Přehled odborných článků, které se zabývají hodnocením bioekvivalence generických cyklosporinů A, včetně randomizované studie u stabilních příjemců ledvinového transplantátu.
Assessment of the bioequivalence of a generic cyclosporine A by a randomized controlled trial in stable renal recipients
Hibberd AD, Trevillian PR, Roger SD, Wlodarczyk JH,
Stein AM, Bohringer EG, Milson-Hawke SM.
Newcastle Transplant Unit, Division of Surgery, John Hunter Hospital, Newcastle, New South Wales, Australia. Adrian.Hibberd@newcastle.edu.au
BACKGROUND: The aim of this study was to determine the
bioequivalence of Cysporin, a generic cyclosporine A, compared with
Neoral in stable renal transplant recipients.
METHODS: Study design consisted of an open label, two-way crossover, randomized controlled trial of Cysporin versus Neoral in stable renal transplant recipients. In all, 33 patients were enrolled; 31 were randomized and 28 were evaluable. AUCs(0-12) were done on day 14 and 28; C(0) and C(2) were done on days 0, 7, 21 and 35. Dose conversion was 1:1. Outcome measures for serum cyclosporin A concentrations expressed as the mean+/-SD were AUC(0-12) (microg x hr/L), C(max) (microg/L), C(2) (microg/L), T(max) (hr) and T(1/2) (hr). Mean and 90% CI of the ratio Cysporin/Neoral of log-transformed data were calculated using a general linear model.
RESULTS: The main pharmacokinetic features were: AUC(0-12): Cysporin 3495+/-1319, Neoral 3853+/-1378 (P<0.05); C(max): Cysporin 755+/-301, Neoral 881+/-368 (P<0.05); C(2): Cysporin 613+/-235, Neoral 672+/-255 (P>0.05); T(max): Cysporin 1.9+/-0.8, Neoral 1.4+/-0.6 (P<0.005); and T1/2: Cysporin 8.8+/-4.3, Neoral 8.7+/-6.2 (P>0.05). Estimated ratios of Cysporin/Neoral were: AUC 0.93 (90% CI 0.88-0.98; P<0.05); C(max) 0.88 (90% CI 0.80-0.97; P<0.05); and T(max) 1.32 (90% CI 1.14-1.53; P<0.005).
CONCLUSIONS: Both the extent and rate of absorption of Cysporin are significantly less than those of Neoral. The 90% CI for the ratios of Cysporin/Neoral for AUC and C(max) lie within 0.80-1.25. Hence in this clinical context Cysporin is pharmacologically bioequivalent with Neoral. This study illustrates the importance of testing bioequivalence of generic cyclosporine A products in transplant recipients not healthy volunteers.
Administration diluents differentiate Neoral from a generic cyclosporine oral solution.
Kovarik JM, Barilla D, McMahon L, Wang Y, Kisicki J,
Novartis Pharmaceuticals, Basel, Switzerland. email@example.com
A non-microemulsion cyclosporine oral solution was recently recalled from the market because of the lack of bioequivalence when administered with apple juice compared with water as the diluent. This open-label, randomized, two-period, crossover study assessed the effect of apple juice on Neoral, a microemulsion cyclosporine oral solution. The study enrolled 34 subjects who received 180 mg Neoral oral solution diluted in 200 mL tap water or apple juice. Cyclosporine was measured in whole blood by a liquid chromatography method. Pharmacokinetic parameters were compared by standard bioequivalence tests. With water vs. apple juice, cyclosporine Cmax was 1263 +/- 203 vs. 1191 +/- 225 ng/mL and AUC was 4714 +/- 1117 vs. 4788 +/- 1320 ng h/mL, respectively. Bioequivalence was demonstrated for both parameters. These data were comparable with those from a previous study in which subjects received 180 mg Neoral oral solution with orange juice. Cyclosporine bioavailability is unaltered when Neoral is administered diluted in apple juice or orange juice compared with tap water which conforms to the cyclosporine product label.
Differentiation of innovator versus generic cyclosporine via a drug interaction on sirolimus
Kovarik JM, Noe A, Wang Y, Mueller I, DeNucci G,
Novartis Pharmaceuticals, Building WSJ 103.426, 4002 Basel, Switzerland. firstname.lastname@example.org
OBJECTIVE: Both sirolimus and cyclosporine are
immunosuppressants used in a combined regimen after organ
transplantation. When coadministered with the innovator formulation
of cyclosporine, sirolimus blood levels increase 3.3-fold due to a
pharmacokinetic interaction. We assessed this drug interaction for
potential differences when the innovator formulation is replaced by
a generic cyclosporine.
METHODS: In this randomized single-dose crossover study, 28 healthy subjects received 5 mg sirolimus oral solution with 250 mg cyclosporine soft gelatin capsules given as the innovator formulation (reference treatment) versus a generic formulation (test treatment). Sirolimus peak blood concentration (Cmax) and area under the concentration-time curve (AUC) were compared between test and reference treatments by standard bioequivalence testing.
RESULTS: Sirolimus Cmax was significantly lower by 17% in the presence of generic versus innovator cyclosporine (p=0.0003) and failed bioequivalence criteria with a test/reference ratio of 0.83 (90% confidence interval, 0.77-0.90). Nearly half of the subjects (46%) had sirolimus Cmax changes which fell outside the bioequivalence window with individual Cmax decreases up to 52% and increases up to 39%. Sirolimus AUC was significantly lower by 11% in the presence of generic versus innovator cyclosporine (p=0.041) but satisfied average bioequivalence criteria with a test/reference ratio of 0.89 (0.83-0.95). Nonetheless, over a third of the subjects (43%) had sirolimus AUC changes outside the standard bioequivalence window with individual AUC decreases up to 39% and increases up to 42%.
CONCLUSIONS: Switching between innovator and generic cyclosporine may have a clinically-relevant impact on coadministered sirolimus pharmacokinetics. If such a switch is initiated by the prescriber, follow-up therapeutic monitoring of both cyclosporine and sirolimus blood levels should be performed to guide dose adjustments as necessary. If the switch is made without consulting the prescriber, potentially significant changes in sirolimus exposure could go unnoticed by the clinician and patient.
Generic cyclosporine formulations: more open questions than answers
Cattaneo D, Perico N, Remuzzi G.
Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo, Mario Negri Institute for Pharmacological Research, Italy. email@example.com
The introduction of cyclosporine (CsA) in clinical practice has significantly improved patient and allograft survival after organ transplantation. The new microemulsion CsA formulation, Neoral, has been associated with a more reproducible absorption and a better patient outcome as compared to the old formulation Sandimmune. Recently, several generic CsA formulations have been tested as bioequivalent to Neoral. Bioequivalence tests have been performed in selected groups of young, healthy male volunteers usually in single-dose studies, and then extended to completely different population, such as transplant recipients. However, growing body of evidence shows that CsA pharmacokinetics in healthy subjects is different from that of transplant patients, treated chronically with CsA. Therefore, converting patients from Neoral to the new generic formulations could be detrimental, exposing patients to increased risk of graft function deterioration and graft loss. Thus, more research and more accurate bioequivalence tests are required to address the unanswered problems dealing with the generic CsA formulations.
Generic cyclosporine: a word of caution
IRCCS Istituto Auxologico, Milano, Italy. firstname.lastname@example.org
Cyclosporine (CsA) has been the cornerstone of immunosuppression for organ transplantation since its introduction. However, CsA is a critical drug as it has low therapeutic index and high inter- and intra-individual variations in bioavailability. The new microemulsion Neoral has increased bioavailability and is not influenced by bile or food. When compared with the old formulation, Neoral was able to significantly reduce rejection and to allow a better long-term graft survival in renal transplant patients. Moreover, the measurement of CsA at peak, around 2 hours after Neoral administration, proved to be a reliable index of the drug exposure, thus allowing efficient drug monitoring. Recently, different CsA galenics have been approved on the basis of bioequivalence tests performed in a small number of healthy volunteers after a single administration. Transplant experts expressed their concern about the adequacy of these tests in organ transplantation. The few short-term studies of bioequivalence in renal transplant recipients reported conflicting results. Certainly, the bioequivalence tests used, cannot capture a subset of low-absorbers who are exposed to the risk of underimmunosuppression. Another matter of concern is the lack of studies with galenic CsA to evaluate the role of C2 measurement for therapeutic drug monitoring. Observational studies reported a lower 1-year renal allograft survival in patients treated with galenic CsA than in patients given Neoral. A main problem is the absence of long-term studies with generic CsA, in the complex setting of organ transplantation.
Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients
Johnston A, Belitsky P, Frei U, Horvath J, Hoyer P,
Helderman JH, Oellerich M, Pollard S, Riad H, Rigotti P, Keown P,
Clinical Pharmacology, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, EC1M 6BQ, UK. A.Johnston@qmul.ac.uk
Cyclosporine (CsA) is a critical-dose drug for which a minor change in absorption can have important clinical implications. Generic formulations of CsA are becoming more widely available, but standard criteria for bioequivalence require only that a single study in healthy volunteers demonstrate that mean pharmacokinetic parameters fall within 80-125% of the mean values for Neoral, the reference formulation of CsA. However, CsA absorption is known to differ between healthy volunteers and transplant patients and between different types of transplant patients, such that standard bioequivalence testing may be inadequate to ensure interchangeability of CsA formulations in all patients. The limited available clinical evidence has shown that stable renal transplant patients receiving Neoral have a significant reduction in mean CsA trough level after transfer to the Cicloral formulation. Mean pharmacokinetic values have been reported as equivalent following transfer to Gengraft in one study, but mean CsA trough fell and mean serum creatinine rose significantly in a separate trial. The only clinical outcomes data available are from a retrospective study of de novo renal transplant patients, which reported a significantly higher incidence of biopsy-proven acute rejection in patents receiving Gengraf versus Neoral (39% versus 25%, P<0.05). Until robust clinical data demonstrate that different formulations of CsA are interchangeable, it is advisable to prescribe CsA by brand, and any transfer to a different CsA formulation should be undertaken with close supervision and only at the direction of the transplant physician.
Therapeutic drug monitoring of cyclosporine: 20 years of progress
University of Texas Medical School at Houston, Division of Immunology and Organ Transplantation, Houston, TX 77030, USA. Barry.D.Kahan@uth.tmc.edu
Since its introduction 20 years ago, cyclosporine (CyA), a powerful immunosuppressant with a narrow therapeutic window, remains the cornerstone of many drug regimens in renal transplantation. However, attempts to balance its therapeutic value with its pleiotropic side effects continue to challenge clinicians. To address the wide intraindividual and interindividual differences in absorption, distribution, metabolism, and elimination of the oil-based formulation of CyA (Sandimmune), a microemulsion (Neoral) was introduced; it displayed better absorption and lower intraindividual variability. Neoral also improves the utility of therapeutic monitoring of CyA to estimate exposure to the drug and predict patient outcomes. Drug monitoring techniques are undergoing continual refinement: today, a limited sampling strategy--C2 monitoring--shows great promise as a comparatively simple, safe, and effective method to optimize patient outcomes during both short-term and maintenance CyA therapy. However, it is not clear whether this method is useful for treatment optimization with generic formulations of CyA. Although generic substitutes meet federal bioequivalence criteria, they may not display the same pharmacokinetic properties. Further, preliminary data have shown a 10% lower 1-year graft survival rate among patients treated with generic versus Neoral CyA. Current challenges in optimizing CyA therapy include determining pretransplant patient characteristics relevant to selection of the appropriate exposure or the development of a Bayesian forecasting technique that predicts dose adjustments necessary to achieve the optimal drug regimen during the critical period immediately posttransplant.
Comment in: Bone Marrow Transplant. 2005 Aug;36(4):367.
Experience with cyclosporine
University Hospital Birmingham, Birmingham, UK. Andrew.Ready@uhb.nhs.uk
The introduction of cyclosporine (CyA) was a landmark in transplantation, and in the two decades that have followed, enormous experience has been acquired in its use. This has led to both an understanding of its mechanism, pharmacokinetics and toxicity, and the continued evolution of its clinical application. Many of the initial complexities related to the hydrophobic nature of the molecule, and its variable absorption were addressed by the introduction of the microemulsion formulation Neoral. Despite this, the therapeutic window for CyA remains narrow, and therapeutic drug monitoring, recognized early after its introduction, is essential. However, this too has been redefined with single-point, 2-hour, postdose monitoring being demonstrated to correlate better with dose and outcome than the traditional 12-hour trough level. Implementation of such techniques may impact on efficacy and the long-term effects of nephrotoxicity. The need to gain experience with new facets of CyA is likely to continue. In particular, the use of reduced doses to minimize nephrotoxicity during long-term management has produced favorable early results. Furthermore, in the near future the availability of generic CyA formulations will increase. It cannot be assumed that these will be bioequivalent to the current preparations, and modifications of therapy, outside of current experience, may be required. However, if 20 years of CyA usage has taught us anything, it is that different formulations may have very different biological behavior, and at least this situation can be approached with a caution gained from long experience.
Pokrok v imunosupresivní léčbě hrál podstatnou roli při dosažení výborných výsledků transplantací. V současné době se začínají objevovat generická imunosupresiva.
Biosimilars nejsou generické kopie! Přednáška o farmakologických, chemických a regulatorních rozdílech mezi originálem, generikem a biosimilars zazněla na Brněnských onkologických dnech 2012.
Vývoj nového léku je proces zdlouhavý, finančně nákladný a hlavně rizikový. Ze 100 000 nově vyvinutých látek se pouze 5–10 dostane do fáze klinických hodnocení na člověku a jen jedna léčivá látka je následně registrována jako léčivo vhodné pro pacienty.