Pharmacokinetics of Total and Unbound Prednisone and Prednisolone in Stable Kidney Transplant Recipients With Diabetes Mellitus

Abstract

Background and Objective The corticosteroid prednisone is an important component of post transplantation immunosuppressive therapy. Pharmacokinetic parameters of prednisone or its pharmacologically active metabolite, prednisolone, are not well characterized in transplant recipients. The objective of the present study was to compare the pharmacokinetics of total and unbound prednisone and prednisolone in diabetic and nondiabetic stable kidney transplant recipients and to evaluate the factors influencing plasma protein binding of prednisolone. Study Design Prednisone and prednisolone concentration-time profiles were obtained in 20 diabetic and 18 nondiabetic stable kidney transplant recipients receiving an oral dose of 5-10 mg prednisone per day. In addition to drug and metabolite exposures, factors influencing prednisolone protein binding were evaluated using a nonlinear mixed effects modeling approach. This model takes into account binding of prednisolone and cortisol to Corticosteroid Binding Globulin (CBG) in a saturable fashion and binding of prednisolone to albumin in a non-saturable fashion. Finally, we have investigated the influence of several covariates including diabetes, glucose concentration, hemoglobin A1c, creatinine clearance, body mass index, gender, age and time post transplantation on the affinity constant (K) between corticosteroids and their binding proteins. Results In diabetic patients, the values of dose-normalized area under the concentration-time curves were 27% and 23% higher for total and unbound prednisolone, respectively. Moreover, the ratio of total prednisolone to prednisone concentrations (active /inactive forms) was higher in diabetic subjects (P <0.001). Modeling protein binding results revealed that the affinity constant of CBG-prednisolone (KCBG,PL) was related to patient's gender and diabetes status. Conclusions Higher prednisolone exposure could potentially lead to the increased risk of corticosteroid related complications in diabetic kidney transplant recipients.

Alternative Matrices for Therapeutic Drug Monitoring of Immunosuppressive Agents Using LC–MS/MS

“…Prednisolone is widely prescribed as a part of immunosuppressive therapy regimens in solid organ transplantation [73]. The free fraction of PLN increases in certain clinical conditions such as diabetes [52]. In addition, the free fraction is dose-dependent and exhibits circadian variability (approximately 22% higher in the morning) [74].…”

Prednisolone Replacement Therapy Mimics the Circadian Rhythm More Closely Than Other Glucocorticoids

“…The traditional view is that the prednisolone to hydrocortisone bioequivalence ratio is 1:4 (11). This view is based on the antiinflammatory action of steroids seen at higher doses (12) and may be influenced by exogenous corticosteroids binding serum proteins in a nonlinear fashion (17). With increasing serum concentrations of prednisolone, there is a larger fraction of free prednisolone, promoting greater body clearance (18).…”

Pharmacokinetics and population pharmacokinetics in pediatric oncology

“…45 Example 4: Plasma protein binding: The corticosteroid prednisolone used in acute lymphoblastic leukemia has both linear and nonlinear binding to plasma proteins. [46][47][48] The binding to albumin is linear in contrast to the saturable binding to corticosteroid binding globulin (CBG). The concentration of free unbound prednisolone depends on CBG, albumin, and free prednisolone.…”