DJAR Moes (1, 3), S Jönsson (2), J den Hartigh (1), T van der Straaten (1), JJ Homan van der Heide (4), JS Sanders (5), FJ Bemelman (4), H-J Guchelaar (1), MO Karlsson (2) & JW de Fijter (3)
(1) Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. (2) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. (3) Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands. (4) Department of Nephrology, Academic Medical Center, Amsterdam, The Netherlands. (5) Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands.
Objectives: Everolimus is an emergent non-nephrotoxic alternative for calcineurin inhibitors with substantial potential non-renal benefits in renal transplantation. Despite its proven efficacy and close therapeutic drug monitoring, everolimus is also known for relatively high discontinuation rates and some serious side effects. The primary objective of this study was to develop time-to-event models for the time to drug discontinuation and the key side effect (i.e pneumonitis, infection and new onset diabetes mellitus) to identify risk factors that may determine therapy outcome.
Methods: An extensive dataset consisting of demographic, transplant related and pharmacogenetic data of 99 stable adult renal transplant recipients on a regimen of everolimus and prednisone dual therapy was used for a systematic analysis using a parametric survival model for each different endpoint to describe the time to discontinuation and the most hazardous side effects including pneumonitis, infection and new onset diabetes mellitus. Modelling was performed using NONMEM v7.3.0 and R statistics was used for summary statistics and plotting.
Results: The baseline hazard of discontinuation, pneumonitis and infection data, respectively, was best described by a Gompertz function and an exponential hazard function was used to describe the baseline hazard of new onset diabetes mellitus. Risk factors for everolimus discontinuation were excess everolimus exposure and increasing age. Furthermore, risk factors for the hazardous side-effect non-infectious interstitial pneumonitis were excess everolimus exposure and PXR(NR1|2)(-24113G>A):AA genotype. For infection and new onset diabetes mellitus no significant risk factors could be identified.
Conclusions: The current findings indicate that discontinuation rates and non-infectious pneumonitis in renal transplant recipients on everolimus can be prevented by avoiding excess initial and/or excess maintenance everolimus exposure.
Reference: PAGE 24 () Abstr 3341 [www.page-meeting.org/?abstract=3341]
Poster: Drug/Disease modeling - Safety