Bioequivalence of a New Cyclosporine A Formulation to Neoral®

Abstract

New cyclosporine A (CsA) formulations must prove their bioequivalence to Neoral, the reference CsA formulation, to allow free prescription for the patients. The aim of this study was to compare the pharmacokinetics (PK) of a new CsA formulation (Zinograf-ME), produced by Strides-Arcolab, to Neoral and to demonstrate their interchangeability in stable renal transplant recipients. Twelve-hour PK studies were obtained from 18 (13 M/5 F) adult patients (mean age 44.7 +/- 12 years). They received their renal allografts from 13 cadaver and 5 living donors. Before enrollment, all patients were receiving a third generic CsA for a mean of 48 months. Nine patients were also under azathioprine and 9 under mycophenolate mofetil; 17 received prednisone. A single oral dose of either Zinograf or Neoral was administered. The first PK study was performed with one formulation, and 1 week later, a second PK was done with the other formulation. During the washout period, patients continued taking the third CsA formulation. The drug substitution was done milligram-for-milligram. The CsA whole-blood level was measured by TDx immunoassay. Mean +/- SD of area under the curve (AUC), maximum concentration (C(max)), and concentration at the second hour (C2) of Zinograf were not statistically different from those with Neoral (4019 +/- 1466 vs 3971 +/- 1325 ng x h/mL, 998 +/- 376 vs 1021 +/- 356 ng/mL, and 707 +/- 254 vs 734 +/- 229 ng/mL, respectively). In the same way, the Zinograf 90% confidence interval for either C(max) (-123, +77 ng/mL) or AUC (-214, +311 ng.mL/h) were within the Neoral bioequivalence interval for the same parameters (+/-204 ng/mL and +/-794 ng x mL/h, respectively). These data demonstrate that the ZinografME CsA formulation is bioequivalent to Neoral.

Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis

“…Study designs included randomized controlled trials (n=17; eight crossover and nine parallel), non-randomized interventional studies (n=15), and observational studies (n=18; cohort and before/after designs). Innovator drugs studied included Neoral (cyclosporine; n=32 studies,31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 28 in kidney transplants, three in heart transplants, and one in liver transplants), Prograf (tacrolimus; n=12 studies,63 64 65 66 67 68 69 70 71 72 73 74 seven in kidney transplants, one in heart transplants, one in liver transplants, and three in a mixture of liver, kidney, or heart transplants), and Cellcept (mycophenolate mofetil; n=6 studies,75 76 77 78 79 80 five in kidney transplants and one in liver transplants). Neoral was compared with 12 different generics (Iminoral, Equoral, Gengraf, Cysporin, Zinograf-ME, Neoplanta, Consupren, SangCya (Sang-35), Sigmasporin Microral, Pliva, Cicloral, and Arpimune); Prograf was compared with four different generics (Tacni, Tacrobell, Adoport, and Sandoz-tacrolimus); and Cellcept was compared with five different generics (Myfenax, Medis, Linfonex, Mycept, and Myconol).…”

Intercambialidade de medicamentos: abordagem clínica e o ponto de vista do consumidor

“…On the other hand, a study of cyclosporin, 8 another drug with narrow therapeutic window, confirmed bioequivalence between reference and generic drugs in the steady state, without significant intra-and interindividual variability, indicating that interchangeability between generic and reference drugs is possible. Aiming at reducing the impact of interindividual variability in bioequivalence tests for drugs with narrow therapeutic window, Health Canada limited the acceptable variability range between comparison variables in bioequivalence tests for these drugs.…”

Conversion from Brand-Name Neoral to the Generic Ciqorin in Stable Renal Transplant Recipients

“…However, transplant societies have raised concerns regarding the validity of extrapolating data derived from healthy subjects to the target patient populations [8][9][10] . Indeed, although most of the generic CsA conversion trials in stable renal transplant recipients found the tested products to have similar pharmacokinetic profiles compared to Neoral [11][12][13][14] , few others have reported significant differences between generic and innovator products [15,16] . Along the same line, in the de novo kidney transplant setting, some studies found similar renal graft outcomes with Neoral or generic CsA formulations [17,18] , whereas others indicated a higher rate of acute rejection with generic products [19,20] .…”