Pharmacokinetic, hemodynamic, and metabolic effects of cyclosporine sandimmune versus the microemulsion neoral in heart transplant recipients.

BACKGROUND

Cyclosporine is a potent immunosuppressive agent that is, however, associated with systemic hypertension and renal dysfunction. The purpose of this investigation was to study the pharmacokinetic and long-term renal and hypertensive effects of Sandimmune (Sandoz) versus the new Neoral (Novartis) formulation of cyclosporine in heart transplant recipients.

METHODS

Twenty heart transplant recipients with stable conditions and aged 54 +/- 9 years were studied in an open-labeled single-arm conversion protocol. Twelve-hour pharmacokinetic studies were performed on Sandimmune and after 4 weeks of treatment with Neoral at similar dosage. The 24-hour blood pressure monitoring, creatinine clearance, and complete biochemistry profile were studied simultaneously to the pharmacokinetic studies. Six-month follow-up with serial measurements of cyclosporine levels, and biochemistry profile was completed.

RESULTS

Conversion to Neoral resulted in a 24% increase in area-under-the-curve in spite of no significant changes in cyclosporine trough levels (165 +/- 48 [Sandimmune] vs 169 +/- 32 nmol/L; p = 0.26). Respectively, 16%, 68%, and 16% were poor, average, and good absorbers on Sandimmune versus 26% and 74% being average or good absorbers on Neoral. Averaged systolic and diastolic blood pressure were not affected by Neoral, but blood pressure readings increased in 20% of patients previously known as having hypertension. The 24-hour blood pressure data yielded no significant changes with Neoral, but the nocturnal drop in systolic blood pressure was attenuated by Neoral. Twenty-four-hour creatinine clearance was not affected by Neoral, but serum magnesium levels decreased significantly at 6 months.

CONCLUSIONS

Neoral resulted in 24% increase in cyclosporine exposure without significant changes in trough levels, and improved absorption status. This greater drug exposure is well tolerated and resulted in a slight increase in blood pressure in a subset of patients and some decrease in magnesium levels, but it had no effect on renal function.