Comparative methylprednisolone pharmacokinetics in renal transplant patients receiving double- or triple-drug immunosuppression

OBJECTIVE: To assess the pharmacokinetics of chronic methylprednisolone therapy in renal transplant patients receiving double-drug (methylprednisolone and azathioprine) and triple-drug (methylprednisolone, azathioprine, and cyclosporine) immunosuppression. DESIGN: Parallel, randomized trial. PATIENTS: Fourteen renal transplant recipients (aged 29-65 y) evaluated in a public, university-affiliated hospital clinic. INTERVENTIONS: All patients received their chronic oral dose of methylprednisolone via a 10-20-minute intravenous infusion. MAIN OUTCOME MEASURES: Serum methylprednisolone concentrations were determined by HPLC and were used to generate pharmacokinetic parameters for this drug. RESULTS: The mean daily methylprednisolone dosage was 19 +/- 19 mg in the double-drug group and 9 +/- 2 mg in the triple-drug group. Mean serum creatinine concentrations were 124 +/- 44 and 124 +/- 27 mumol/L, respectively. Mean methylprednisolone clearances were similar in both groups: 405 +/- 205 (double-drug) and 373 +/- 365 mL/h/kg (triple-drug) (p > 0.05). Mean steady-state volume of distribution was 1.5 +/- 0.8 L/kg in the double-drug group and 1.3 +/- 0.8 L/kg in the triple-drug group (p > 0.05). Plasma half-life ranged from 1.7 to 4.3 h (mean 2.7) in the double-drug group versus 1.4 to 3.4 h (mean 2.6) in the triple-drug group (p > 0.05). CONCLUSIONS: These data indicate that cyclosporine had no definitive influence on methylprednisolone disposition. The results reveal a wide variation in methylprednisolone metabolism in renal transplant recipients receiving either a double- or triple-drug immunosuppressive regimen. Typically, methylprednisolone is prescribed according to a standardized dosing protocol that assumes minimal interpatient variation. Therefore, the pharmacokinetic variability noted in this study may have important clinical implications regarding the development of chronic toxicity (e.g., osteoporosis, hypothalamic-pituitary-adrenal suppression) and the attainment of successful immunosuppression.