Anne Dubois, Maud Bénéton and Marylore Chenel
Department of Clinical Pharmacokinetics, Institut de Recherches Internationales Servier, Suresnes, France
Objectives: Simultaneous administration of several treatments can lead to pharmacokinetic interactions (PKI) of one administered drug on another. For examples, the cytochrome P450 isozymes or transporters (PgP, BcRP…) are implicated in the ADME of many drugs and may be influenced by the administration of others. In this context, our objective was to evaluate the potential PKI of a drug S (in development at Servier) on the pharmacokinetics (PK) of the prednisolone using population PK modelling.
Methods: We used prednisolone PK data of 15 patients from a clinical trial where drug S was evaluated. To be included in this study, patients must be receiving stable oral dose of prednisolone for at least 4 weeks. The concentration of total prednisolone was measured in plasma at one sampling time before any drug S treatment and at several visits under drug S treatment. A maximum of 4 observations per patient was available. For some patients, prednisolone concentrations were available only after drug S administration. Moreover, the PK samples were performed at different times after last prednisolone administration. Due to the very sparse sampling and the heterogeneous sampling times, classic statistical methods such as ANOVA could not be used to compare the prednisolone concentration level before and after drug S administration. So, we used published population PK modelling on prednisolone PK. First we simulated unbound plasma prednisolone concentrations using the model of Mager et al [1]. Then, we derived the corresponding total plasma concentrations using the model of Petersen et al [2] describing the nonlinear binding of prednisolone to the plasma proteins. We computed the 5th, 50th and 95th percentiles of the distribution of the simulated plasma concentrations. At last, we graphically superimposed the predicted and observed plasma concentrations. If there was no major PKI, we expected that most of the observed concentrations should lie in the 90th predicted interval.
Results: Most of the observed concentrations of total prednisolone in plasma were comprised in the 90th predicted interval. No major difference could be observed in the prednisolone concentration levels before and after drug S administration.
Conclusions: Using population PK modelling, we demonstrated that there is no major PK interaction of drug S on prednisolone. This methodology will be applied for the other drugs co-administered with drug S. However, using such approach to conclude on PKI should be discussed with the regulatory agencies.
References:
[1] Mager D, Lin S, Blum R, Lates C and Jusko W. Dose equivalency evaluation of major corticosteroids: pharmacokinetics and cell trafficking and cortisol dynamics. Journal of Clinical Pharmacology. 2003, 43: 1216-1227.
[2] Petersen K, Jusko W, Rasmussen M and Schmiegelow K. Population pharmacokinetics of prednisolone in children with acute lymphoblastic leukemia. Cancer Chemotherapy and Pharmacology. 2003, 51: 465-473.
Reference: PAGE 22 (2013) Abstr 2887 [www.page-meeting.org/?abstract=2887]
Poster: Other Modelling Applications