Prednisolone and Prednisone Pharmacokinetics in Adult Renal Transplant Recipients

Background: Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase. Methods: This single-center, prospective, observational study included stable renal Tx recipients, >18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval [n = 26 samples per area under the curve (AUC(0-24))], within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. Results: In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure [median, range AUC(0-24) = 3821 (2232-5382) mcg h/L], paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio [median, range 11 (3-47)%]. A negative correlation (r = -0.83) between PL AUC(0-24) and morning CL levels was observed. The best single PK variable to predict PL AUC(0-24) was PL C-6 (r(2) = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC(0-24) with a low percentage prediction error (PPE = 5.2 +/- 1.5%) and a good correlation of determination (r(2) = 0.91). PL AUC(0-24) varied 3-fold among study participants, whereas CL AUC(0-24) varied by 18-fold. Conclusions: The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC(0-24) and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.

Automated summary

This study characterized the pharmacokinetics of PL and PN in renal Tx recipients, revealing a wide variability in PL exposure and suppression of endogenous CL. Therapeutic drug monitoring may be necessary due to this variability. An abbreviated profile within the first 4 hours after PL dosing was found to provide a good prediction of PL exposure, with a potential surrogate marker for drug exposure being morning CL levels.