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Converting renal transplant patients maintained on sandimmune to a new microemulsion formulation, sandimmune neoral
Converting Renal Transplant Patients Maintained on Sandimmune to a New Microemulsion Formulation, Sandimmune Neoral S.H. Chu, S.T. Pang, Y.J. Chiang, C.K. Chuang, H.W. Chen, C.S. Chen, C.C. Chou, and C.C. Huang
S
ANDIMMUNE Neoral (Neoral) is a new galenic form of cyclosporine (CyA) that is now commercially available. It is a water-free microemulsion of CyA that can create micelles that are more readily absorbed in the small intestine independent of the bile.1 In pharmacokinetic studies, it has demonstrated less variability in absorption and yielded a stronger correlation between trough concentration and systemic exposure compared with Sandimmune (SIM). Thus, this new formulation can provide a consistent blood concentration in transplant patients that may lead to improved graft survival.2–5 Owing to this advantage, shifting from the conventional to the microemulsion formulation of CyA has been carried out in several institutions and was well documented.6 – 8 However, data on the effects of this conversion are still limited and the studied population were mostly Caucasian. The aim of our study was to investigate the feasibility and safety of a 1:1 drug conversion among a group of Taiwanese renal allograft patients. MATERIALS AND METHODS One hundred fifty-two stable renal allograft recipients who were maintained on SIM over a period of 6 months were enrolled in the study. The study was performed in the renal transplant outpatient clinic from June 1996 to June 1997. Patients were randomly stratified according to graft age: .5 years (n 5 48, 31.5%); 3 to 5 years (n 5 43, 28.3%); 1 to 3 years (n 5 48, 31.6%); and ,1 year (n 5 13, 8.6%). The obligatory conversion ratio between SIM and Neoral was 1:1 at start. Dose adjustment was made to keep patients’ monoclonal CyA trough levels within the therapeutic window of 80 to 120 ng/mL. At least seven regular visits to the outpatient clinic were mandatory. These included an examination by a physician and laboratory tests at day 0 (baseline and conversion), day 7 and 30, as well as at months 3, 6, 9, and 12. Serum creatinine, uric acid, alanine aminotransferase (ALT), cholesterol, and CyA trough level (Cyclo-Trac SP, Incstar, Stillwater, Minn.) were measured at the regular visits. Furthermore, the mean, systolic, and diastolic blood pressures as well as
CyA dose were routinely registered by a trained nurse. Any adverse events were also recorded. Data are presented as mean 6 SD. The values of all parameters before and after the conversion were compared and expressed as percentage increase or decrease. The comparisons were assessed with t test and P , .05 was considered significant.
RESULTS Demographic Data
The 152 patients included 92 (60.5%) males and 60 (39.5%) females. Their mean age was 38 years and body weight was 61.51 kg. Dose Change
After 1 year of conversion 77 patients (50.65%) remained on the same dose. Forty seven (30.92%) patients needed a dose reduction and 28 (18.42%) patients otherwise needed a dose increment. The mean dose of SIM at the start was 198.7 6 88.2 mg/d. However, the dose of Neoral at month 12 was 185.4 6 68.6 mg/d. Overall, there was a 6.6% (P , .05) reduction of CyA dose after conversion. During this period the CyA trough level increased from 107.9 6 52.4 ng/mL to 113.6 6 54.3 ng/mL (P , .05) (Table 1). Increase Dosage Group
Twenty eight patients needed a dose increment. The mean CyA dose and trough levels before conversion were lower than the overall mean value (165.2 6 65.4 vs 198.7 6 88.2; From the Division of Urology, Department of Surgery (S.H.C., S.T.P., Y.J.C., C.K.C., H.W.C., C.S.C., C.C.C.) and Division of Nephrology, Department of Internal Medicine (C.C.H.), Chang Gung Memorial Hospital, Chang Gung University, Taipel, Taiwan. Address reprint requests to Sheng-Hsien Chu, MD, Division of Urology, 199, Tung-Hwa North Road, Taipei, 105, Taiwan.
Table 1. Change of CyA Dose and Trough Level of All Patients Day/Month
D0
D7
D30
M3
M6
M9
M12
CyA dose (mg/d) CyA trough level (ng/mL)
198.7 6 88.2 107.9 6 52.4
197.6 6 52.1 108.2 6 51.1
190.3 6 72.3 110.8 6 48.5
187.2 6 43.5 102.4 6 39.2
185.7 6 68.8 111.3 6 52.7
184.3 6 28.7 114.3 6 78.5
185.4* 6 68.6 113.6* 6 54.3
All data reported as mean 6 standard deviation. *P , .05.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)01121-X
Transplantation Proceedings, 30, 3521–3523 (1998)
3521
3522
CHU, PANG, CHIANG ET AL Table 2. Increase Dosage Group Day/Month
D0
D7
D30
M3
M6
M9
M12
CyA dose (mg/d) Trough level (ng/mL) Creatinine (mg/dL)
165.2 6 65.4 92.8 6 30.4 1.56 6 0.6
169.2 6 63.1 93.5 6 42.5 1.58 6 0.53
172.7 6 59.3 98.1 6 39.5 1.51 60.41
194.6 6 74.5 100.0 6 68.5 1.60 6 0.74
195.1 6 55.4 123.0 6 72.3 1.58 6 0.65
184.5 6 70.3 121.6 6 60.3 1.56 6 0.52
203 6 61.8* 120.5 6 71.4* 1.57 6 0.53†
All data reported as mean 6 standard deviation. *P , .001. †P 5 NS.
92.8 6 30.4 vs 107.9 6 52.4, P , .01). The dose increased from 165.2 6 65.4 to 203.2 6 61.8 (23.1%, P , .001). However, the creatinine remained the same during the conversion (Table 2). Decrease Dosage Group
Forty seven patients needed a dose reduction. The mean CyA dose and trough levels before conversion were higher than the overall mean value (246.2 6 61.3 vs 198.7 6 88.2; 133.4 6 54.1 vs 107.9 6 52.4, P , .01). The dose decreased from 246.2 6 61.3 to 187.4 6 56.7 (23.9%, P , .001). Creatinine also was not changed during the conversion (Table 3). Safety Parameters
After conversion, serum creatinine, uric acid, and ALT were not significantly changed when comparing the initial value with the final value at month 12. However, cholesterol levels were elevated (209.8 6 38.3 vs 216 6 36.8; P , .05). The mean systolic and diastolic blood pressure remained unchanged during the study (Table 4). Adverse Events
At total 24 adverse events were recorded. The most frequent adverse event was hand tremor (n 5 6; 25%). Only two patients (8%) had acute rejection during the conversion.
CyA concentration and systemic exposure, and reduced intra- and interindividual variability for a range of pharmacokinetic parameters. Furthermore, its absorption is not significantly affected by food. Therefore, Neoral has successfully replaced SIM as the immunosuppressive drug in renal allograft patients in several institutions. In our study, we confirmed that the 1:1 conversion of SIM to Neoral was also effective and safe when used in an Oriental population. We did not find a higher adverse effect after the conversion. Due to its less variability, we expected that the trough CyA blood concentration can be more closely related to the AUC level. Therefore, we used the trough CyA blood level as a guide to the dosage requirement. We found that this is more practical to perform in the clinic. There is no difficulty in monitoring and maintaining the patient in an optimal therapeutic condition when done this way. During the conversion, up to one-half of the patients needed a dose adjustment. Attention should be paid to those patients with a higher or lower therapeutic CyA trough level because dose adjustment may be necessary in these patients. The drug should be changed gradually and trough level should be monitored closely until the optimal dose is reached. From our experience, the conversion of SIM to Neoral is easy, safe, and effective. Because a fair number of patients needed dose adjustment, patients should be monitored individually during the conversion. REFERENCES
DISCUSSION
The conventional formulation of CyA SIM is characterized by poor and unpredictable drug absorption. A new formulation of CyA Neoral has been developed that attempts to overcome these limitations. Several studies have shown that the microemulsion formulation of CyA increased the area under the whole-blood concentration (AUC), increased maximum concentration (Cmax), gave a shorter time to Cmax, had a more predictable relationship between trough
1. Styrbjo ¨rn F, Ba¨ckman L: Clin Pharmacokinet 30:181, 1996 2. Mueller EA, Kovarik JM, et al: Transplantation 57:1178, 1994 3. Holt DW, Mueller EA, et al: Transplant Proc 26:2935, 1994 4. Kovarvik JM, Mueller EA, et al: Transplantation 58:658, 1994 5. Sketris IS, Lawen SG, et al: Transplant Proc 26:2961, 1994 6. Neumayer HH, Fa¨rber L, et al: Transplant Proc 26:2944, 1994 7. Neumayer HH, Fa¨rber L, et al: Nephrol Dial Transplant 11:165, 1996 8. Wahlberg J, Wilczek HE, et al: Transplantation 60:648, 1995
Table 3. Decrease Dosage Group Day/Month
D0
D7
D30
M3
M6
M9
M12
CyA dose (mg/d) Trough level (ng/mL) Creatinine (mg/dL)
246.2 6 61.3 133.4 6 54.1 1.53 6 0.63
240.7 6 80.3 130.8 6 44.3 1.53 6 0.51
230.1 6 59.7 131.5 6 60.5 1.56 6 0.72
201.8 6 86.5 128.5 6 39.1 1.53 6 0.45
193.5 6 68.3 126.7 6 55.2 1.51 6 0.39
181.2 6 70.2 127.3 6 62.3 1.55 6 0.55
187.4 6 56.7* 124.1 6 56.6† 1.56 6 0.64‡
All *P † P ‡ P
data reported as mean 6 standard deviation. , .001. , .05. 5 NS.
CONVERTING RENAL TRANSPLANT PATIENTS
3523
Table 4. Safety Parameter Results After 1-Year Study of All Patients Day/Month
D0
D7
D30
M3
M6
M9
M12
Creatine (mg/dL) Uric acid (mg/dL) ALT (U/L) Cholesterol (mg/dL) MBP (mm Hg) SBP (mm Hg) DBP (mm Hg)
1.55 6 0.55 7.3 6 1.92 25.6 6 11.3 209.8 6 38.3 101.7 6 30.7 124.5 6 18.2 78.9 6 10.8
1.55 6 0.49 7.2 6 1.75 26.1 6 6.2 210.3 6 40.1 102.4 6 25.6 125.1 6 22.5 81.8 6 9.2
1.55 6 0.39 7.6 6 1.53 25.3 6 7.2 202.5 6 29.4 100.3 6 29.1 122.9 6 20.3 80.2 6 13.3
1.56 6 0.72 7.3 6 1.42 28.7 6 9.3 198.2 6 50.3 100.5 6 47.6 125.7 6 18.5 77.6 6 10.8
1.58 6 0.65 8.0 6 1.38 26.3 6 6.5 200.4 6 44.2 103.3 6 32.8 123.2 6 16.4 80.5 6 12.4
1.57 6 0.58 7.4 6 1.69 26.9 6 5.7 212.6 6 58.1 101.6 6 25.5 122.8 6 15.4 78.4 6 9.5
1.57 6 0.59* 7.4 6 1.78* 25.8 6 9.4* 216 6 36.8† 102.7 6 27.9* 123.9 6 16.6* 79.2 6 11.6*
All data reported as mean 6 standard deviation. ALT, alanine aminotransferase; MBP, mean blood pressure; SBP,, systolic blood pressure; DBP, diastolic blood pressure. *P 5 NS. † P , .05.
S
ANDIMMUNE Neoral (Neoral) is a new galenic form of cyclosporine (CyA) that is now commercially available. It is a water-free microemulsion of CyA that can create micelles that are more readily absorbed in the small intestine independent of the bile.1 In pharmacokinetic studies, it has demonstrated less variability in absorption and yielded a stronger correlation between trough concentration and systemic exposure compared with Sandimmune (SIM). Thus, this new formulation can provide a consistent blood concentration in transplant patients that may lead to improved graft survival.2–5 Owing to this advantage, shifting from the conventional to the microemulsion formulation of CyA has been carried out in several institutions and was well documented.6 – 8 However, data on the effects of this conversion are still limited and the studied population were mostly Caucasian. The aim of our study was to investigate the feasibility and safety of a 1:1 drug conversion among a group of Taiwanese renal allograft patients. MATERIALS AND METHODS One hundred fifty-two stable renal allograft recipients who were maintained on SIM over a period of 6 months were enrolled in the study. The study was performed in the renal transplant outpatient clinic from June 1996 to June 1997. Patients were randomly stratified according to graft age: .5 years (n 5 48, 31.5%); 3 to 5 years (n 5 43, 28.3%); 1 to 3 years (n 5 48, 31.6%); and ,1 year (n 5 13, 8.6%). The obligatory conversion ratio between SIM and Neoral was 1:1 at start. Dose adjustment was made to keep patients’ monoclonal CyA trough levels within the therapeutic window of 80 to 120 ng/mL. At least seven regular visits to the outpatient clinic were mandatory. These included an examination by a physician and laboratory tests at day 0 (baseline and conversion), day 7 and 30, as well as at months 3, 6, 9, and 12. Serum creatinine, uric acid, alanine aminotransferase (ALT), cholesterol, and CyA trough level (Cyclo-Trac SP, Incstar, Stillwater, Minn.) were measured at the regular visits. Furthermore, the mean, systolic, and diastolic blood pressures as well as
CyA dose were routinely registered by a trained nurse. Any adverse events were also recorded. Data are presented as mean 6 SD. The values of all parameters before and after the conversion were compared and expressed as percentage increase or decrease. The comparisons were assessed with t test and P , .05 was considered significant.
RESULTS Demographic Data
The 152 patients included 92 (60.5%) males and 60 (39.5%) females. Their mean age was 38 years and body weight was 61.51 kg. Dose Change
After 1 year of conversion 77 patients (50.65%) remained on the same dose. Forty seven (30.92%) patients needed a dose reduction and 28 (18.42%) patients otherwise needed a dose increment. The mean dose of SIM at the start was 198.7 6 88.2 mg/d. However, the dose of Neoral at month 12 was 185.4 6 68.6 mg/d. Overall, there was a 6.6% (P , .05) reduction of CyA dose after conversion. During this period the CyA trough level increased from 107.9 6 52.4 ng/mL to 113.6 6 54.3 ng/mL (P , .05) (Table 1). Increase Dosage Group
Twenty eight patients needed a dose increment. The mean CyA dose and trough levels before conversion were lower than the overall mean value (165.2 6 65.4 vs 198.7 6 88.2; From the Division of Urology, Department of Surgery (S.H.C., S.T.P., Y.J.C., C.K.C., H.W.C., C.S.C., C.C.C.) and Division of Nephrology, Department of Internal Medicine (C.C.H.), Chang Gung Memorial Hospital, Chang Gung University, Taipel, Taiwan. Address reprint requests to Sheng-Hsien Chu, MD, Division of Urology, 199, Tung-Hwa North Road, Taipei, 105, Taiwan.
Table 1. Change of CyA Dose and Trough Level of All Patients Day/Month
D0
D7
D30
M3
M6
M9
M12
CyA dose (mg/d) CyA trough level (ng/mL)
198.7 6 88.2 107.9 6 52.4
197.6 6 52.1 108.2 6 51.1
190.3 6 72.3 110.8 6 48.5
187.2 6 43.5 102.4 6 39.2
185.7 6 68.8 111.3 6 52.7
184.3 6 28.7 114.3 6 78.5
185.4* 6 68.6 113.6* 6 54.3
All data reported as mean 6 standard deviation. *P , .05.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)01121-X
Transplantation Proceedings, 30, 3521–3523 (1998)
3521
3522
CHU, PANG, CHIANG ET AL Table 2. Increase Dosage Group Day/Month
D0
D7
D30
M3
M6
M9
M12
CyA dose (mg/d) Trough level (ng/mL) Creatinine (mg/dL)
165.2 6 65.4 92.8 6 30.4 1.56 6 0.6
169.2 6 63.1 93.5 6 42.5 1.58 6 0.53
172.7 6 59.3 98.1 6 39.5 1.51 60.41
194.6 6 74.5 100.0 6 68.5 1.60 6 0.74
195.1 6 55.4 123.0 6 72.3 1.58 6 0.65
184.5 6 70.3 121.6 6 60.3 1.56 6 0.52
203 6 61.8* 120.5 6 71.4* 1.57 6 0.53†
All data reported as mean 6 standard deviation. *P , .001. †P 5 NS.
92.8 6 30.4 vs 107.9 6 52.4, P , .01). The dose increased from 165.2 6 65.4 to 203.2 6 61.8 (23.1%, P , .001). However, the creatinine remained the same during the conversion (Table 2). Decrease Dosage Group
Forty seven patients needed a dose reduction. The mean CyA dose and trough levels before conversion were higher than the overall mean value (246.2 6 61.3 vs 198.7 6 88.2; 133.4 6 54.1 vs 107.9 6 52.4, P , .01). The dose decreased from 246.2 6 61.3 to 187.4 6 56.7 (23.9%, P , .001). Creatinine also was not changed during the conversion (Table 3). Safety Parameters
After conversion, serum creatinine, uric acid, and ALT were not significantly changed when comparing the initial value with the final value at month 12. However, cholesterol levels were elevated (209.8 6 38.3 vs 216 6 36.8; P , .05). The mean systolic and diastolic blood pressure remained unchanged during the study (Table 4). Adverse Events
At total 24 adverse events were recorded. The most frequent adverse event was hand tremor (n 5 6; 25%). Only two patients (8%) had acute rejection during the conversion.
CyA concentration and systemic exposure, and reduced intra- and interindividual variability for a range of pharmacokinetic parameters. Furthermore, its absorption is not significantly affected by food. Therefore, Neoral has successfully replaced SIM as the immunosuppressive drug in renal allograft patients in several institutions. In our study, we confirmed that the 1:1 conversion of SIM to Neoral was also effective and safe when used in an Oriental population. We did not find a higher adverse effect after the conversion. Due to its less variability, we expected that the trough CyA blood concentration can be more closely related to the AUC level. Therefore, we used the trough CyA blood level as a guide to the dosage requirement. We found that this is more practical to perform in the clinic. There is no difficulty in monitoring and maintaining the patient in an optimal therapeutic condition when done this way. During the conversion, up to one-half of the patients needed a dose adjustment. Attention should be paid to those patients with a higher or lower therapeutic CyA trough level because dose adjustment may be necessary in these patients. The drug should be changed gradually and trough level should be monitored closely until the optimal dose is reached. From our experience, the conversion of SIM to Neoral is easy, safe, and effective. Because a fair number of patients needed dose adjustment, patients should be monitored individually during the conversion. REFERENCES
DISCUSSION
The conventional formulation of CyA SIM is characterized by poor and unpredictable drug absorption. A new formulation of CyA Neoral has been developed that attempts to overcome these limitations. Several studies have shown that the microemulsion formulation of CyA increased the area under the whole-blood concentration (AUC), increased maximum concentration (Cmax), gave a shorter time to Cmax, had a more predictable relationship between trough
1. Styrbjo ¨rn F, Ba¨ckman L: Clin Pharmacokinet 30:181, 1996 2. Mueller EA, Kovarik JM, et al: Transplantation 57:1178, 1994 3. Holt DW, Mueller EA, et al: Transplant Proc 26:2935, 1994 4. Kovarvik JM, Mueller EA, et al: Transplantation 58:658, 1994 5. Sketris IS, Lawen SG, et al: Transplant Proc 26:2961, 1994 6. Neumayer HH, Fa¨rber L, et al: Transplant Proc 26:2944, 1994 7. Neumayer HH, Fa¨rber L, et al: Nephrol Dial Transplant 11:165, 1996 8. Wahlberg J, Wilczek HE, et al: Transplantation 60:648, 1995
Table 3. Decrease Dosage Group Day/Month
D0
D7
D30
M3
M6
M9
M12
CyA dose (mg/d) Trough level (ng/mL) Creatinine (mg/dL)
246.2 6 61.3 133.4 6 54.1 1.53 6 0.63
240.7 6 80.3 130.8 6 44.3 1.53 6 0.51
230.1 6 59.7 131.5 6 60.5 1.56 6 0.72
201.8 6 86.5 128.5 6 39.1 1.53 6 0.45
193.5 6 68.3 126.7 6 55.2 1.51 6 0.39
181.2 6 70.2 127.3 6 62.3 1.55 6 0.55
187.4 6 56.7* 124.1 6 56.6† 1.56 6 0.64‡
All *P † P ‡ P
data reported as mean 6 standard deviation. , .001. , .05. 5 NS.
CONVERTING RENAL TRANSPLANT PATIENTS
3523
Table 4. Safety Parameter Results After 1-Year Study of All Patients Day/Month
D0
D7
D30
M3
M6
M9
M12
Creatine (mg/dL) Uric acid (mg/dL) ALT (U/L) Cholesterol (mg/dL) MBP (mm Hg) SBP (mm Hg) DBP (mm Hg)
1.55 6 0.55 7.3 6 1.92 25.6 6 11.3 209.8 6 38.3 101.7 6 30.7 124.5 6 18.2 78.9 6 10.8
1.55 6 0.49 7.2 6 1.75 26.1 6 6.2 210.3 6 40.1 102.4 6 25.6 125.1 6 22.5 81.8 6 9.2
1.55 6 0.39 7.6 6 1.53 25.3 6 7.2 202.5 6 29.4 100.3 6 29.1 122.9 6 20.3 80.2 6 13.3
1.56 6 0.72 7.3 6 1.42 28.7 6 9.3 198.2 6 50.3 100.5 6 47.6 125.7 6 18.5 77.6 6 10.8
1.58 6 0.65 8.0 6 1.38 26.3 6 6.5 200.4 6 44.2 103.3 6 32.8 123.2 6 16.4 80.5 6 12.4
1.57 6 0.58 7.4 6 1.69 26.9 6 5.7 212.6 6 58.1 101.6 6 25.5 122.8 6 15.4 78.4 6 9.5
1.57 6 0.59* 7.4 6 1.78* 25.8 6 9.4* 216 6 36.8† 102.7 6 27.9* 123.9 6 16.6* 79.2 6 11.6*
All data reported as mean 6 standard deviation. ALT, alanine aminotransferase; MBP, mean blood pressure; SBP,, systolic blood pressure; DBP, diastolic blood pressure. *P 5 NS. † P , .05.