Original articlesComparative Bioavailability Evaluation of Two Cyclosporine Oral Formulations in Healthy Mexican Volunteers
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.
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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
References (27)
- et al.
Reduced inter- and intra-individual variability in cyclosporine pharmacokinetics from a microemulsion formulation
J Pharm Sci
(1994) Cyclosporine in cadaveric renal transplantationone year follow-up of multicentre trial
Lancet
(1983)- et al.
Effect of dietary fat on the pharmacokinetics and pharmacodynamics of cyclosporine in kidney transplant recipients
Clin Pharmacol Ther
(1995) - et al.
Cyclosporine kinetics in renal transplantation
Clin Pharmacol Ther
(1985) - et al.
The absorption site of cyclosporine in the human gastrointestinal tract
Br J Clin Pharmacol
(1992) - et al.
Effect of dietary fat on the pharmacokinetics and pharmacodynamics of cyclosporine in renal transplant recipients
Transplant Proc
(1994) - et al.
Effect of food on the pharmacokinetics of cyclosporine in healthy subjects after oral and intravenous administration
J Clin Pharmacol
(1990) - et al.
Effects of dietary fat on drug absorption
Clin Pharmacol Ther
(1995) - et al.
Effects of bile on cyclosporine absorption in liver transplant patients
Br J Clin Pharmacol
(1984) - et al.
Rationale for the development of Sandimmun Neoral
Transplant Proc
(1994)
Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation
Clin Pharmacol Ther
A new microemulsion formulation of cyclosporine
Clin Pharmacokinet
Bioavailability of oral cyclosporine in healthy Mexican volunteersevidence for interethnic variability
J Clin Pharmacol
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