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Comparative efficacy of liposomal FK506 with FK506
TACROLIMUS
Comparative Efficacy of Liposomal FK506 With FK506 S.D. Moffatt, V. McAlister, R.Y. Calne, and S. Metcalfe
F
K506 IS A potent immunosuppressive agent that has improved the success of clinical organ transplantation.1 Neurotoxicity, nephrotoxicity, and diabetogenicity are characteristic adverse effects of FK506 and, hence, restrict the permissible dosage.2 Liposomal FK506 (LFK506) was developed to reduce the adverse side effect profile without lessening the immunosuppressive activity. One such liposomal formulation has been shown to be effective in canine liver transplantation.1 FK506 has been shown to be concentrated in the reticuloendothelial system and, in particular, in the liver and spleen.3 Our own LFK506 preparation shows a similar biodistribution profile to that previously published3 and it is tested here for efficacy in vivo. MATERIAL AND METHODS All mice were obtained from Harlan UK. CBA/Ca (H2k) recipients were grafted with BALB/c (H2d) hearts, thus representing both minor and major histocompatibility mismatches. Untreated allograft rejection time was 7 days.
Heart Transplantation Heterotopic heart grafts were performed in the right neck as previously described.4 Liposomal FK506 and FK506 LFK506 consisted of 5% Phopholipon 90 –H, Loranlan–CH cholesterol, and 0.02% tacrolimus. FK506 was generously supplied by Fujisawa GmbH, Germany. Both formulations were administered in
a dose of 1 mg/kg intraperitoneally starting on Day 0 through Day 14. Experimental Groups All groups consisted of 6 allografts. Group 1 received LFK506. Group 2 received FK506. Group 3 received liposomes. All hearts were palpated daily, and cessation of beating was taken as rejection. Serum FK506 levels were measured on day 7 in Group 1 and on day 7 and 21 in Group 2. RESULTS
No adverse effects of liposomes or LFK506 were observed. One mouse in the FK506 group died secondary to GI disturbance. Results of the experimental group survival times and drug levels are presented in Table 1.
From the Department of Surgery, Addenbrooke’s Hospital, Cambridge, UK and the Department of Surgery, Dalhousie University, Halifax, N.S., Canada. Dr Moffatt is supported by the Canadian Surgical Research Fund and the NATO International Scientific Exchange Programme. Address reprint requests to Dr S.D. Moffatt, Department of Surgery, Addenbrooke’s Hospital, Cambridge, UK, CB2 2QQ.
Table 1. Graft Survival in Allografts Treated With LFK506 or FK506
Group
Drug (1 mg/kg)
n
Survival Range (d)
1 2 3
LFK506 FK506 Liposomes
6 6 6
14, 25, 25, 25, 27, .100 51, 25, 27, 29, .100, .100 7, 7, 7, 8, 7, 7
Mean FK506 (mg/L) Day 7
Mean FK506 (mg/L) Day 21
2.4 21.0
,2.0
1
Death.
0041-1345/98/$19.00 PII S0041-1345(98)01342-6
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
4066
Transplantation Proceedings, 30, 4066–4067 (1998)
EFFICACY OF LIPOSOMAL FK506
4067
DISCUSSION
REFERENCES
LFK506 treated allografts have a significantly prolonged survival, and hence, this formulation has the potential to be immunosuppressive without notable side effects. LFK506 biodistribution is likely to enhance immunosuppression and to allow for prolonged graft survival at low serum levels when compared to conventional FK506. Therefore, LFK506 has a potential major benefit for clinical immunsuppression.
1. Ko S, Nakajima Y, Kanehiro H, et al: Transplantation 59:1384, 1995 2. Ko S, Nakajima Y, Kanehiro H, et al: Transplantation 58:1142, 1995 3. Sakaguchi K, Suzuki M, Ogata Y, et al: Jpn J Artif Organs 22:560, 1993 4. Chen Z, Transplantation 52:1099, 1991
Comparative Efficacy of Liposomal FK506 With FK506 S.D. Moffatt, V. McAlister, R.Y. Calne, and S. Metcalfe
F
K506 IS A potent immunosuppressive agent that has improved the success of clinical organ transplantation.1 Neurotoxicity, nephrotoxicity, and diabetogenicity are characteristic adverse effects of FK506 and, hence, restrict the permissible dosage.2 Liposomal FK506 (LFK506) was developed to reduce the adverse side effect profile without lessening the immunosuppressive activity. One such liposomal formulation has been shown to be effective in canine liver transplantation.1 FK506 has been shown to be concentrated in the reticuloendothelial system and, in particular, in the liver and spleen.3 Our own LFK506 preparation shows a similar biodistribution profile to that previously published3 and it is tested here for efficacy in vivo. MATERIAL AND METHODS All mice were obtained from Harlan UK. CBA/Ca (H2k) recipients were grafted with BALB/c (H2d) hearts, thus representing both minor and major histocompatibility mismatches. Untreated allograft rejection time was 7 days.
Heart Transplantation Heterotopic heart grafts were performed in the right neck as previously described.4 Liposomal FK506 and FK506 LFK506 consisted of 5% Phopholipon 90 –H, Loranlan–CH cholesterol, and 0.02% tacrolimus. FK506 was generously supplied by Fujisawa GmbH, Germany. Both formulations were administered in
a dose of 1 mg/kg intraperitoneally starting on Day 0 through Day 14. Experimental Groups All groups consisted of 6 allografts. Group 1 received LFK506. Group 2 received FK506. Group 3 received liposomes. All hearts were palpated daily, and cessation of beating was taken as rejection. Serum FK506 levels were measured on day 7 in Group 1 and on day 7 and 21 in Group 2. RESULTS
No adverse effects of liposomes or LFK506 were observed. One mouse in the FK506 group died secondary to GI disturbance. Results of the experimental group survival times and drug levels are presented in Table 1.
From the Department of Surgery, Addenbrooke’s Hospital, Cambridge, UK and the Department of Surgery, Dalhousie University, Halifax, N.S., Canada. Dr Moffatt is supported by the Canadian Surgical Research Fund and the NATO International Scientific Exchange Programme. Address reprint requests to Dr S.D. Moffatt, Department of Surgery, Addenbrooke’s Hospital, Cambridge, UK, CB2 2QQ.
Table 1. Graft Survival in Allografts Treated With LFK506 or FK506
Group
Drug (1 mg/kg)
n
Survival Range (d)
1 2 3
LFK506 FK506 Liposomes
6 6 6
14, 25, 25, 25, 27, .100 51, 25, 27, 29, .100, .100 7, 7, 7, 8, 7, 7
Mean FK506 (mg/L) Day 7
Mean FK506 (mg/L) Day 21
2.4 21.0
,2.0
1
Death.
0041-1345/98/$19.00 PII S0041-1345(98)01342-6
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
4066
Transplantation Proceedings, 30, 4066–4067 (1998)
EFFICACY OF LIPOSOMAL FK506
4067
DISCUSSION
REFERENCES
LFK506 treated allografts have a significantly prolonged survival, and hence, this formulation has the potential to be immunosuppressive without notable side effects. LFK506 biodistribution is likely to enhance immunosuppression and to allow for prolonged graft survival at low serum levels when compared to conventional FK506. Therefore, LFK506 has a potential major benefit for clinical immunsuppression.
1. Ko S, Nakajima Y, Kanehiro H, et al: Transplantation 59:1384, 1995 2. Ko S, Nakajima Y, Kanehiro H, et al: Transplantation 58:1142, 1995 3. Sakaguchi K, Suzuki M, Ogata Y, et al: Jpn J Artif Organs 22:560, 1993 4. Chen Z, Transplantation 52:1099, 1991