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Sirolimus(SRL) in heart transplantation: preliminary results of a multicenter registry in Spain
The Journal of Heart and Lung Transplantation Volume 23, Number 2S
Abstracts
S141
I. Adamidis,1 I. Kaczmarek,1 B. Meiser,1 P. Landwehr,1 M. Mueller,1 J. Groetzner,1 P. Ueberfuhr,1 B. Reichart,1 1Cardiac Surgery, Ludwig-Maximilians-University, Grosshadern University Hospital, Munich, Bavaria, Germany
Correlation (r2) between CsA or MPA AUC0 –12 hr and Single Time Points
Background: Immunosuppressive compounds might have detrimental effects on gonadal function resulting in infertility and impotence. These effects could be augmented by the antiproliferative action of sirolimus. Therefore, the impact of sirolimus on gonadal function was evaluated in heart transplant recipients. Methods: 23 male heart transplant recipients (mean age 51.4 ⫾ 12.4, 2.7 ⫾ 2.4 years after HTx) receiving a sirolimus-based immunosuppressive regimen were matched with a control of 23 male recipients (mean age 51.1 ⫾ 13.2, 2.8 ⫾ 2.5 years after HTx) with a sirolimus-free immunosuppression. Patients were matched according to age and date of HTx. Total testosterone (TT), free androgen-index (FA), luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex hormone binding globulin (SHBG) were determined. Further covariables evaluated were serum creatinine, diabetes mellitus, sirolimus trough levels and steroid administration. Results: The sirolimus-group revealed significantly higher levels for the gonadotropines LH (12.4 ⫾ 18.8 versus 5.3 ⫾ 2.9 mlU/ml; p ⬍ 0.05) and FSH (12.7 ⫾ 18.7 versus 6.8 ⫾ 4.2 mlU/ml; p ⬍ 0.05) than the control group. TT was lower in the sirolimus-group but the difference was not significant (4.0 ⫾ 1.5 versus 4.7 ⫾ 1.9 ng/ml; p ⫽ ns). There were no differences for SHBG, FA, creatinine levels and steroid administration. The incidence of post transplant diabetes mellitus was significantly higher in the control group (8% versus 37%, p ⫽ 0.018). Conclusion: Sirolimus blocks the activation of the cell-cycle-specific kinase (TOR) resulting in a decrease of cell-cycle progression at the juncture of G1 and S phase which might lead to gonadal impairment. The elevation of LH and FSH levels indicate a pituitary feed-back for a beginning lack of testosterone in the sirolimus group. Further studies with a longer follow-up are necessary to prove this initial evidence.
MPA C0 MPA C1 MPA C2 MPA C3 MPA C4 MPA C6 MPA C8 MPA C12
293 OPTIMAL TIME POINT TO PREDICT CYCLOSPORINE, TACROLIMUS AND MYCOPHENOIC ACID AREA-UNDER-THECURVE (AUC)0-12 hr IN LONG-TERM HEART/HEART-LUNG TRANSPLANT PATIENTS M. Cantarovich,1 N. Giannetti,1 R. Cecere,2 G. Fontaine,3 J.-G. Besner,4 1Medicine; 2Cardiovascular and Thoracic Surgery; 3 Nursing, Transplant Program, McGill University Health Center, Montreal, QC, Canada; 4Faculte de Pharmacie, Universite de Montreal, Montreal, QC, Canada Currently, therapeutic drug monitoring (TDM) of cyclosporine (CsA) and tacrolimus (Tacro) is based on trough level concentration (C0). However, either acute rejection or renal dysfunction may be observed in the presence of “therapeutic” C0 levels. TDM of mycophenolate mofetil (MMF) with mycophenolic acid (MPA) is usually based on side-effects and not on C0 levels. Purpose: To determine the optimal time point to predict CsA, Tacro and MPA AUC0-12 hr in long-term heart(H)/heart-lung(HL) and lung(L) transplant (Tx) patients (pts). Methods: We studied 14 HTx pts on maintenance CsA microemulsion and MMF, and 9 pts (HTx ⫽ 7, HLTx ⫽ 1, LTx ⫽ 1) on maintenance Tacro and MMF. All the pts were stable, ⬎1 yr. post-Tx. Results: Results are shown in the tables.
CsA C0
CsA C1
CsA C2
CsA C3
CsA C4
CsA C6
CsA C8
CsA C12
0.31
0.34
0.87
0.74
0.51
0.65
0.62
0.29
0.48
0.08
0.09
0.23
0.44
0.60
0.44
0.38
Correlation (r2) between Tacrolimus or MPA AUC 0 –12 hr Tacro C0
Tacro C1
Tacro C2
Tacro C3
Tacro C4
Tacro C6
Tacro C8
Tacro C12
0.63
0.75
0.81
0.91
0.95
0.81
0.88
0.72
MPA C0 MPA C1 MPA C2 MPA C3 MPA C4 MPA C6 MPA C8 MPA C12 0.87
0.66
0.54
0.40
0.59
0.73
0.82
0.62
Conclusion: Our results suggest that in long-term HTx, CsA C2 is the best predictor of CsA AUC0-12 hr and is presently being assessed in de novo HTx pts. In HTx, HLTx and LTx pts, Tacro C1, C2, C3 or C4 are superior time point predictors of Tacro AUC0-12 hr compared to C0. When using Tacro, MMF TDM can be performed with C0. However, when using CsA, MMF TDM with C0 may be clinically irrelevant. Tacro TDM may be more accurate using C3 or C4 rather than C0. 294 SIROLIMUS(SRL) IN HEART TRANSPLANTATION: PRELIMINARY RESULTS OF A MULTICENTER REGISTRY IN SPAIN M.G. Crespo,1 N. Manito,2 G. Ra ´ bago,3 J.F. Delgado,4 J.M. Arizo ´ n,5 E. Lage,6 J. Palomo,7 1Cardiologı´a, H.Juan Canalejo; 2H.Bellvitge; 3 C.U.Navarra; 4H.Doce Octubre; 5H.Reina Sofı´a; 6H.Virgen Rocı´o; 7 H.Gregorio Maran ˜o ´n Background: SRL is a non nephrotoxic immunosuppressive drug, that inhibits intimal proliferation, what could play a role in graft vascular disease (GVD) in heart transplantation (HT). SRL exhibits also preclinical antitumoral properties. Methods: a registry of heart receptors who received SRL through a compassionate use after therapies based on calcineurin inhibitors (CNI), has been created in Spain in order to characterize efficacy and safety. Results: 71 patients (91% male) (mean age 61 years) were included. Initial immunosuppression was based on cyclosporine in 67% and tacrolimus in 33%. SRL was started on a median of 75 months (range: 0.3-184) post transplant. 66% of patients suffered at least one episode of rejection before starting on SRL. The reasons to introduce SRL were renal function impairment in 70%, GVD in 60%, neurotoxicity in 8%, and distinct neoplasias in 27%. The mean initial dose of SRL was 1.9 mg/day (range: 1-4). Mean first through SRL levels achieved was 10.4 ng/ml (range: 2.5-45). A loading dose of SRL was used in 6% and CNI withdrawal was progressive and was achieved in 43% at 6th month. With a mean follow up of 7.3 months, two patients developed rejection. 9 patients(12.7%) died due to: progression of neoplasia (n ⫽-2), infection (n-⫽ 2), neumonitis (n-⫽ 2), sudden death (n ⫽ 2) and cerebrovascular disease (n ⫽ 1). Survival of patients with GVD at 6th month was 84%. Mean creatinine clearance of patients recruited due to nephrotoxicity changed from 46 ml/min at baseline to 38 ml/min at 6th month (p ⫽ 0.01). Lipids at baseline and at 6th month were: triglycerides, 128 and 174 mg/dl (p ⫽ 0.002); cholesterol, 171 and 208 mg/dl (p ⫽ 0.001). Conclusion: a registry of HT recipients treated with SRL has been developed. Most of the patients were included due to renal function impairment and GVD. Improvement in CNI related nephrotoxocity may require an earlier introduction of SRL and a shorter time of concomitant use with CNI. Safety and efficacy parameters for GVD and tumors will require longer follow up.
Abstracts
S141
I. Adamidis,1 I. Kaczmarek,1 B. Meiser,1 P. Landwehr,1 M. Mueller,1 J. Groetzner,1 P. Ueberfuhr,1 B. Reichart,1 1Cardiac Surgery, Ludwig-Maximilians-University, Grosshadern University Hospital, Munich, Bavaria, Germany
Correlation (r2) between CsA or MPA AUC0 –12 hr and Single Time Points
Background: Immunosuppressive compounds might have detrimental effects on gonadal function resulting in infertility and impotence. These effects could be augmented by the antiproliferative action of sirolimus. Therefore, the impact of sirolimus on gonadal function was evaluated in heart transplant recipients. Methods: 23 male heart transplant recipients (mean age 51.4 ⫾ 12.4, 2.7 ⫾ 2.4 years after HTx) receiving a sirolimus-based immunosuppressive regimen were matched with a control of 23 male recipients (mean age 51.1 ⫾ 13.2, 2.8 ⫾ 2.5 years after HTx) with a sirolimus-free immunosuppression. Patients were matched according to age and date of HTx. Total testosterone (TT), free androgen-index (FA), luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex hormone binding globulin (SHBG) were determined. Further covariables evaluated were serum creatinine, diabetes mellitus, sirolimus trough levels and steroid administration. Results: The sirolimus-group revealed significantly higher levels for the gonadotropines LH (12.4 ⫾ 18.8 versus 5.3 ⫾ 2.9 mlU/ml; p ⬍ 0.05) and FSH (12.7 ⫾ 18.7 versus 6.8 ⫾ 4.2 mlU/ml; p ⬍ 0.05) than the control group. TT was lower in the sirolimus-group but the difference was not significant (4.0 ⫾ 1.5 versus 4.7 ⫾ 1.9 ng/ml; p ⫽ ns). There were no differences for SHBG, FA, creatinine levels and steroid administration. The incidence of post transplant diabetes mellitus was significantly higher in the control group (8% versus 37%, p ⫽ 0.018). Conclusion: Sirolimus blocks the activation of the cell-cycle-specific kinase (TOR) resulting in a decrease of cell-cycle progression at the juncture of G1 and S phase which might lead to gonadal impairment. The elevation of LH and FSH levels indicate a pituitary feed-back for a beginning lack of testosterone in the sirolimus group. Further studies with a longer follow-up are necessary to prove this initial evidence.
MPA C0 MPA C1 MPA C2 MPA C3 MPA C4 MPA C6 MPA C8 MPA C12
293 OPTIMAL TIME POINT TO PREDICT CYCLOSPORINE, TACROLIMUS AND MYCOPHENOIC ACID AREA-UNDER-THECURVE (AUC)0-12 hr IN LONG-TERM HEART/HEART-LUNG TRANSPLANT PATIENTS M. Cantarovich,1 N. Giannetti,1 R. Cecere,2 G. Fontaine,3 J.-G. Besner,4 1Medicine; 2Cardiovascular and Thoracic Surgery; 3 Nursing, Transplant Program, McGill University Health Center, Montreal, QC, Canada; 4Faculte de Pharmacie, Universite de Montreal, Montreal, QC, Canada Currently, therapeutic drug monitoring (TDM) of cyclosporine (CsA) and tacrolimus (Tacro) is based on trough level concentration (C0). However, either acute rejection or renal dysfunction may be observed in the presence of “therapeutic” C0 levels. TDM of mycophenolate mofetil (MMF) with mycophenolic acid (MPA) is usually based on side-effects and not on C0 levels. Purpose: To determine the optimal time point to predict CsA, Tacro and MPA AUC0-12 hr in long-term heart(H)/heart-lung(HL) and lung(L) transplant (Tx) patients (pts). Methods: We studied 14 HTx pts on maintenance CsA microemulsion and MMF, and 9 pts (HTx ⫽ 7, HLTx ⫽ 1, LTx ⫽ 1) on maintenance Tacro and MMF. All the pts were stable, ⬎1 yr. post-Tx. Results: Results are shown in the tables.
CsA C0
CsA C1
CsA C2
CsA C3
CsA C4
CsA C6
CsA C8
CsA C12
0.31
0.34
0.87
0.74
0.51
0.65
0.62
0.29
0.48
0.08
0.09
0.23
0.44
0.60
0.44
0.38
Correlation (r2) between Tacrolimus or MPA AUC 0 –12 hr Tacro C0
Tacro C1
Tacro C2
Tacro C3
Tacro C4
Tacro C6
Tacro C8
Tacro C12
0.63
0.75
0.81
0.91
0.95
0.81
0.88
0.72
MPA C0 MPA C1 MPA C2 MPA C3 MPA C4 MPA C6 MPA C8 MPA C12 0.87
0.66
0.54
0.40
0.59
0.73
0.82
0.62
Conclusion: Our results suggest that in long-term HTx, CsA C2 is the best predictor of CsA AUC0-12 hr and is presently being assessed in de novo HTx pts. In HTx, HLTx and LTx pts, Tacro C1, C2, C3 or C4 are superior time point predictors of Tacro AUC0-12 hr compared to C0. When using Tacro, MMF TDM can be performed with C0. However, when using CsA, MMF TDM with C0 may be clinically irrelevant. Tacro TDM may be more accurate using C3 or C4 rather than C0. 294 SIROLIMUS(SRL) IN HEART TRANSPLANTATION: PRELIMINARY RESULTS OF A MULTICENTER REGISTRY IN SPAIN M.G. Crespo,1 N. Manito,2 G. Ra ´ bago,3 J.F. Delgado,4 J.M. Arizo ´ n,5 E. Lage,6 J. Palomo,7 1Cardiologı´a, H.Juan Canalejo; 2H.Bellvitge; 3 C.U.Navarra; 4H.Doce Octubre; 5H.Reina Sofı´a; 6H.Virgen Rocı´o; 7 H.Gregorio Maran ˜o ´n Background: SRL is a non nephrotoxic immunosuppressive drug, that inhibits intimal proliferation, what could play a role in graft vascular disease (GVD) in heart transplantation (HT). SRL exhibits also preclinical antitumoral properties. Methods: a registry of heart receptors who received SRL through a compassionate use after therapies based on calcineurin inhibitors (CNI), has been created in Spain in order to characterize efficacy and safety. Results: 71 patients (91% male) (mean age 61 years) were included. Initial immunosuppression was based on cyclosporine in 67% and tacrolimus in 33%. SRL was started on a median of 75 months (range: 0.3-184) post transplant. 66% of patients suffered at least one episode of rejection before starting on SRL. The reasons to introduce SRL were renal function impairment in 70%, GVD in 60%, neurotoxicity in 8%, and distinct neoplasias in 27%. The mean initial dose of SRL was 1.9 mg/day (range: 1-4). Mean first through SRL levels achieved was 10.4 ng/ml (range: 2.5-45). A loading dose of SRL was used in 6% and CNI withdrawal was progressive and was achieved in 43% at 6th month. With a mean follow up of 7.3 months, two patients developed rejection. 9 patients(12.7%) died due to: progression of neoplasia (n ⫽-2), infection (n-⫽ 2), neumonitis (n-⫽ 2), sudden death (n ⫽ 2) and cerebrovascular disease (n ⫽ 1). Survival of patients with GVD at 6th month was 84%. Mean creatinine clearance of patients recruited due to nephrotoxicity changed from 46 ml/min at baseline to 38 ml/min at 6th month (p ⫽ 0.01). Lipids at baseline and at 6th month were: triglycerides, 128 and 174 mg/dl (p ⫽ 0.002); cholesterol, 171 and 208 mg/dl (p ⫽ 0.001). Conclusion: a registry of HT recipients treated with SRL has been developed. Most of the patients were included due to renal function impairment and GVD. Improvement in CNI related nephrotoxocity may require an earlier introduction of SRL and a shorter time of concomitant use with CNI. Safety and efficacy parameters for GVD and tumors will require longer follow up.