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 .