Thomas Dumortier, Ovidiu Chiparus, Martin Fink
Novartis Pharmacometric department
Objectives: Support a pediatric investigational plan (PIP) for everolimus® in liver transplantation (Tx) in 2015, using a model based approach.
Methods: The paediatric study included 22 patients treated with everolimus (EVR) and tacrolimus (TAC) for a 12-months period (‘analysis period’), starting from 1.5 to 6 months after Tx. The analysis of this study was supported by an extrapolation from an adult phase 3 study, using a PKPD approach. In that study, 740 patients were treated with TAC and EVR or TAC alone. The effect of drug concentration on the hazard of efficacy event (acute rejection, graft loss, death) was estimated from the adult data by means of a time-to-event model, similarly as done in [1]. In this model, the concentration was predicted from population PK models. The extrapolation concept is that this concentration-event relationship also holds in children. Under this assumption, the efficacy of patients treated similarly to those in the paediatric study could be predicted. This concept was validated using internal and external methods.
Results: The final model developed from the adult data includes a concentration-response relationship for TAC and a treatment effect for EVR. The validation of the extrapolation procedure was based on very high probabilities (predicted from the final model) to observe the actual results of the paediatric study (no events among the 22 patients during the analysis period) and the results of a published paediatric study [2]. Therefore the final adult model could be used to calculate with high precision the probability for a paediatric patient to experience events during the analysis period, as equal to 0.023 (95% CI = [0.012-0.039]).
Conclusions: In indications such as transplantation, enrolling a sufficient numbers of patients is challenging. In this context, leveraging relevant available data in adults may facilitate the evaluation of paediatric treatment effectiveness. Extrapolation using a PKPD approach supported evidence from the pediatric study that efficacy was the same or better in children than adults.
References:
[1] Dumortier T. Estimating the contribution of everolimus to immunosuppressive efficacy when combined with tacrolimus in liver transplantation: a model-based approach. Clin. Pharmacol. Ther. (2015) Apr;97(4):411-8
[2] Kelly D. Tacrolimus and steroids versus ciclosporin microemulsion, steroids, and azathioprine in children undergoing liver transplantation. Lancet (2004) Sep 18-24;364(9439):1054-61
Reference: PAGE 25 (2016) Abstr 5968 [www.page-meeting.org/?abstract=5968]
Poster: Drug/Disease modeling - Paediatrics