Pharmacokinetic conversion study of a new cyclosporine formulation in stable adult renal transplant recipients.

Cyclosporine A (CyA) is a standard component of immunosuppressive regimens. It is a critical-dose drug for which a minor change in absorption can have important clinical consequences. The aim of the study was to compare the pharmacokinetics and safety of the new generic CyA formulation, Equoral capsules, after a switch from original formulation, Neoral capsules, in seventy stable adult renal transplant recipients. The extent and rate of pharmacokinetic parameters for bioequivalence were compared in a non-randomized, steady-state clinical study with fixed non-replicate study design. Pharmacokinetic analysis of CyA have shown that both the rate and extent of absorption of Equoral does not differ significantly from that of Neoral. At identical dosing, the new formulation was found to have geometric means of C(max) 717 ng/ml and AUCtau 3108 ng/ml.h, while corresponding results of comparator were 725 ng/ml and AUCtau 3039 ng/ml.h, respectively. The 90 % confidence intervals of C(max) and AUCtau were within 80- 125 % interval of the mean values. The results suggest that Equoral capsules can be used as an alternative treatment to Neoral capsules in CyA regimen.

Cyclosporine lymphocyte maximum level: a new alternative for cyclosporine monitoring in kidney transplantation.

OBJECTIVES: To determine the relationship between clinical outcome, lymphocyte count (LC), and cyclosporine (CsA) lymphocyte maximum level (LT(m)L) in kidney transplant recipients. MATERIALS AND METHODS: CsA LT(m)L was determined in patients with biopsy-proven graft dysfunction and in patients with normal graft function. Clinical outcome was compared according to CsA LT(m)L, dosage, blood trough (C(0)) and maximum (C(max)) levels, hematocrit level, and LC. RESULTS: Rejecting patients had significantly lower LT(m)L than did those with normal graft function (27 -/+ 11 pg/Lc vs 71 -/+ 79 pg/Lc; P < 0.01) and similar LTmL to those with nephrotoxicity (27 -/+ 8 pg/Lc). Patients with normal graft function exhibited significantly lower LC (0.001292 -/+ 696 x 10(9)/L) and serum creatinine levels (88.4 -/+ 35 micromol/L) when compared with rejecting patients (0.001717 -/+ 364 x 10(9)/L, 132.6 -/+ 8.8 micromol/L) and those with nephrotoxicity (0.001884 -/+ 582 x 10(9)/L, 123.7 -/+ 8.8 micromol/L) (P < 0.03, P < 0.001). No significant difference was observed among the 3 groups with regard to CsA dosage, C(0), C(max), mycophenolate mofetil (MMF) dosage, and mycophenolic acid (MPA) plasma levels. CsA LT(m)L closely correlated in an exponential (R(2) = 0.98) and linear (R(2) = 0.35) fashion with LC and hematocrit level, respectively. Conversely, CsA C(max) failed to correlate with C(0) and these 2 latter parameters. Weak correlations were observed between CsA C(max) and its corresponding LT(m)L. CONCLUSIONS: CsA LT(m)L appears to correlate better than CsA C(max) with rejection-free outcome and LC. An increase in hematocrit appears to have an adverse effect on CsA lymphocyte binding. CsA LT(m)L may offer a new alternative for CsA monitoring in kidney transplantation.

The mosaic of immunosuppressive drugs.

Graft rejections as well as tolerance are true representation of the specificity, sophistication and redundancy of an elegantly and meticulously designed immune system. Tolerance is in a way similar to the process of self-recognition where lymphoid clones, during development, baring self-reactive receptor are eliminated or rendered in active by "clonal deletion" leading to a state of accommodation and acceptance (anergic). On the other hand, both acute and chronic rejections are manifestation of the purpose of existence of the immune system, which is to defend the host against foreign invaders. Thus, in order to treat (control) graft rejection it is necessary to determine and understand the steps leading to recognition, stimulation, activation, and amplification of the immune system. The first step leading to the initiation of the immune system cascade is recognition. Which can either be direct where donor antigens of the major histocompatibility complex (MHC) expressed on the donor cells (passenger leukocytes) or tissues are recognised by the host immune system. The direct recognition pathway initiates acute graft rejection. Alternatively processed donor MHC peptides presented by the recipient antigen presenting cells (APC) initiate the indirect pathway of immune response, which is as important as the direct recognition especially in chronic rejection. Recognition is followed by the ligation of a series of adhesion molecules starting with an antigen to its specific T-cell receptor (TCR)/cluster of differentiation (CD) complex, expressed on the surface of the T cell. In order for the activation to precede additional costimulatory signals, such as ligation of the CD28/B7, CD4/HLA class II and CD/HLA class I antigens are required. The activation process is accompanied by an increase of cytokines production such as interleukin (IL)-2, IL-12, interferon (INF) and tumour necrosis factor (TNF) by the primed T cell. The complexity and the polymorphic nature of the immune system have necessitated designing agents that inhibit the immune system at different levels. Cyclosporine and Tacrolimus, collectively known as calcineurin inhibitors, seems to act on the IL-2 by inhibiting its production thus leading to a decrease in the proliferation of the activated lymphocyte. Rapamycin, which is similar to Tacrolimus, inhibits graft rejection by blocking IL-2 activation and phosphorylation of 70 S6 kinase thus inhibiting the progression of T-cell from G to S phase. While Cellcept (MMF) reduce the proliferation of T cell by inhibiting purine synthesis and by its action on ionosine monophosphate dehydrogenase. Anti-lymphocyte antibodies (ATG) deplete circulating lymphocytes while selective monoclonal antibodies are directed against IL-2 receptor thus reducing the rate of proliferation of activated T cells. Recently, antibodies to the CD40/CD40 ligand have been shown to induce long-term graft survival with the inhibition of the Th1 cytokines (INF), IL-2 and IL-12 and upregulating the Th2 cytokines IL-4 and IL-10. Lastly graft rejection can be reduced by blockade of the B7/CD28 costimulation pathway with the fusion protein CTLA-4Ig. With the availability of such potent and diverse agents it is now possible to develop multi drug regiments that can depress the immune system at the different steps of the activation cascade, with minimal side effects, thus improving graft and patient survival rates.

Bioavailability versus bioequivalence: the cyclosporine model.

The quest for a fixed-dose immunosuppressive drug continues. Experience with cyclosporine, tacrolimus and mycophenolate mofetil has taught us that there is no correlation between dose and clinical events. These data indicate that the concentration of the drug at the site of action (bioavailability) of each of these agents differs from one patient to the next. In addition, the bioequivalence (concentration of intact drug at the site of action resulting in a measurable response [effect]) may differ among individuals. Technically, it is very difficult to measure the drug concentration at a particular site, especially in organs or tissues that are not directly accessible. Therapeutic drug-blood-level monitoring is a simple indirect method that is used to estimate both bioavailability and bioequivalence. However, the immunosuppressive effect of all these drugs is initiated by binding to receptors on the surface of lymphocytes, which leads to inhibition of cytokine production and proliferation of activated lymphocytes. Thus, it would be more advantageous to monitor the level and effect of these drugs at the site of action (bioequivalence), the lymphocyte. This report describes an assay of this type that was developed for monitoring transplant patients at one center. The assay is based on measuring drug levels in the cytoplasm of lymphocytes. It is quick and easy to perform (20 samples per hour), inexpensive, and reproducible. The between-run Coefficient of Variance (CV) is 5.4 and a within-run CV is 3.1. For this study, blood and lymphocyte drug levels in transplant patients were determined and correlated with graft function and clinical events (biopsy-proven rejection and/ or toxicity).

Middle East Society for Organ Transplantation (MESOT) Transplant Registry.

During the seventies, sporadic renal transplants were performed in few MESOT-region countries, mainly Turkey, Iran, Egypt, and Lebanon. Since the introduction of cyclosporine in the early eighties, transplantation has become the preferred therapeutic modality for end-stage renal failure. In 1986, the Islamic theologians (Al Aloma) issued what became known as the Amman declaration, in which they accepted brain death and retrieval and transplantation of organs from living and cadaveric donors. Based on this and similar declarations, all Middle Eastern countries except Egypt passed laws that allow cadaveric transplantation and regulate live donations. Iran, Turkey, Saudi Arabia, Kuwait, Tunisia, Jordan, and Lebanon all have current active cadaveric programs and perform liver, heart, pancreas, and lung transplants. More than 5088 renal transplants/year are performed in the region with Iran leading with 1600. The cumulative number of renal transplant patients is now nearly 60,000. With a 2003 population of 600,682,175, the rate/million for renal transplantation in the MESOT region is a mere 9/million. Rates of renal transplantation range from 31/million in some countries to 0 in others. The major obstacle in establishing an accurate number of transplants is "tourist transplantation," in which the same transplanted patients are registered in different countries. Although cadaveric programs have been active for more than 10 years, live-related and nonrelated transplants account for nearly 85% of the total transplants. The data presented were collected from MESOT representatives in the region and from publications. For proper compilation of the registry, a format is being proposed that will be presented at the Congress for review and adaptation. Even with the limited resources in the region, immunosuppressive drugs for induction and maintenance therapy are available and are used. Costs for transplantation and immunosuppressive therapy are either totally or heavily supported by governmental agencies.