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Clinical experience with Prograf (tacrolimus, FK 506) in Chinese patients after renal transplantation
Clinical Experience With Prograf (Tacrolimus, FK 506) in Chinese Patients After Renal Transplantation L. Yu, Y. Wang, S.J. Fu, and X.J. Cheng
P
ROGRAF (FK 506) is a potent and effective immunosuppressive agent. Its clinical efficacy of anti-rejection after renal transplantation is well documented. Between January 1998 and February 1999, a total of 40 patients received FK 506 as primary immunosuppressant after kidney transplantation and 10 patients were converted to FK 506 from cyclosporine (CyA) because of hepatotoxicity. The results are summarized below.
IMx assay. Blood samples were collected at 72 hours after the first dose of FK 506. The FK 506 blood levels were monitored three times per week during the first 21 days and subsequently twice a week after week 3 and once a week after week 8. Whole-blood trough levels of FK 506 were adjusted to 10 to 20 ng/mL. When blood levels were ⬎20 ng/mL, dosage was reduced by 25%. When blood level was ⬍5 ng/mL, dosage was increased by 25%. Meanwhile, changes in hematology, routine urinalysis, platelet count, CMV-IgG, CMV-IgM, CD3, CD4, and CD8 were monitored.
MATERIALS AND METHODS Patient Selection
RESULTS
A total of 90 patients were randomized to FK 506 (n ⫽ 40) or CyA (n ⫽ 50) after cadaveric renal transplantation between January 1998 and February 1999 in our hospital. The FK 506 was started within 24 hours’ postoperation. There were no significant differences in age, sex, donor age, or cold and warm ischemic time of donor graft between the two groups.
Histological Matching Volume of lymphocytotoxicity was ⬍10% in the two groups; PRA was negative and the numbers of HLA matches were between two and five.
Study Medication Patients assigned to FK 506 received an initial dosage of 0.15 to 0.30 mg/kg per day in two divided doses; the first dose was given within 24 hours after transplantation. Patients assigned to CyA received an initial oral dosage of 8 mg/kg per day. All patients received combination immunosuppressive therapy with steroids, azathioprine, and mycophenolate mofetil (MMF). Oral azathioprine (50 mg) and prednisolone (50 mg) were administered preoperatively. Intravenous (IV) methylprednisolone (1.0 mg) was administered preoperatively and 0.5 g at 24 hours after transplantation. The MMF dosage was 1.0 g daily. Prednisolone started with an initial oral dosage of 30 mg per day after transplantation, then tapered to 25 mg/d at week 2, 20 mg/d at 1 month, and 15 mg/d at 3 months. Rejection episodes were treated similarly for patients in the two groups, and IV methylprednisolone (0.5 g) was administered for 3 days. Both steroid-resistant rejection and severe acute rejection were treated with the addition of OKT3 (5 mg/d, IV for 3 days).
Therapeutic Drug Monitoring and Adjusting The CyA whole-blood trough concentration was measured using TDx assay while FK 506 blood concentration was measured using
All patients except for one graft failure in the CyA group were followed for 6 to 12 months. Renal function was regained within 2 to 26 days after transplantation; 9 patients experienced acute rejection, 2 had pneumonic infections, 1 had urinary tract infection, 2 had nephrotoxicity, 3 had hepatotoxicity, 1 had diarrhea, and 2 had hyperglycemia. Patients and grafts in the FK 506 group all survived. They were followed for 6 to 12 months and renal function was regained within 2 to 13 days. Acute rejection occurred in 4 patients at 8, 10, 13, and 18 days, respectively, following transplantation. The incidence of adverse events reported included nephrotoxicity (2 cases), hepatotoxicity (1 case), diarrhea (22 cases), pneumonic infections (2 cases), and hyperglycemia requiring insulin therapy (14 cases); also, 2 cases experienced tachycardia but this disappeared after treatment with nitroglycerin. DISCUSSION Mechanism of Action of FK 506
The worldwide use of CyA has markedly prolonged graft survival over the past 15 tears, but its dose-related toxicity has prohibited its extensive application. People have been waiting for a novel immunosuppressive agent with lower toxicity. Thus, the appearance of FK 506 triggered significant interest among many investigators. In vivo, oral administration of FK 506 cannot inhibit immune reaction directly, but it does inhibit calcineurin phosphatase activity; this From the Dept. of Kidney Transplant, Nanfang Hospital, Guangzhou, China. Address reprint requests to Lixin Yu, Department of Kidney Transplantation, Nanfang Hospital, The First Medical University, Guangzhou 510515, China.
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/00/$–see front matter PII S0041-1345(00)01405-6
Transplantation Proceedings, 32, 1709–1710 (2000)
1709
1710
effect may prevent activation and transcription of interleukin-2 and interleukin-2 receptor gene. The net result is the inhibition of T-lymphocyte activation, so expressing powerful immunosuppressive effect. However, recent studies have revealed several new facts to the mode of action of FK 506, focusing on differences between this agent and CyA that would tend to indicate the superiority of FK 506. Clinical Pharmacokinetics of FK 506
Blood samples of 10 patients who received FK 506 after renal transplantation were collected at 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours after the first oral dose of FK 506. Whole-blood FK 506 levels were measured by IMx assay. The data suggested that FK 506 mean time to peak concentration was 1 hour and the mean elimination half-life was 8.5 hours. According to this data, FK 506 was administered once or twice a day. In our study, FK 506 was administered twice daily (7 a.m., 1 hour before meal, and 7 p.m., 1 hour after meal); 9 patients attained the mean elimination half-life after 8.5 hours, but 1 patient did not attain the mean elimination half-life even after 12 hours. The Optimal Therapeutic Window of FK 506
According to the results of our study, we believed the optimal therapeutic window of FK 506 (measured by IMx assay) in triple therapy should be as follows: 12 to 15 ng/mL for the first month, 8 to 12 ng/mL for the second month, and 6 to 10 ng/mL for the third month. After 4 months, the blood level should be maintained at 5 to 10 ng/mL. These concentration ranges not only attain satisfactory immunosuppressive effects but also minimize the adverse events of FK 506 and occurrence of rejection. Thus, regular monitoring of FK 506 blood level after renal transplantation is very important to adjust the adequate dosage and to minimize rejection and toxicity of tacrolimus (FK 506).
YU, WANG, FU ET AL
Adverse Events of FK 506 and Treatment
Gastrointestinal disorders including nausea, vomiting, and diarrhea were reported in 22/50 of FK 506-treated patients. After being treated with berberin, the symptoms disappeared. Blood glucose levels often increased at 1 week after the first dose of FK 506 and sometimes could reach 22 to 28 mmol/L. In our study, hyperglycemia occurred in 14 cases, 8 of which were able to discontinue insulin treatment within 6 months. But 6 cases still need insulin after 6 months. Comparison of Efficacy
With the introduction of CyA, rejection reaction rate was reduced markedly after renal transplantation; thus, we believed it was an effective immunosuppressive agent. Subsequently, CyA had serious adverse events, including hepatoxicity, nephrotoxicity, hirsutism, and gum hyperplasia. The clinical results of our 50 renal recipients treated with FK 506 proved to be satisfactory. The occurrence rate of rejection was reduced by 10%, and it had lower toxicity. Also, FK 506 is effective in therapy, especially in CyA toxicity cases. In our study, 10 patients converted to FK 506 from CyA because of hepatoxicity saw their liver function return to normal. CONCLUSIONS
As immunosuppressant for renal transplantation, FK 506 has a better safety profile, efficacy, and fewer side effects than CyA. It can significantly reduce the occurrence of acute rejection, patients regain their renal function quicker than that of CyA, and it can shorten duration of hospitalization. Moreover, FK 506 can be used as rescue therapy for hepatotoxicity caused by CyA. Nevertheless, clinical physicians should pay attention to hyperglycemia. Further observation is necessary for the long-term survival.
P
ROGRAF (FK 506) is a potent and effective immunosuppressive agent. Its clinical efficacy of anti-rejection after renal transplantation is well documented. Between January 1998 and February 1999, a total of 40 patients received FK 506 as primary immunosuppressant after kidney transplantation and 10 patients were converted to FK 506 from cyclosporine (CyA) because of hepatotoxicity. The results are summarized below.
IMx assay. Blood samples were collected at 72 hours after the first dose of FK 506. The FK 506 blood levels were monitored three times per week during the first 21 days and subsequently twice a week after week 3 and once a week after week 8. Whole-blood trough levels of FK 506 were adjusted to 10 to 20 ng/mL. When blood levels were ⬎20 ng/mL, dosage was reduced by 25%. When blood level was ⬍5 ng/mL, dosage was increased by 25%. Meanwhile, changes in hematology, routine urinalysis, platelet count, CMV-IgG, CMV-IgM, CD3, CD4, and CD8 were monitored.
MATERIALS AND METHODS Patient Selection
RESULTS
A total of 90 patients were randomized to FK 506 (n ⫽ 40) or CyA (n ⫽ 50) after cadaveric renal transplantation between January 1998 and February 1999 in our hospital. The FK 506 was started within 24 hours’ postoperation. There were no significant differences in age, sex, donor age, or cold and warm ischemic time of donor graft between the two groups.
Histological Matching Volume of lymphocytotoxicity was ⬍10% in the two groups; PRA was negative and the numbers of HLA matches were between two and five.
Study Medication Patients assigned to FK 506 received an initial dosage of 0.15 to 0.30 mg/kg per day in two divided doses; the first dose was given within 24 hours after transplantation. Patients assigned to CyA received an initial oral dosage of 8 mg/kg per day. All patients received combination immunosuppressive therapy with steroids, azathioprine, and mycophenolate mofetil (MMF). Oral azathioprine (50 mg) and prednisolone (50 mg) were administered preoperatively. Intravenous (IV) methylprednisolone (1.0 mg) was administered preoperatively and 0.5 g at 24 hours after transplantation. The MMF dosage was 1.0 g daily. Prednisolone started with an initial oral dosage of 30 mg per day after transplantation, then tapered to 25 mg/d at week 2, 20 mg/d at 1 month, and 15 mg/d at 3 months. Rejection episodes were treated similarly for patients in the two groups, and IV methylprednisolone (0.5 g) was administered for 3 days. Both steroid-resistant rejection and severe acute rejection were treated with the addition of OKT3 (5 mg/d, IV for 3 days).
Therapeutic Drug Monitoring and Adjusting The CyA whole-blood trough concentration was measured using TDx assay while FK 506 blood concentration was measured using
All patients except for one graft failure in the CyA group were followed for 6 to 12 months. Renal function was regained within 2 to 26 days after transplantation; 9 patients experienced acute rejection, 2 had pneumonic infections, 1 had urinary tract infection, 2 had nephrotoxicity, 3 had hepatotoxicity, 1 had diarrhea, and 2 had hyperglycemia. Patients and grafts in the FK 506 group all survived. They were followed for 6 to 12 months and renal function was regained within 2 to 13 days. Acute rejection occurred in 4 patients at 8, 10, 13, and 18 days, respectively, following transplantation. The incidence of adverse events reported included nephrotoxicity (2 cases), hepatotoxicity (1 case), diarrhea (22 cases), pneumonic infections (2 cases), and hyperglycemia requiring insulin therapy (14 cases); also, 2 cases experienced tachycardia but this disappeared after treatment with nitroglycerin. DISCUSSION Mechanism of Action of FK 506
The worldwide use of CyA has markedly prolonged graft survival over the past 15 tears, but its dose-related toxicity has prohibited its extensive application. People have been waiting for a novel immunosuppressive agent with lower toxicity. Thus, the appearance of FK 506 triggered significant interest among many investigators. In vivo, oral administration of FK 506 cannot inhibit immune reaction directly, but it does inhibit calcineurin phosphatase activity; this From the Dept. of Kidney Transplant, Nanfang Hospital, Guangzhou, China. Address reprint requests to Lixin Yu, Department of Kidney Transplantation, Nanfang Hospital, The First Medical University, Guangzhou 510515, China.
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/00/$–see front matter PII S0041-1345(00)01405-6
Transplantation Proceedings, 32, 1709–1710 (2000)
1709
1710
effect may prevent activation and transcription of interleukin-2 and interleukin-2 receptor gene. The net result is the inhibition of T-lymphocyte activation, so expressing powerful immunosuppressive effect. However, recent studies have revealed several new facts to the mode of action of FK 506, focusing on differences between this agent and CyA that would tend to indicate the superiority of FK 506. Clinical Pharmacokinetics of FK 506
Blood samples of 10 patients who received FK 506 after renal transplantation were collected at 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours after the first oral dose of FK 506. Whole-blood FK 506 levels were measured by IMx assay. The data suggested that FK 506 mean time to peak concentration was 1 hour and the mean elimination half-life was 8.5 hours. According to this data, FK 506 was administered once or twice a day. In our study, FK 506 was administered twice daily (7 a.m., 1 hour before meal, and 7 p.m., 1 hour after meal); 9 patients attained the mean elimination half-life after 8.5 hours, but 1 patient did not attain the mean elimination half-life even after 12 hours. The Optimal Therapeutic Window of FK 506
According to the results of our study, we believed the optimal therapeutic window of FK 506 (measured by IMx assay) in triple therapy should be as follows: 12 to 15 ng/mL for the first month, 8 to 12 ng/mL for the second month, and 6 to 10 ng/mL for the third month. After 4 months, the blood level should be maintained at 5 to 10 ng/mL. These concentration ranges not only attain satisfactory immunosuppressive effects but also minimize the adverse events of FK 506 and occurrence of rejection. Thus, regular monitoring of FK 506 blood level after renal transplantation is very important to adjust the adequate dosage and to minimize rejection and toxicity of tacrolimus (FK 506).
YU, WANG, FU ET AL
Adverse Events of FK 506 and Treatment
Gastrointestinal disorders including nausea, vomiting, and diarrhea were reported in 22/50 of FK 506-treated patients. After being treated with berberin, the symptoms disappeared. Blood glucose levels often increased at 1 week after the first dose of FK 506 and sometimes could reach 22 to 28 mmol/L. In our study, hyperglycemia occurred in 14 cases, 8 of which were able to discontinue insulin treatment within 6 months. But 6 cases still need insulin after 6 months. Comparison of Efficacy
With the introduction of CyA, rejection reaction rate was reduced markedly after renal transplantation; thus, we believed it was an effective immunosuppressive agent. Subsequently, CyA had serious adverse events, including hepatoxicity, nephrotoxicity, hirsutism, and gum hyperplasia. The clinical results of our 50 renal recipients treated with FK 506 proved to be satisfactory. The occurrence rate of rejection was reduced by 10%, and it had lower toxicity. Also, FK 506 is effective in therapy, especially in CyA toxicity cases. In our study, 10 patients converted to FK 506 from CyA because of hepatoxicity saw their liver function return to normal. CONCLUSIONS
As immunosuppressant for renal transplantation, FK 506 has a better safety profile, efficacy, and fewer side effects than CyA. It can significantly reduce the occurrence of acute rejection, patients regain their renal function quicker than that of CyA, and it can shorten duration of hospitalization. Moreover, FK 506 can be used as rescue therapy for hepatotoxicity caused by CyA. Nevertheless, clinical physicians should pay attention to hyperglycemia. Further observation is necessary for the long-term survival.