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Conversion from CNI to sirolimus
Byung Chul ShinDivision of Nephrology
Chosun University Hospital, Gwangju
mTOR inhibitor
mTOR: Mammalian Target Of Rapamycin
1999 USA
EVEROLIMUS(CERTICAN)SIROLIMUS(RAPAMUNE)
mTOR Inhibitors
• Target site : mammalian target of ra-pamycin (mTOR), a key regulatory kinase in cell division.
• Sirolimus (Rapamune®) only available mTOR inhibitor in the US.
• Everolimus (Certican®)• Administered once daily, 24-hour trough
levels monitored.• Metabolized by P450 3A system, with in-
teractions similar to the CNIs.
Sirolimus: Mechanism of ActionSRL: Sirolimus
FKBP: FK Binding Pro-tein
mTOR: Mammalian tar-get of rapamycin
Cdk: cyclin-dependent kinase
Stepkowski, Expert Rev Mol Med, 2000;2(4):1
Halloran, N Eng J Med, 2004;351:3715
Can mTOR inhibitor Replace CNI?
Malignancy?
Nephrotoxicity?
CVA?
N Engl J Med. 2005 Mar 31;352(13):1317-23.
Sirolimus for Kaposi's sarcoma in renal-transplant recipients.
Kaposi’s sarcoma in a transplant recipientKaposi’s sarcoma in a transplant recipient After 1 month of TxAfter 1 month of Tx
Can mTOR Inhibitor Replace CNI?
Malignancy? Nephrotoxicity? CVA?
Synergistic Nephrotoxicity
The Combination of CNI and mTORI
ng/g
0
30
60
90
120
150
CsA
CsA+SR
L
*
Drug interaction between mTORI and CsA in Kidney
0
1.5
3
4.5
6
7.5
SRL CsA+SRL
ng/g
*
CsA conc. SRL conc.
SRL as a Primary Immnosuppressant
Initial combination of SRL + CsA
Acute Re-jection↓
Followed by Elimination of CsA Preserve Graft Function
Lesson form Experimental and Clinical studies
Kidney with already significant injury by CNI may be less likely to benefit from con-version to SRL
Early conversion is essential to preserve graft function
Malignancy? Nephrotoxicity?CVA risk?
Can mTOR Inhibitor Replace CNI?
Lipid Profile
Posttransplant month
mg/dL
168
80 98
58
237179
165
52
302
217
195
88
256
252
174
58
0
50
100
150
200
250
300
350
400
450
0 1 3 4
Chol
TG
LDL-c
HDL-c
SRL itself does not cause serious pancreatic in-
jury.
Synergistic pancreatic injury with CNI.
Conversion to SRL dose not improve DM in estab-
lished CNI-induced DM.
Influence of SRL on Diabetes
Switch from CNI to SRL(N=26)
30% increase of IGTNew PTDM in 4 patients
PTDM by CNI may NOT be considered as an indication for conversion to SRL
Can mTOR Inhibitor Replace CNI?
Malignancy - Yes Yes !
Nephrotoxicity - Yes Yes !
CVA ?
SUMMARY
“ Five" adverse effects ★
Hyperlipidemia
Delayed wound healing
Synergistic nephrotoxicity with
CsA
Proteinuria
Lymphocele
간헐적 발열과 기침 , 객담배양검사에서 음성
SRL 에 의한 interstitial pnenumonitis
의심
Fritz Diekmann et al, Nephrol Dial Transplant (2006) 21: 562–568
Fritz Diekmann et al, Nephrol Dial Transplant (2006) 21: 562–568
Fritz Diekmann et al, Nephrol Dial Transplant (2006) 21: 562–568
Treatment Regimens• SRL conversion : a single loading dose (12-20 mg) between 4 and 24 hours after the last dose of CNI. • On day 2: 4 to 8 mg SRL - trough level 8 to 20 ng/mL• MMF and azathioprine : reduced to 1.5 g/day and 75 mg/day
• CNI continuation : CsA (C0: 50 –250 ng/mL) or tacrolimus (C0: 4 –10 ng/mL)
Schena et al, Transplantation 2009;87: 233–242
Schena et al, Transplantation 2009;87: 233–242
Schena et al, Transplantation 2009;87: 233–242
CHEN LI, et al. Transplantation Proceedings 40, 1411–1415 (2008)
Switch from CNI to SRL(N=16)
Creatinine level < 2.48 mg/dLNo C4d deposition in PTCSerum creatinine level and the deposition of C4d in PTC
-> important factors influencing therapeutic efficacy
CHEN LI, et al. Transplantation Proceedings 40, 1411–1415 (2008)
Slow Conversion Protocol
• SRL start : 2-4mg/daily without loading• CNI reduced : 50%• Short overlap phase : 7-10 days• Target trough levels : 8-12ng/mL• SRL given : 4hr after CsA, simultane-
ously tacrolimus• Steroid Tx : no change• MMF : maximum 1.5g/day
Slow CONVERSION
weeks
0 1 2 3 4
Sirolimus (8-12 ng/mL)
Sirolimus(2-4 mg/
day)
CNI 50%
Sirolimus
CNI (CsA or TAC)
MMF and/or steroid
MMF (≤1.5 g/day) and/or steroids
Abrupt Conversion Protocol
• CNI withdrawn : day 1• SRL loading : 15-18mg• SRL followed : 4-6mg/day• SRL trough levels : 8-12ng/mL• Other immunosuppressive drugs :
unchanged• Bactrim prophylaxis : 6 months
Viorica Bumbea et al, Nephrol Dial Transplant 20: 2517-2523, 2005
Abrupt CONVERSION
weeks
0 1 2 3 4
Sirolimus (8-20 ng/mL)
D1: Sirolimus (12-20 mg/day)
Sirolimus
CNI (CsA or TAC)
MMF or AZA MMF (≤1.5 g/day) or AZA (75 mg/day)
D2: Sirolimus (4-8 mg/day) -> 3-5 mg/day
Bactrim
결론 mTORI 는 CNI 를 대체할 수 있는 유용한 약제이
다 .
비가역적인 손상이 오기전에 조기전환이 중요 .
mTOR inhibitor 의 부작용을 잘 알고 있어야 한
다 .