Elsevier

Archives of Medical Research

Volume 30, Issue 4, July–August 1999, Pages 315-319
Archives of Medical Research

Original articles
Comparative Bioavailability Evaluation of Two Cyclosporine Oral Formulations in Healthy Mexican Volunteers

https://doi.org/10.1016/S0188-0128(99)00034-2Get rights and content

Abstract

Background

The use of conventional cyclosporine (Sandimmune®) requires great care, as this drug exhibits a narrow therapeutic index and wide interindividual variability in its pharmacokinetics. Recently, a new microemulsion formulation (Neoral®) was developed. With this formulation, cyclosporine is absorbed at the small intestine without the presence of bile. Therefore, the objective of this study was to compare the bioavailability of cyclosporine after the administration of conventional and microemulsion formulations in healthy Mexican volunteers in order to approach the optimal dosage regimen of microemulsion in the Mexican population.

Methods

The trial was conducted using 23 healthy volunteers according to a randomized crossover design. Volunteers received one 7.5-mg/kg dose as each formulation, with a 1-week washout period between treatments. Blood samples of 0.5 mL were obtained according to the following schedule: 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 h after medication.

Results

These indicated that Cmax and AUC0-24 values were higher with the microemulsion than with the conventional formulation.

Conclusions

The microemulsion had a better absorption profile than the conventional formulation, because plasma levels with the conventional formulation demonstrated oscillations rather than reflecting an erratic absorption. Lower doses of the microemulsion are required to obtain Cmax values similar to those obtained with conventional cyclosporine.

Introduction

Cyclosporine is widely used as an immunosuppressive agent, especially in organ transplantation. Since its introduction, kidney graft survival has considerably improved (1). 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 2, 3.

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 (4). 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 (5). This enhancement is observed in both patients and healthy volunteers (6). 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 (7). This oil formulation is not ideal, as cyclosporine absorption is highly bile-dependent (8). Poor absorption through the gastrointestinal mucosa seems to be one of the main reasons for the low, variable bioavailability of cyclosporine (9).

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 (10). 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 (11).

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 (12). 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.

Section snippets

Subjects and Methods

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

Results

Figure 1 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 Cmax 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 Cmax was reached. However, extent of bioavailability, expressed as AUC0-24, was about

Discussion

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 Cmax and AUC as well as in a reduction of tmax. These results indicated that the microemulsion formulation is absorbed more rapidly than the conventional formulation.

The pharmacokinetic properties of the

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