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
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
(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.
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.
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.
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.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-93719DOI: 10.1111/j.1365-2125.2004.02177.xPubMedID: 15373930OAI: oai:DiVA.org:uu-93719DiVA: diva2:167287