Transplant International ISSN 0934-0874
REVIEW
Generic cyclosporine formulations: more open questions
than answers
Dario Cattaneo,1,2 Norberto Perico1,2 and Giuseppe Remuzzi1,2
1 Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo, Mario Negri Institute for Pharmacological Research, Bergamo, Italy
2 Center for Research on Organ Transplantation, ‘‘Chiara Cucchi De Alessandri & Gilberto Crespi’’ Mario Negri Institute for Pharmacological
Research, Ranica, Bergamo, Italy
Keywords Summary
bioequivalence, cyclosporine, generic
formulation, organ transplantation. The introduction of cyclosporine (CsA) in clinical practice has significantly
improved patient and allograft survival after organ transplantation. The new
Correspondence microemulsion CsA formulation, Neoral, has been associated with a more
Dario Cattaneo Pharmacol.D, Mario Negri reproducible absorption and a better patient outcome as compared to the old
Institute for Pharmacological Research, Via
formulation Sandimmune. Recently, several generic CsA formulations have
Gavazzeni 11, 24125 Bergamo, Italy. Tel.:
+39-035-319888; fax: +39-035-319331;
been tested as bioequivalent to Neoral. Bioequivalence tests have been per-
e-mail: dcattaneo@marionegri.it formed in selected groups of young, healthy male volunteers usually in single-
dose studies, and then extended to completely different population, such as
Received: 21 June 2004 transplant recipients. However, growing body of evidence shows that CsA phar-
Revised: 10 November 2004 macokinetics in healthy subjects is different from that of transplant patients,
Accepted: 1 December 2004 treated chronically with CsA. Therefore, converting patients from Neoral to the
new generic formulations could be detrimental, exposing patients to increased
doi:10.1111/j.1432-2277.2005.00078.x
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.
tions underline the role of the pharmaceutical formulation
Introduction
and related factors to clinical outcome. The excipients used
Cyclosporine (CsA), one of the principal immunosuppres- in a drug formulation are, by definition, inactive and play
sants currently used to prevent graft rejection, has largely no role in the pharmacological action of the drug. How-
contributed to improve patient and allograft survival [1]. ever, early [5,6] it was realized that the nature of the excipi-
CsA is characterized by a narrow therapeutic index, sig- ents used, and changes in the way oral drug preparations
nificant side effects, and a strong correlation between CsA were formulated could have very great effects on the
exposure and clinical outcome. To this, major efforts have amount of drug absorbed. In addition, some excipients are
been devoted to individualize CsA dosing based on phar- known to modify the activity of the multidrug resistance
macokinetic parameters, in order to minimize the toxicity proteins (MDR1), an efflux pump which removes lipophi-
and improve the risk-to-benefit ratio [2]. lic drugs from the intracellular space, and/or metabolic
Despite more than 20 years of its clinical use, one of the enzymes like cytochrome P450 subclass 3A4 [7]. Thus, the
challenge in CsA management is the poor, variable and variable oral CsA bioavailability represents a biopharma-
unpredictable absorption, associated with a great intra- and ceutical risk factor and deserves particular attention when
inter-patient variability. This is a key factor, since the new formulations are used.
greater the day-to-day variability in CsA exposure, the
higher the risk of acute rejection in organ transplant recipi-
Limits of the CsA Sandimmune formulation
ents [3]. It has been also shown that high intra-individual
variability of CsA exposure enhances chronic rejection inci- Sandimmune (Novartis, Basel, Switzerland), an oil-based
dence, and eventually health care costs [4]. These observa- suspension of CsA immiscible with water, was first used
Transplant International 18 (2005) 371–378 ª 2005 European Society for Organ Transplantation 371
, Generic cyclosporine formulations Cattaneo et al.
in preclinical studies in 1977 and thereafter, introduced reproducible absorption profile compared with the old
in clinical practice in 1984 [8]. formulation. As a consequence, a closer pharmacokinetic
The bioavailability of Sandimmune is extremely vari- relationship between CsA trough concentration and area
able, ranging from 5% to 50%. This formulation is char- under the time–concentration curve (AUC0)12) [14,15]
acterized by intra-individual erratic oral absorption, was reported. These findings renewed the interest for the
greatly influenced by bile flow, the composition of biliary, application of CsA therapeutic drug monitoring.
pancreatic, and duodenal/small bowel secretion, the func- The favorable kinetic profile of Neoral compared to the
tion and motility of the small bowel, and food [9,10]. conventional formulation was confirmed in the early
The excipients may also play a significant role, influen- phase post-transplant [16] as well as in stable renal trans-
cing the pharmacokinetic properties of Sandimmune. plant recipients [17]. Although safety and tolerability of
Recently, it has been shown that Sandimmune capsules, the two formulations were comparable, the incidence of
where the drug is dissolved in olive oil in a soft gelatin acute rejection was lower in the Neoral group. In patients
capsule, and Sandimmune solution, where the drug is dis- previously treated with Sandimmune, the conversion to
solved in corn oil, were not bioequivalent in a subset of Neoral was associated with an increase in the CsA expo-
poor absorbers [11]. Indeed, it should be taken into sure. Of note, 20% of patients categorized as ‘low’
account that inter-individual variation in the Sand- absorbers while on traditional formulation, became ‘inter-
immune absorption has been also reported, which segre- mediate’ or ‘high’ absorbers as early as 15 days after con-
gates three distinct populations of patients, defined as version to Neoral (Fig. 1), further supporting the
‘low’, ‘intermediate’, and ‘high’ absorbers [12]. beneficial pharmacokinetic effect of the new formulation.
To overcome these limitations, therapeutic drug monit- The advent of Neoral, with its peculiar kinetic profile,
oring and adjusting CsA Sandimmune dose to individual has also provided new opportunities to explore more sen-
need of CsA trough blood levels (C0) has widely adopted. sitive and feasible CsA monitoring strategies as surrogate
However, with this CsA formulation, the pharmacokinetic markers of drug exposure in transplant patients. Several
approach is not of universal help, as documented by find- single- or limited-sampling point tools have been devel-
ings that some patients experience acute graft rejection oped so far for patients on Neoral-based immunosuppres-
even in the presence of adequate or high blood CsA con- sion [18]. On this line, recent evidence in liver and
centration, while others develop toxicity at CsA trough kidney transplant recipients indicate that 2-h postdose
level below normal [13]. point sampling (C2) is a sensitive tool for fine-tuning
The variations in CsA absorption profile with Sand- CsA dosage [19,20] when Neoral formulation is used.
immune led to efforts in developing a new CsA formula- The more reproducible absorption and blood CsA con-
tion. centrations achieved with Neoral are likely to result in the
reduction in the incidence of acute rejection episodes in
the early period as well as in the stable transplant recipi-
The novel CsA Neoral formulation
ents [21].
The new formulation, CsA Neoral (Novartis, Basel, Swit- Overall, these observations further underline the impact
zerland), was based on a microemulsion that in the gut of the pharmaceutical formulation on patient monitoring
disperses more rapidly, leading to increased and more and clinical outcome and support the superiority of the
800
CsA blood level (ng/ml)
Sandimmune Neoral 15 days Neoral 6 months
600
400
200
0
0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 2 4 6 8 10 12
Time (h) Time (h) Time (h)
Figure 1 CsA blood concentration in ‘low’ absorber patients before (Sandimmune) and after conversion to Neoral formulation (day 15 and
month 6) (modified from [17]).
372 Transplant International 18 (2005) 371–378 ª 2005 European Society for Organ Transplantation
