Cyclosporine is widely used as an immunosuppressive agent, especially in organ transplantation. Since its introduction, kidney graft survival has considerably improved. However, cyclosporine also produces serious side effects, such as nephrotoxicity, hypertension, and liver and cerebral toxicity. However, the wide intra- and interindividual variability of cyclosporine pharmacokinetics and pharmacodynamics makes optimum immunosuppression difficult. Monitoring of blood cyclosporine concentrations has facilitated dosing individualization. Despite extensive clinical experience, the variability of cyclosporine pharmacokinetics and clinical response is not as yet thoroughly explained.

Cyclosporine, a cyclic polypeptide with a molecular weight of 1,203 daltons in addition to a high degree of lipophilicity and binding to lipoproteins, is absorbed predominantly in the small intestine. Oral cyclosporine was initially introduced in therapeutics as an oil-based formulation (Sandimmune^®). A high-fat meal offered concomitantly with a cyclosporine dose, which is dissolved in olive oil additionally diluted in milk or orange juice, is associated with a significant increase in cyclosporine area under the plasma concentration-time curve (AUC) compared with administration of a low-fat meal or vehicle alone in kidney transplant recipients. This enhancement is observed in both patients and healthy volunteers. A stimulation of bile flow, which accompanies dietary fat consumption, may be the contributing factor to the improved solubility and subsequent increased absorption of cyclosporine. This oil formulation is not ideal, as cyclosporine absorption is highly bile-dependent. Poor absorption through the gastrointestinal mucosa seems to be one of the main reasons for the low, variable bioavailability of cyclosporine.

The absorption of the conventional formulation of cyclosporine displays considerable inter- and intra-patient variability. Cyclosporine bioavailability varies between 20% and 60% and increases with time after kidney transplantation. This low, variable bioavailability renders it difficult to institute and monitor immunosuppressive therapy after organ transplantation. Better bioavailability of cyclosporine would facilitate immunosuppressive treatment.

Recently, a new galenic formulation of cyclosporine was introduced (Neoral^®), which is a water-free microemulsion of cyclosporine. The microemulsion creates micelles, which are absorbed in the small bowel without the presence of bile. This enhances the bioavailability of cyclosporine, especially after liver transplantation.

We observed an increase of adverse events with this new microemulsion formulation in Mexican patients who were receiving doses similar to those used with the conventional cyclosporine formulation. This higher incidence of adverse events may be due to a higher bioavailability of Neoral^® than that observed with the conventional formulations. In a previous study, our group reported that bioavailability of cyclosporine, administered as Sandimmune^®, was higher than the bioavailability reported in Caucasians. Therefore, it is important to compare the bioavailability of the two formulations of cyclosporine to design the adequate dosage regimens that should be used with the Neoral^® formulation in the Mexican population.

Twenty-three healthy volunteers (10 female and 13 male) participated in the study conducted according to the recommendations of the Helsinki Declaration and was approved by the local Ethics Committee of our Institution. All subjects gave written informed consent for participation. Volunteers were physically fit and no abnormalities were detected in routine clinical and laboratory tests. Hepatic, renal and cardiovascular disorders were excluded by medical history, physical examination, and suitable laboratory determinations. None of the subjects smoked, used drugs, abused alcohol, or was taking any medication.

The study was carried out according to a randomized crossover design, allowing a washout period of 1 week. After an overnight fast (10 h), subjects received the fat-rich diet customary in a Mexican breakfast (carbohydrates: 43.81%, proteins: 9.6%, and lipids: 45.71%) and were administered 7.5 mg/kg cyclosporine oral solution 30 min later (Group A, conventional solution, and Group B, Neoral^®, Sandoz de México, Mexico City) dissolved in 100 mL of orange juice. An indwelling cannula with a heparin lock was inserted into a forearm vein and 0.5-mL blood samples were drawn in tubes with EDTA anticoagulant at 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 h after medication. The fresh whole-blood samples were assayed for cyclosporine by specific monoclonal radioimmunoassay according to manufacturer instructions (Sandimmune Kit, Sandoz Ltd., Basel, Switzerland). This kit uses ³H-tracer and has a monoclonal antibody with high specificity for unchanged cyclosporine.

A compartment-independent pharmacokinetic analysis was used. Maximal whole blood concentration (C_max) and its time of occurrence (t_max) were compiled from the concentration-time data. AUC_0-24 was calculated by the linear trapezoidal rule.

To establish whether the formulations tested were bioequivalent, analysis of variance for a crossover design was carried out for logarithmically transformed bioavailability parameters (C_max and AUC_0-24). An additional evaluation of the ratio between test and reference formulations was calculated, as well as the 90%-confidence limits. The probability of obtaining values outside the limits of acceptance was determined by the two one-sided t test. Limits of acceptance for considering the two formulations tested bioequivalently were 80 to 125%.

It depicts the circulating concentrations against time curves obtained after administration of the two formulations assayed. It can be clearly seen that the microemulsion formulation was more rapidly absorbed, reaching C_max in 2.3 h, whereas the maximum observed with the conventional formulation was reached in 3.69 h. As a consequence of this faster absorption with the microemulsion formulation, a higher C_max was reached. However, extent of bioavailability, expressed as AUC_0-24, was about 10% higher with microemulsion than with the conventional formulation. Bioavailability parameters obtained with the two. In order to establish whether the two formulations are bioequivalent, the ratios (T/R, test/reference) for AUC and C_max obtained with the two formulations were calculated. Subsequently, 90%-confidence limits were estimated and the probability of obtaining values outside the limits of acceptance was calculated. It demonstrates the values obtained. It is clearly shown that the formulations are bioinequivalent, because the probability of obtaining values outside the limits of acceptance is higher than 0.05. In general, both treatments were well tolerated. No subject experienced clinically relevant changes in vital signs during the course of the investigation. Nausea and generalized burning sensations were the main adverse effects.

A comparison in the bioavailability of cyclosporine in two different oral formulations, microemulsion, and conventional solution, was carried out in healthy Mexican volunteers. In our study, a higher bioavailability with Neoral^® was observed, reflected in the increased values of both C_max and AUC as well as in a reduction of t_max. These results indicated that the microemulsion formulation is absorbed more rapidly than the conventional formulation.