Prednisolone and Prednisone Pharmacokinetics in Adult Renal Transplant Recipients

Abstract

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 chromatography2tandem 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 = 20.83) 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 6 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.

In vitro assessments predict that CYP3A4 contributes to a greater extent than CYP3A5 to prednisolone clearance

“…Although experimental conditions, inter-individual variability, extrahepatic metabolism or non-linear kinetics may cause discrepancies between in vitro and in vivo data, 50,51 the observations from this study may imply that other factors than genetic polymorphisms in CYP3A5 determine the considerable inter-individual variability of prednisolone demonstrated in earlier studies. 23,24 A further corroboration of these results with an in vitro study of the relative contribution of rCYP3A4 and rCYP3A5 in the metabolism of prednisolone in human liver microsomes is warranted, with assessment of scaling factors to convert the results into in vivo relevance. Furthermore, clinical studies allowing for a comparison of PL metabolism between CYP3A5 expressors and non-expressors, where also a potential effect of a CYP3A inhibitor is evaluated, are necessary to quantify the eventual contribution by CYP3A5-mediated metabolism of prednisolone in a clinical setting.…”

“…In an earlier study investigating adult renal transplant recipients, we observed three CYP3A5 expressors (*1/*3) presenting a mean dose/BW-adjusted prednisolone-AUC 0-24 , which was 25% lower compared with CYP3A5 non-expressors (n = 25). 23 Moreover, in a population of nine paediatric renal transplant recipients, we found that the patient with the lowest prednisolone-AUC 0-12 and the highest prednisolone-CL/F was a CYP3A5 expressor (*1/*3). 24 Hence, the aim of this in vitro study was to examine the relative contribution by recombinant CYP3A4 (rCYP3A4) and recombinant CYP3A5 (rCYP3A5) in the metabolism of prednisolone and to compare the extent of formation of 6β-OH-prednisolone by the two enzymes.…”

“…All samples were analysed for concentrations of prednisolone and 6β-OH-prednisolone using protein precipitation, followed by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS), performed as described in a previous article 23 with some minor modifications to include 6β-OH-prednisolone in the assay (Tables 1 and 2 and Figure 2). Stock solutions of calibrators (1 mg/ml) and internal standards (IS; 1 mg/ml) were prepared in MeOH.…”

Fingerprick Microsampling Methods Can Replace Venepuncture for Simultaneous Therapeutic Drug Monitoring of Tacrolimus, Mycophenolic Acid, and Prednisolone Concentrations in Adult Kidney Transplant Patients

“…46 Twenty-four-hour trough measurement of prednisolone is likely to be inappropriate because of the agents' short half-life, with prednisolone area under the curve or cortisol levels being a potential alternative measure. 47 A literature review by Bergman et al found a greater than 3-fold variability in dose-adjusted exposure to total prednisolone in transplant patients, and Skauby et al also found 3-fold variation in prednisolone area under the curve and a correlating 18-fold difference in cortisol levels. 46,47 Further research is required to assess the relationship between prednisolone exposure and clinical outcomes in kidney transplant patients.…”

Current status of glucocorticoid usage in solid organ transplantation

“…AUC 0-24 of prednisolone and cortisol varied by three-fold and eighteen-fold, respectively, among patients. These results reveal large inter-individual variability in both prednisolone exposure and suppression of endogenous cortisol that signify a possible need for therapeutic drug monitoring of GCs[ 137 ].…”