主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
A mammalian target of rapamycin (mTOR) inhibitor everolimus (EVR) is approved as one of the immunosuppressive drugs for the prevention of graft organ rejection as well as the agent against various types of cancer and tuberous sclerosis complex. EVR in combination with cyclosporine was approved as an immunosuppressive regimen for the patients after heart transplantation in 2007 in Japan. After that, EVR was also approved for the prevention of graft kidney rejection in 20111. Tacrolimus has been used as a primary calcineurin inhibitor (CNI) in patients after kidney transplantation, and therefore, it is important to establish the methodology of EVR monitoring including the appropriate target range.
Minimizing the use of CNI after organ transplantations reduces long-term complications, including nephrotoxicity and myelosuppression2,3. It was reported that another mTOR inhibitor sirolimus reduced interstitial fibrosis and glomerular sclerosis after kidney transplantation in patients with chronic allograft nephropathy4. In the subtotal nephrectozised (5/6Nx) rats, which are well acknowledged as a good animal model of chronic renal failure in human, marked activation of the mTOR pathway was found at glomeruli and proximal tubules in remnant kidneys5. EVR treatment reduced the expression levels of the phosphorylated S6 which is a marker of activated mTOR. In addition, EVR-treatment restored the tubular reabsorption of albumin, suggesting the regeneration from the functional impairment of tubular epithelial cells5.
Taken together, both of the results of the clinical trials and animal experiments suggest that EVR in combination with the minimized CNI would be a strong strategy in patients after organ transplantation preventing long-term CNI-induced nephrotoxicity such as fibrotic renal disease.
References:
1 Highlights of prescribing information of ZORTRESS® (everolimus) (2016).
2 van Gelder, T., Fischer, L., Shihab, F. & Shipkova, M. Transplant Rev 31, 151-157 (2017).
3 Shipkova, M. et al. Ther Drug Monit 38, 143-169 (2016).
4 Chan, L. et al. Transplantation 85, 821-826 (2008).
5 Nakagawa, S., Masuda, S., Nishihara, K. & Inui, K. Biochem Pharmacol 79, 67-76 (2010).
Grant information: KAKENHI from MEXT Japan (15H04666)
