Thomas Dumortier, Michael Looby, Olivier Luttringer
Modeling & Simulation, Novartis Pharma
Objectives: At the mid cycle review meeting, the FDA challenged the seemingly favorable results of everolimus (EVR) in combination with tacrolimus at low exposure (low TAC) from a registration study in liver transplantation, on the grounds that there was insufficient information to determine whether EVR has a significant contribution to the efficacy of the combination. This regulatory challenge was justified. Not addressing it would have jeopardized the registration. A dose-exposure-response analysis was conducted to assess the contribution of EVR to the efficacy of the combination.
Methods: In this study where the combination (EVR + low TAC) was compared with TAC alone at high exposure (high TAC alone), the absence of a putative placebo group (low TAC alone) prevented a direct comparison with the combination and thus an easy way to assess the contribution of EVR to the efficacy of the combination. We proposed to (1) establish the relationship between TAC exposure and the occurrence of rejection, (2) predict the efficacy of low TAC alone from this relationship, and finally (3) estimate the contribution of EVR to the efficacy of the combination, using a Cox proportional hazard model adjusted for time-varying TAC exposure. In the context of sparse PK samples (<10 by subject) but frequent TAC dose changes (10 by subject on average), a one-compartment population PK model with first order absorption was used to get an accurate estimate of the time-varying TAC exposure.
Results: Using this model-based approach, the probability of rejection over a 12 month period in an hypothetical subject treated with low TAC alone was estimated equal to 27%, which is much higher than the 10% and 6% with high TAC alone and the combination, respectively. The hazard ratio for the comparison between low TAC alone and the combination was equal to 5.1 (95% CI=[2,3,11.4]), indicating that the instantaneous risk of rejection is decreased 5 times when EVR is added to low TAC.
Conclusion: By combining dose and concentration histories in a model-based approach, it was possible to account for the frequent changes in dose strength and to provide an accurate estimate of the TAC exposure which serves as precise basis for the subsequent exposure-response analysis. Using this model-based methodology, the contribution of EVR to the efficacy of the combination was successfully characterized, addressing the FDA’s challenge; as a result the FDA approved the combination.
Reference: PAGE 22 () Abstr 2921 [www.page-meeting.org/?abstract=2921]
Poster: New Modelling Approaches