharmacodynamics of the monoclonal antibody ATM-027 and its effects on Vbeta5.2/5.3+ T cells. The pharmacodynamic variables were the number of target T cells and the expression of its receptor. The latter was modelled in both a categorical and continuous way. The modelling was performed with a nonlinear mixed effects approach using the software NONMEM. The joint continuous models were used to simulate the phase II trial from the phase I data.

RESULTS:

The pharmacokinetics of ATM-027 were characterized by a two-compartment model with a total volume of distribution of 5.9 litres and a terminal half-life of 22.3 days (phase II parameter estimates) in the typical patient. Continuous receptor expression was modelled using an inhibitory sigmoidal Emax-model. Similar results from the phase I and phase II data were obtained, and EC50 was estimated to be 138 and 148 microg litre(-1), respectively. Categorical receptor expression was modelled using a proportional odds model, and the EC50 values obtained were highly correlated with those from the continuous model. The numbers of target T cells were also modelled and treatment with ATM-027 decreased the number of cells to 25.7% and 28.9% of their baseline values in the phase I and II trials, respectively. EC50s for the decrease in the number of T cells were 83 microg litre(-1) and 307 microg litre(-1), respectively. Simulations of the phase II trial from the phase I models gave good predictions of the dosing regimens administered in the phase II study.

CONCLUSION:

All aspects of effects of the monoclonal antibody ATM-027 on Vbeta5.2/5.3+ T cells were modelled and the phase II trial was simulated from phase I data. The effects of categorizing a continuous scale were also evaluated.

Place, publisher, year, edition, pages
2004. Vol. 58, no 4, 378-389 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93719DOI: 10.1111/j.1365-2125.2004.02177.xPubMedID: 15373930OAI: oai:DiVA.org:uu-93719DiVA: diva2:167287
Available from: 2005-11-11 Created: 2005-11-11 Last updated: 2011-11-30Bibliographically approved
In thesis
1. Models for Ordered Categorical Pharmacodynamic Data
Open this publication in new window or tab >>Models for Ordered Categorical Pharmacodynamic Data
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In drug development clinical trials are designed to investigate whether a new treatment is safe and has the desired effect on the disease in the target patient population. Categorical endpoints, for example different ranking scales or grading of adverse events, are commonly used to measure effects in the trials.

Pharmacokinetic/Pharmacodynamic (PK/PD) models are used to describe the plasma concentration of a drug over time and its relationship to the effect studied. The models are utilized both in drug development and in discussions with drug regulating authorities. Methods for incorporation of ordered categorical data in PK/PD models were studied using a non-linear mixed effects modelling approach as implemented in the software NONMEM. The traditionally used proportional odds model was used for analysis of a 6-grade sedation scale in acute stroke patients and for analysis of a T-cell receptor expression in patients with Multiple Sclerosis, where the results also were compared with an analysis of the data on a continuous scale. Modifications of the proportional odds model were developed to enable analysis of a spontaneously reported side-effect and to analyze situations where the scale used is heterogeneous or where the drug affects the different scores in the scale in a non-proportional way. The new models were compared with the proportional odds model and were shown to give better predictive performances in the analyzed situations.

The results in this thesis show that categorical data obtained in clinical trials with different design and different categorical endpoints successfully can be incorporated in PK/PD models. The models developed can also be applied to analyses of other ordered categorical scales than those presented.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 20
Keyword
Pharmacokinetics/Pharmacotherapy, Pharmacodynamic, Modelling, Categorical data, NONMEM, Proportional odds model, Markov model, Differential drug effect model, Farmakokinetik/Farmakoterapi
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-6125 (URN)91-554-6394-0 (ISBN)
Public defence
2005-12-02, B42, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-11-11 Created: 2005-11-11 Last updated: 2011-07-08Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Karlsson, Mats O.

Search in DiVA

By author/editor
Karlsson, Mats O.
By organisation
Department of Pharmaceutical BiosciencesDivision of Pharmacokinetics and Drug Therapy
In the same journal
British Journal of Clinical Pharmacology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 560 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf