UNDERSTANDING IMMUNOSUPPRESSANT USE IN KIDNEY TRANSPLANTATION: MAJOR CHANGES IN DRUG REGIMEN, SHIFTS IN DOSING OVER TIME, AND KAPLAN-MEIER SURVIVAL ESTIMATES BY MAJOR ERA USING THE ANZDATA REGISTRY

D METZ1, N HOLFORD2, JKAUSMAN1, N CRANSWICK1, AWALKER1, F IERINO3
1Royal Children’s Hospital, Elsternwick, Australia, 2University of Auckland, Auckland, New Zealand, 3St Vincent’s Hospital Melbourne, Fitzroy, Australia

Aims: To define key immunosuppressant eras as reflected in the ANZDATA transplant registry and the change in doses at different time points post-transplant
Methods: Data from all transplant recipients in the ANZDATA registry from 1963 to 2015 were collected, including time-varying dosing data. Era onset for the ‘predominant use’ of each immunosuppressant was defined as use in >50% of incident transplant episodes/year. Dosing of each immunosuppressant was summarized for each year of use, by median and interquartile range (IQR) dose/day. Kaplan-Meier estimates of survival and graft survival based upon these eras were generated using R version 3.4.2.
Results: From 1963 to 1980 azathioprine was combined with large doses of prednisolone. First appearing in 1980, cyclosporine was in predominant use by 1985. Mycophenolate was in predominant use by 1998, replacing azathioprine. Tacrolimus use increased from 2000 (35% of incident transplants) to predominance in 2007, over cyclosporine.
Dosing for all immunosuppressants has decreased over the most recent era. Tacrolimus dosing between 2000- 2015: at 12 months- 0.09mg/kg (0.05-0.13) to 0.05mg/kg (0.03-0.08); at 5 years, 0.06mg/kg (0.04-0.09) to 0.05 (0.03-0.08). Mycophenolate dosing between 1998 to 2015: at 3-months, 2g/day to 1.5g/day (1-2g/day); at 12months, 2g/day to 1.5g/day (1-1.5); and at 5 years, 2g/day (1.5-2) to 1g (1-1.5). Prednisolone dosing between 1995 to 2015: at 3 months, 15mg/day (10-20) to 10mg/day (7.5-12.5); at 12 months, 7mg/day (5-10) to 5mg/day (5-7.5); and at 5 years, 7.5mg/day (5-10) to 5mg/day (5-6).
Conclusion:  Distinct immunosuppressant drug eras have been identified. Dosing of these immunosuppressant drugs has reduced over time in both early and maintenance phases. This preliminary analysis will help inform the time varying hazard for subsequent parametric time to event analysis.


Biography:
Dr David Metz is a Paediatric Nephrologist and Clinical Pharmacologist based at the Royal Children’s Hospital in Melbourne. He is interested in quantitative pharmacology, and pharmacometric techniques to optimizing immunosuppression.

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