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Pharmacokinetic and safety evaluation of SangCya vs Neoral or Sandimmune in stable renal transplant recipients
Pharmacokinetic and Safety Evaluation of SangCya vs Neoral or Sandimmune in Stable Renal Transplant Recipients R. Gaston, R.R. Alloway, A.O. Gaber, S.J. Rossi, T.J. Schroeder, W.D. Irish, D.M. Canafax, and M.R. First
S
ANGCYA IS a new oral cyclosporine formulation that produces equivalent blood levels and is bioequivalent when compared with the Neoral cyclosporine formulation. Demonstration of bioequivalence is based on Food and Drug Administration (FDA) required healthy volunteer study design and statistical methods for data analysis and gives confidence that two formulations are interchangeable and produce the same therapeutic response.1 To further support this finding of bioequivalence and compare the characteristics of SangCya in renal transplant patients, additional studies were conducted using the FDA bioequivalence study design (randomized, crossover) to assess SangCya pharmacokinetic behavior compared with Sandimmune and Neoral. In addition, patients were given long-term, chronic SangCya therapy to further assess pharmacokinetic and safety parameters. MATERIALS AND METHODS Four studies were conducted at 3 transplant centers in stable adult renal transplant recipients. Patients in all studies received their current dose of cyclosporine oral solution twice daily, had serial blood levels drawn over the 12 hours between doses, and were given 1 week to achieve steady state between formulation changes (Studies, A, B, C, and D) or dose change (Study C).
Study A (SangCya vs Neoral) Thirty-two patients were enrolled in a open label, single-center 3-period (1 week each; 2 Neoral and 1 SangCya) crossover study with a 1:1 dose. The study patient demographics included: 13 females/19 males and 16 African Americans/16 Caucasians with an overall mean age of 46 years.
Study B (SangCya vs Sandimmune) Twelve patients were enrolled in a open label, single-center 3-period (1 week each; 2 Sandimmune and 1 SangCya) crossover study with a 1:1 dose. The patient demographics included: 6 females/6 males and 8 African Americans/4 Caucasians with an overall mean age of 50 years. The patients received their current stable dose of cyclosporine twice daily.
Study C (Sandimmune Conversion to SangCya) Forty-two patients were enrolled in an area-under-the-concentration-time curve (AUC) based, dose-adjusted protocol with multiple 0041-1345/99/$–see front matter PII S0041-1345(98)01647-9
blood levels drawn over the 12 hours between cyclosporine doses at weekly intervals. SangCya dose adjustments were made to match SangCya AUC to the Sandimmune AUC and the dose could not be changed more than 20%. The protocol required #3 SangCya dose adjustments to target SangCya AUC within 10% of Sandimmune AUC, measured prior to SangCya conversion. The patient demographics included: 20 females/22 males, 15 African Americans/25 Caucasians/2 Asian-Americans, with a mean age of 42 years.
Study D (SangCya vs Neoral) Preliminary analysis of this ongoing study is based on 30 patients in a randomized, crossover, double-blinded design over 2 weeks. The study patient demographics included: 9 females/21 males, 10 African Americans/20 Caucasians, with a mean age of 48 years. For all studies, the pharmacokinetic parameter estimates were calculated from the cyclosporine concentration-time data measured by whole blood FPIA monoclonal antibody assay (Abbott Labs, N. Chicago, Ill). The arithmetic mean 6 SD parameters are reported in the results section. Using the FDA bioequivalence testing for normal subjects guidelines, the 90% confidence intervals (CI) were calculated using the least-square means (geometric means) of the log-transformed ratios (SangCya vs reference).
RESULTS
Table 1 lists the final pharmacokinetic parameter comparisons between SangCya and Neoral in renal transplant patients from completed Studies A, B, and C. Study D remains blinded and preliminary results comparing pharmacokinetics between SangCya vs Neoral (arithmetic mean 6 SD) include: AUC0 –12 3329 6 1314 vs 3401 6 1320 ng z h/mL, Cmax 682 6 323 vs 791 6 350 ng/mL, Tmax 1.5 6 0.7 vs 1.2 6 0.3 hours. No serious adverse events and no changes in serum creatinine level occurred in these studies during the pharmacokinetic testing periods. In Study C, after 4 months of follow-up, two serious adverse events, not related to the study drug, were reported (chest pain, bowel obstruction), From the University of Alabama (R.G.), University of Cincinnati (M.R.F.), University of Tennessee (R.R.A., A.O.G.), and SangStat Medical Corporation (S.J.R., T.J.S., W.D.I., D.M.C.), Menlo Park, California, USA. Supported in part by a grant from SangStat Medical Corporation. Address reprint requests to Robert G. Gaston, MD, Universty of Alabama. © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
326
Transplantation Proceedings, 31, 326–327 (1999)
SANGCYA VS NEORAL OR SANDIMMUNE
327
Table 1. Results of Pharmacokinetic Parameter Comparisons for SangCya and Neoral or Sandimmune in Renal Transplant Patients.* Study
Study A SangCya Neoral (Period 1) P-values Study B SangCya Sandimmune (Period 1) P-values Study C (before dose adjustment) SangCya Sandimmune P-values Study C (after dose adjustment) SangCya Sandimmune P-values
n
32
12
42
42
AUC (ng z h/mL)
Cmax (ng/mL)
Tmax(h)
90% CI AUC (ratio)
90% CI Cmax (ratio)
86 –105 (95%)
84 –102 (93%)
4120 6 1508 4377 6 1579
890 6 332 994 6 391
1.4 6 0.6 1.3 6 0.4
.28
.11
.38
4550 6 1858 3468 6 1402
1079 6 426 600 6 297
1.3 6 0.3 2.4 6 1.4
113–152
134 –249
.01
,.01
.02
(131%)
(183%)
5673 6 1675 4738 6 1272
1128 6 406 800 6 304
1.5 6 0.8 2.7 6 0.9
,.01
,.01
,.01
4586 6 1356 4738 6 1272
870 6 302 800 6 304
1.6 6 0.8 2.7 6 0.9
93–99
102–118
.04
.05
,.01
(96%)
(109%)
*Ninety percent confidence intervals based on the logarithmic transformation and analysis of variance for comparing period, sequence, patient, and formulation effects. P-value based on ANOVA. Abbreviation: AUC, area-under-the-concentration-time curve; CI, confidence interval.
serum creatinine levels were stable; and no patient had an acute rejection episode. DISCUSSION
The most important finding from the combined results of these studies is that cyclosporine blood levels and pharmacokinetic parameters are similar when comparing SangCya with Neoral. This is expected since SangCya has been shown to be bioequivalent compared with Neoral using the FDA-defined criteria. In addition, these studies indicate that SangCya is bioequivalent to Neoral in stable kidney
transplant recipients. Furthermore, stable renal allograft recipients on Neoral or Sandimmune can be safely converted to SangCya to achieve equivalent cyclosporine exposure. The potential benefits of SangCya will be a new cyclosporine formulation that can reduce the cost of immunosuppressive therapy.
REFERENCES 1. Schroeder TJ, Cho MJ, Pollack GM, et al: J Clin Pharmacol 38:807, 1998
S
ANGCYA IS a new oral cyclosporine formulation that produces equivalent blood levels and is bioequivalent when compared with the Neoral cyclosporine formulation. Demonstration of bioequivalence is based on Food and Drug Administration (FDA) required healthy volunteer study design and statistical methods for data analysis and gives confidence that two formulations are interchangeable and produce the same therapeutic response.1 To further support this finding of bioequivalence and compare the characteristics of SangCya in renal transplant patients, additional studies were conducted using the FDA bioequivalence study design (randomized, crossover) to assess SangCya pharmacokinetic behavior compared with Sandimmune and Neoral. In addition, patients were given long-term, chronic SangCya therapy to further assess pharmacokinetic and safety parameters. MATERIALS AND METHODS Four studies were conducted at 3 transplant centers in stable adult renal transplant recipients. Patients in all studies received their current dose of cyclosporine oral solution twice daily, had serial blood levels drawn over the 12 hours between doses, and were given 1 week to achieve steady state between formulation changes (Studies, A, B, C, and D) or dose change (Study C).
Study A (SangCya vs Neoral) Thirty-two patients were enrolled in a open label, single-center 3-period (1 week each; 2 Neoral and 1 SangCya) crossover study with a 1:1 dose. The study patient demographics included: 13 females/19 males and 16 African Americans/16 Caucasians with an overall mean age of 46 years.
Study B (SangCya vs Sandimmune) Twelve patients were enrolled in a open label, single-center 3-period (1 week each; 2 Sandimmune and 1 SangCya) crossover study with a 1:1 dose. The patient demographics included: 6 females/6 males and 8 African Americans/4 Caucasians with an overall mean age of 50 years. The patients received their current stable dose of cyclosporine twice daily.
Study C (Sandimmune Conversion to SangCya) Forty-two patients were enrolled in an area-under-the-concentration-time curve (AUC) based, dose-adjusted protocol with multiple 0041-1345/99/$–see front matter PII S0041-1345(98)01647-9
blood levels drawn over the 12 hours between cyclosporine doses at weekly intervals. SangCya dose adjustments were made to match SangCya AUC to the Sandimmune AUC and the dose could not be changed more than 20%. The protocol required #3 SangCya dose adjustments to target SangCya AUC within 10% of Sandimmune AUC, measured prior to SangCya conversion. The patient demographics included: 20 females/22 males, 15 African Americans/25 Caucasians/2 Asian-Americans, with a mean age of 42 years.
Study D (SangCya vs Neoral) Preliminary analysis of this ongoing study is based on 30 patients in a randomized, crossover, double-blinded design over 2 weeks. The study patient demographics included: 9 females/21 males, 10 African Americans/20 Caucasians, with a mean age of 48 years. For all studies, the pharmacokinetic parameter estimates were calculated from the cyclosporine concentration-time data measured by whole blood FPIA monoclonal antibody assay (Abbott Labs, N. Chicago, Ill). The arithmetic mean 6 SD parameters are reported in the results section. Using the FDA bioequivalence testing for normal subjects guidelines, the 90% confidence intervals (CI) were calculated using the least-square means (geometric means) of the log-transformed ratios (SangCya vs reference).
RESULTS
Table 1 lists the final pharmacokinetic parameter comparisons between SangCya and Neoral in renal transplant patients from completed Studies A, B, and C. Study D remains blinded and preliminary results comparing pharmacokinetics between SangCya vs Neoral (arithmetic mean 6 SD) include: AUC0 –12 3329 6 1314 vs 3401 6 1320 ng z h/mL, Cmax 682 6 323 vs 791 6 350 ng/mL, Tmax 1.5 6 0.7 vs 1.2 6 0.3 hours. No serious adverse events and no changes in serum creatinine level occurred in these studies during the pharmacokinetic testing periods. In Study C, after 4 months of follow-up, two serious adverse events, not related to the study drug, were reported (chest pain, bowel obstruction), From the University of Alabama (R.G.), University of Cincinnati (M.R.F.), University of Tennessee (R.R.A., A.O.G.), and SangStat Medical Corporation (S.J.R., T.J.S., W.D.I., D.M.C.), Menlo Park, California, USA. Supported in part by a grant from SangStat Medical Corporation. Address reprint requests to Robert G. Gaston, MD, Universty of Alabama. © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
326
Transplantation Proceedings, 31, 326–327 (1999)
SANGCYA VS NEORAL OR SANDIMMUNE
327
Table 1. Results of Pharmacokinetic Parameter Comparisons for SangCya and Neoral or Sandimmune in Renal Transplant Patients.* Study
Study A SangCya Neoral (Period 1) P-values Study B SangCya Sandimmune (Period 1) P-values Study C (before dose adjustment) SangCya Sandimmune P-values Study C (after dose adjustment) SangCya Sandimmune P-values
n
32
12
42
42
AUC (ng z h/mL)
Cmax (ng/mL)
Tmax(h)
90% CI AUC (ratio)
90% CI Cmax (ratio)
86 –105 (95%)
84 –102 (93%)
4120 6 1508 4377 6 1579
890 6 332 994 6 391
1.4 6 0.6 1.3 6 0.4
.28
.11
.38
4550 6 1858 3468 6 1402
1079 6 426 600 6 297
1.3 6 0.3 2.4 6 1.4
113–152
134 –249
.01
,.01
.02
(131%)
(183%)
5673 6 1675 4738 6 1272
1128 6 406 800 6 304
1.5 6 0.8 2.7 6 0.9
,.01
,.01
,.01
4586 6 1356 4738 6 1272
870 6 302 800 6 304
1.6 6 0.8 2.7 6 0.9
93–99
102–118
.04
.05
,.01
(96%)
(109%)
*Ninety percent confidence intervals based on the logarithmic transformation and analysis of variance for comparing period, sequence, patient, and formulation effects. P-value based on ANOVA. Abbreviation: AUC, area-under-the-concentration-time curve; CI, confidence interval.
serum creatinine levels were stable; and no patient had an acute rejection episode. DISCUSSION
The most important finding from the combined results of these studies is that cyclosporine blood levels and pharmacokinetic parameters are similar when comparing SangCya with Neoral. This is expected since SangCya has been shown to be bioequivalent compared with Neoral using the FDA-defined criteria. In addition, these studies indicate that SangCya is bioequivalent to Neoral in stable kidney
transplant recipients. Furthermore, stable renal allograft recipients on Neoral or Sandimmune can be safely converted to SangCya to achieve equivalent cyclosporine exposure. The potential benefits of SangCya will be a new cyclosporine formulation that can reduce the cost of immunosuppressive therapy.
REFERENCES 1. Schroeder TJ, Cho MJ, Pollack GM, et al: J Clin Pharmacol 38:807, 1998