Pharmacokinetics Of Prednisolone Research Articles

Saliva monitoring of prednisolone in children with first onset steroid-sensitive nephrotic syndrome: Is it possible?

Prednisolone is the cornerstone of treatment for idiopathic nephrotic syndrome in children, but is associated with marked side-effects. Therapeutic drug monitoring using saliva would be a patient-friendly option to monitor prednisolone treatment. To assess the feasibility of saliva monitoring, we described the pharmacokinetics (PK) of unbound prednisolone in plasma and saliva of children with first onset steroid-sensitive nephrotic syndrome (SSNS). Children (age 2-16 years) with SSNS participating in a randomized, placebo-controlled trial with levamisole were treated with an 18-week tapering schedule of prednisolone. Five serial samples were collected at 4 (saliva) and 8weeks (saliva and plasma) after first onset. A nonlinear mixed-effects model was used to estimate the PK parameters of unbound prednisolone and the saliva-to-plasma ratio. Monte Carlo simulations were performed to assess the predictive performance of saliva monitoring. From 39 children, 109 plasma and 275 saliva samples were available. Estimates (relative squared error) of unbound plasma clearance and volume of distribution were 93 (5%) L h-1 70 kg-1 and 158 (7%) L 70 kg-1, respectively. Typical saliva-to-plasma ratio was 1.30 (8%). Monte Carlo simulations demonstrated that on basis of 4 saliva samples and a single plasma sample unbound plasma area-under-the-concentration-time curve can be predicted within 20% imprecision in 79% of the patients compared to 87% based on 4 plasma samples. Saliva proved to be a reliable and patient-friendly option to determine prednisolone plasma exposure in children with SSNS. This opens opportunities for further PK and pharmacodynamics studies of prednisolone in a variety of paediatric conditions.

In vivo assessment of black seed oil single dose on prednisolone pharmacokinetics.

To investigate the effect of blackseed oil (BSO) single dose on prednisolone pharmacokinetics via p-gp inhibition. Three groups of rats (n = 5) were orally administered the vehicle, verapamil (50 mg/kg) or BSO (5 ml/kg) 15 min prior to prednisolone (5 mg/kg) administration. Blood samples were collected over 24 h and quantified. Non-compartmental analysis was employed to calculate maximum plasma concentration (Cmax), area under the curve (AUC0-last), time to reach Cmax (Tmax), apparent clearance (CL/F), and half-life (t1/2). Statistical significance was considered at p<0.05. Prednisolone Cmax and AUC0-last decreased by 65% and 25% in the BSO group compared to the negative control (P < .0001, .0029, respectively) while they increased by 1.75-folds and 8-folds in verapamil group (P < .0001). Tmax was achieved at 0.16, 0.5, and 0.25 h in the negative control, verapamil, and BSO-treated groups, respectively. CL/F in the treatment group was 1.3-fold and 10-fold higher compared to the negative and positive control, respectively, whereas the t1/2 remained comparable. Administration of BSO decreased prednisolone Cmax and AUC0-last in rats indicating that there is a herb-drug interaction; however, p-gp inhibition cannot be concluded. Patients relying on folk medicine in chronic illnesses treatment might need to avoid combining BSO with prednisolone.

Optimising prednisolone or prednisone replacement in adrenal insufficiency.

Patients with adrenal insufficiency (AI) have higher mortality than the general population, possibly because of excess glucocorticoid exposure at inappropriate times. The cortisol circadian rhythm is difficult to mimic with twice or thrice-daily hydrocortisone. Prednisolone is a once-daily alternative which may improve patient compliance and convenience. Prednisolone day curves can be used to accurately down-titrate patients to the minimum effective dose. We aimed to review prednisolone day curves and determine therapeutic ranges at different timepoints after administration. Between August 2013 and May 2021, 108 prednisolone day curves from 76 individuals receiving prednisolone replacement were analysed. Prednisolone concentrations were determined by ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Spearman's correlation coefficient was used to determine the relationship between 2-, 4- and 6-hour prednisolone levels compared to the validated standard 8-hour prednisolone level (15-25 μg/L). The median dose was 4mg prednisolone once daily. There was strong correlation between the 4-hour and 8-hour (R=0.8829, p ≤0.0001), and 6-hour and 8-hour prednisolone levels (R=0.9530, p ≤ 0.0001). Target ranges for prednisolone were 37-62 μg/L at 4-hours, 24-39 μg/L at 6-hours and 15-25 μg/L at 8-hours. Prednisolone doses were successfully reduced in 21 individuals and of these, three were reduced to 2mg once daily. All patients were well upon follow-up. This is the largest evaluation of oral prednisolone pharmacokinetics in humans. Low dose prednisolone of 2-4mg is safe and effective in most patients with AI. Doses can be titrated with either 4-hour, 6-hour, or 8-hour single timepoint drug levels.

Evaluation of the Drug-Drug Interaction Potential of Ensitrelvir Fumaric Acid with Cytochrome P450 3A Substrates in Healthy Japanese Adults.

Management of drug-drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor. The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir. This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day -2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day -2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals with ensitrelvir were reported during the study. The inhibitory effect for CYP3A was confirmed after the last dose of ensitrelvir, and the effect diminished over time. In addition, ensitrelvir at 375/125 mg showed CYP3A inhibitory potential similar to that at 750/250 mg. These findings can be used as a clinical recommendation for prescribing ensitrelvir with regard to concomitant medications. Japan Registry of Clinical Trials identifier: jRCT2031210202.

Prednisolone pharmacokinetics after oral prednisone administration in paediatric patients with kidney transplant.

Glucocorticoids are 1 of the primary treatments in paediatric kidney transplantation. The aims of this study were: (i) to build a population pharmacokinetics (PPK) model of free prednisolone, which is the active form of prednisone, in paediatric kidney transplant recipients; (ii) to identify covariates accounting for interindividual variability (IIV) of pharmacokinetics (PK) parameters; and (iii) to investigate drug exposure-safety relationships. Ninety-seven samples were obtained from 39 paediatric kidney transplant recipients (aged 3.4-17.2years) in order to investigate prednisone PPK. We selected children receiving oral prednisone as part of their immunosuppressive regimen. A PPK analysis was performed using Monolix. A 1-compartment model best described prednisolone concentrations. Large IIV was observed as prednisolone was undetectable at H12 in some patients but could still be detected at H24 in others. Both bodyweight and ciclosporin cotreatment influenced the PK. The clearance (CLU ) and volume of distribution of free prednisolone allometrically scaled to 70 kg were 27.6L/h and 101 L. Ciclosporin cotreatment decreased CLU by 67%. High blood pressure and new onset diabetes after transplantation were associated with daily free prednisolone exposure. This study is the first analysis of prednisolone PPK in kidney-transplanted children. Some of the IIV in the PK parameters was explained by bodyweight and ciclosporin cotreatment. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy and limit side effects. The use of therapeutic drug monitoring in kidney-transplanted children may be useful, especially with respect to safety issues.

Pharmacokinetics of Orally Administered Prednisolone in Alpacas.

This study aimed to determine the pharmacokinetics of prednisolone following intravenous and oral administration in healthy adult alpacas. Healthy adult alpacas were given prednisolone (IV, n = 4), as well as orally (PO, n = 6). Prednisolone was administered IV once (1 mg/kg). Oral administration was once daily for 5 days (2 mg/kg). Each treatment was separated by a minimum 4 month washout period. Samples were collected at 0 (pre-administration), 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, and 24 h after IV administration, and at 0 (pre-administration), 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, 24 after the first and 5th PO administration. Samples were also taken for serial complete blood count and biochemistry analysis. Prednisolone concentration was determined by high pressure liquid chromatography. Non-compartmental pharmacokinetic parameters were then determined. After IV administration clearance was 347 mL/kg/hr, elimination half-life was 2.98 h, and area under the curve was 2,940 h*ng/mL. After initial and fifth oral administration elimination half-life was 5.27 and 5.39 h; maximum concentration was 74 and 68 ng/mL; time to maximum concentration was 2.67 and 2.33 h; and area under the curve was 713 and 660 hr*ng/mL. Oral bioavailability was determined to be 13.7%. Packed cell volume, hemoglobin, and red blood cell counts were significantly decreased 5 days after the first PO administration, and serum glucose was significantly elevated 5 days after the first PO administration. In conclusion, serum concentrations of prednisolone after IV and PO administration appear to be similar to other veterinary species. Future research will be needed to determine the pharmacodynamics of prednisolone in alpacas.

A randomised controlled unblinded multicentre non-inferiority trial with activated vitamin D and prednisolone treatment in patients with minimal change nephropathy (ADAPTinMCN)

BackgroundMinimal change nephropathy (MCN) is a common cause of nephrotic syndrome in both adults and children. International guidelines recommend treatment with prednisolone 1 mg/kg/day to adults. This dose is derived from an empirically established dose in children, although children generally attain remission faster and relapse more rapidly than adults. Prednisolone is associated with multiple and serious adverse events. Activated vitamin D has been shown to reduce albuminuria in other glomerular renal diseases with a minimum of adverse events. This study tests the hypothesis that a new treatment regimen in MCN combining reduced dose prednisolone and active vitamin D is as efficient in inducing remission and has fewer and less severe adverse events than standard prednisolone. Furthermore, we aim to establish models allowing for more personalized medicine based on assessment of the individual’s prednisolone metabolism.MethodsA randomised controlled multicentre non-inferior unblinded trial including 96 adult, incident patients with biopsy-proven MCN, albuminuria > 3 g/day, and an estimated glomerular filtration rate (eGFR) > 30 ml/min from renal departments in Denmark. Patients are randomised to standard prednisolone (1 mg/kg/day) or reduced prednisolone (0.5 mg/kg/day) and alfacalcidol (0.5 μg/day). The primary outcome is the rate of remissions after 16 weeks and the time from diagnosis to remission. The study will include a saliva test to characterise prednisolone pharmacokinetics and compare them to genetic variations in specific liver enzymes responsible for prednisolone metabolism.DiscussionReducing the prednisolone dose is expected to reduce the number of severe adverse events. This study will examine if reduced prednisolone dose with active vitamin D but without additional immunosuppression is feasible in the treatment of MCN and will reduce the number of adverse events. The findings can potentially change current guidelines for treatment of MCN in adults. Additional outcomes on inter-individual pharmacokinetic and metabolic variations may allow for a more personalised treatment strategy.Trial registrationEudraCT 2017-001206-16, ClinicalTrials.gov NCT03210688. Registered on June 3, 2017.

Physiologically Based Pharmacokinetic Modeling Involving Nonlinear Plasma and Tissue Binding: Application to Prednisolone and Prednisone in Rats.

The pharmacokinetics (PK) of prednisolone (PNL) exhibit nonlinearity related to plasma protein binding, tissue binding, metabolic interconversion with prednisone (PN), and renal elimination. Blood and 11 tissues were collected from male Wistar rats after steady-state (SS) infusion and after subcutaneous boluses of 50 mg/kg of PNL. Concentrations of PNL and PN were measured by liquid chromatography-tandem mass spectrometry. Plasma and tissue profiles were described using a complex physiologically based pharmacokinetics (PBPK) model. Concentrations of PN and PNL were in rapid equilibrium in plasma and tissues. The tissue partition coefficients (K p ) of PNL calculated from most subcutaneously dosed tissue and plasma areas were similar to SS infusion and in silico values. The blood-to-plasma ratio of PNL was 0.71 with similar red blood cell and unbound-plasma concentrations. Plasma protein binding (60%-90%) was related to corticosteroid-binding globulin (CBG) saturation. Tissue distribution was nonlinear. The equilibrium dissociation constant (K d ) of PNL shared by all tissues was 3.01 ng/ml, with the highest binding in muscle, followed by liver, heart, intestine, and bone and the lowest binding in skin, spleen, fat, kidney, lung, and brain. Fat and bone distribution assumed access only to interstitial space. Brain PNL concentrations (K p = 0.05) were low owing to presumed P-glycoprotein-mediated efflux. Clearances of CBG-free PNL were 1789 from liver and 191.2 ml/h from kidney. The PN/PNL ratio was nonlinear for plasma, spleen, heart, intestine, bone, fat, and linear for the remaining tissues. Our PBPK model with multiple complexities well described the PK profiles of PNL and PN in blood, plasma, and diverse tissues. SIGNIFICANCE STATEMENT: Because steroids, such as prednisolone and prednisone, have similar and complex pharmacokinetics properties in various species, receptors in most tissues, and multiple therapeutic and adverse actions, this physiologically based pharmacokinetics (PBPK) model may provide greater insights into the pharmacodynamic complexities of corticosteroids. The complex properties of these compounds require innovative PBPK modeling approaches that may be instructive for other therapeutic agents.

Evaluation of the Pharmacokinetics of Prednisolone in Pediatric ALL Patients Treated According to DCOG Protocols and its Relation to Early Treatment Response

Evaluation of the Pharmacokinetics of Prednisolone in Pediatric ALL Patients Treated According to DCOG Protocols and its Relation to Early Treatment Response

Free prednisolone pharmacokinetics predicted from total concentrations in patients with inflammatory - immunonologic conditions.

Prednisone is an anti-inflammatory drug widely used in internal medicine and rheumatology, but dosing remains empirical. The active metabolite of prednisone is free prednisolone. The aim of this work was to build a population pharmacokinetic (PK) model that can predict free prednisolone concentrations in patients with inflammatory/immunologic conditions.A total of 107 patients from the department of internal medicine of Cochin hospital provided 343 observations. Blood samples drawn for biological analyses were used for drug determination. Total plasma prednisolone concentrations were measured by liquid chromatography-mass spectrometry, and the data were modelled using Monolix. The pharmacokinetics was ascribed a one-compartment open model with three transit compartments standing for the absorption and metabolism process. The model used predicts free concentrations that served to derive total concentrations given published binding constants. Only size parameters influenced the pharmacokinetics. Free prednisolone CLU /F and VU /F, scaled allometrically on lean body weight, were, respectively, 26.7L/h and 94.3L for 50kg LBW. CLU /F interindividual variability was 0.20. The additive and proportional residual variabilities were, respectively, 4.3µg/L and 0.20. The results point out some dosing issues, that is the possibility of under- or over-dosage in thin or overweight patients respectively.

Pharmacokinetics of prednisolone in children: an open-label, randomised, two-treatment cross-over trial investigating the bioequivalence of different prednisolone formulations in children with airway disease

IntroductionOne in three Danish children under 3 years of age experience asthma-like symptoms, and one-third will later be diagnosed with asthma. Oral prednisolone is used in various formulations to treat...

Tear Fluid Pharmacokinetics Following Oral Prednisone Administration in Dogs With and Without Conjunctivitis.

Purpose: To describe the pharmacokinetics (PK) of prednisone and prednisolone in tear fluid of dogs receiving oral prednisone at anti-inflammatory to immunosuppressive doses and to assess the impact of induced conjunctivitis on lacrimal drug levels.Methods: Six healthy Beagle dogs were administered 4 courses of prednisone at 0.5, 1.0, 2.0, and 4.0 mg/kg given orally once a day for 5 days. At steady state, topical histamine was applied to induce mild (1 mg/mL) or severe (375 mg/mL) conjunctivitis in 1 eye of each dog and tear samples were collected from both eyes at selected times. Prednisone and prednisolone were quantified in tears by liquid chromatography-mass spectrometry.Results: Lacrimal prednisone and prednisolone concentrations ranged from 2 to 523 ng/mL and 5 to 191 ng/mL, respectively. Drug concentrations were overall greater in dogs receiving higher doses of prednisone, but were not correlated with tear flow rate. Eyes with conjunctivitis often had larger amounts of prednisone and prednisolone in tear fluid compared to control eyes (up to +64%), but differences were not statistically significant. Significantly greater, but clinically insignificant, levels of prednisolone were found in eyes with severe versus mild conjunctivitis for oral prednisone doses ≥1.0 mg/kg.Conclusions: Disruption of the blood–tear barrier with conjunctivitis did not significantly affect drug levels in tears. Based on drug PK in tears, oral prednisone is likely safe for the management of reflex uveitis and ocular surface diseases. However, further prospective trials using systemic corticotherapy in diseased animals are warranted to confirm findings from this preclinical study.

Characterizing the pharmacokinetics and pharmacodynamics of immunosuppressant medicines and patient outcomes in elderly renal transplant patients.

This review examines what is currently known about the pharmacokinetics and pharmacodynamics of commonly prescribed immunosuppressant medicines, tacrolimus, cyclosporine, mycophenolate and prednisolone, in elderly renal transplant recipients, and reported patient outcomes in this cohort. Renal transplantation is increasing rapidly in the elderly, however, currently, long-term patient outcomes are relatively poor compared to younger adults. Some studies have suggested that elderly recipients may have higher dose-adjusted exposure and/or lower clearance of the calcineurin inhibitors tacrolimus and cyclosporine; with one study reporting up to 50% reduction in tacrolimus exposure in the elderly. Elderly transplant recipients do not appear to have higher dosage-adjusted exposure to mycophenolic acid (MPA). The effects of ageing on the pharmacokinetics of prednisolone are unknown. Only one study has examined how aging effects drug target enzymes, reporting no difference in baseline inosine 5'-monophosphate dehydrogenase (IMPDH) activity and MPA-induced IMPDH activity in elderly compared to younger adult renal transplant recipients. In elderly transplant recipients, immunosenescence likely lowers the risk of acute rejection, but increases the risk of drug-related adverse effects. Currently, the three main causes of death in elderly renal transplant recipients are cardiovascular disease, infection and malignancy. One study has showed that renal transplant recipients aged over 65 years are seven times more likely to die with a functioning graft compared with young adults (aged 18-29 years). This suggests that an optimal balance between immunosuppressant medicine efficacy and toxicity is not achieved in elderly recipients, and further studies are needed to foster long-term graft and patient survival. Lower maintenance immunosuppressant targets in elderly recipients may decrease patient susceptibility to drug side effects, however, further studies are required and appropriate targets need to be established.

Prednisolone and Prednisone Pharmacokinetics in Pediatric Renal Transplant Recipients-A Prospective Study.

Prednisolone is a standard component of immunosuppressive protocols in renal transplantation (Tx) and despite standardized treatment regimens, adverse side effects are still frequent. The aim of this study was to characterize the pharmacokinetics of prednisolone and prednisone in pediatric renal transplant recipients in the first 52 weeks post Tx, to describe the relationship between prednisolone and prednisone, and to investigate a possible relationship between the development of new-onset diabetes after Tx (NODAT) and glucocorticoid exposure. Renal transplant recipients receiving prednisolone (n = 11, age 1-15 years) were included in this prospective open-label, descriptive, nonrandomized, and noninterventional study. Blood samples were drawn pre-Tx and during selected dose intervals (0, 1, 2, 4, 6, and 12 hours postdose; less frequent in children <10 kg) at 1, 2, 3, 4, 12, and 52 weeks post-Tx. Concentrations of prednisolone and cortisol, their inactive keto forms, plus methylprednisolone, were measured using a validated LC-MS/MS method. Genetic variants in the CYP3A4, CYP3A5, ABCB1, and HSD11B2 genes were analyzed using real-time polymerase chain reaction and Sanger sequencing. Correlation with NODAT was investigated. The patients displayed considerable intra- and inter-individual variability in prednisolone exposure, with up to 5-fold differences in the area under the concentration-time curve (AUC). There were up to 7-fold differences in prednisolone/prednisone AUC ratio between patients, and patients experiencing NODAT tended to have a higher ratio (>12) compared with patients without NODAT (<12). Genetic variants in CYP3A5 and ABCB1 were found, but due to the limited study population causality cannot be definitive. The study suggests that a high prednisolone/prednisone AUC ratio may be a possible risk factor for NODAT. Further studies of individualization of glucocorticoid treatment in pediatric organ Tx are warranted.

Altered Pharmacokinetics of Prednisolone and Cortisol Suppression During Oral Prednisolone Therapy in Patients with Nephrotic Syndrome

Background : Steroid preparation exerts its pharmacological effect through the binding of the free unbound fraction to its receptor. However, in patients with nephrotic syndrome, the plasma protein concentration fluctuates, which affects the ratio of bound versus unbound steroid. We investigated the plasma pharmacokinetics of prednisolone administered to patients with nephrotic syndrome through their disease course. Also the suppression of endogenous cortisol during prednisolone therapy was studied. Methods : Fifteen patients(aged 16―75 years, nine minimal change group, four membranous nephropathy, two lupus nephritis)were studied on one or more occasions over a period of one to nine months during prednisolone treatment. Plasma total concentrations of prednisolone were measured by employing gas chromatography/mass spectrometry simultaneously with endogenous cortisol at several time points on each occasion. Individualized estimation of the patient's kinetic parameters was done by a computer curve fitting of the total plasma prednisolone. Results : Blood sampling at several time points on each occasion made it possible to characterize the intraand inter-individual variability in the pharmacokinetic behavior of prednisolone. There was a negative correlation(r = 0.4676, P = 0.0031)between the prednisolone clearance and plasma albumin concentrations. As the plasma albumin level increases, the area under the plasma total prednisolone concentration-time curve(AUCtotal)increased, whereas the area under the plasma unbound prednisolone concentration-time curve(AUCunbound)decreased. The discrepancy between AUCtotal and AUCunbound was observed at the plasma albumin concentration below 3.0 g/dl. The endogenous cortisol concentration immediately declined after administering the first prednisolone dose. Adrenal suppression is less in patients in whom prednisolone was administered only in the morning than in patients in whom prednisolone was administered in two or three divided doses. Conclusion : Concentration of free unbound prednisolone decreases as the plasma albumin concentration is recovered. It is recommended that the dosage reduction be started after the plasma albumin concentration is normalized and stabilized(above 3.0 g/dl). In addition administration of prednisolone once daily in the morning is recommended to prevent adrenal suppression. 原 著

Exploratory study of total and free prednisolone plasma exposure and cushingoid appearance, quality of life and biochemical toxicity in adult male kidney transplant recipients.

Long-term adverse effects of oral glucocorticoids are frequent and serious. Large between-patient variability in the pharmacokinetics of prednisolone might explain why drug dose is a poor predictor of drug-related toxicity. The aim of the study was to investigate relationships between prednisolone exposure and adverse effects. Male kidney transplant recipients were recruited for serial blood sampling and assessment of glucocorticoid-related adverse effects including dyslipidaemia, abnormal body fat distribution, Cushingoid appearance and impaired quality of life. Total and free prednisolone plasma concentrations were determined using ultra-high-performance liquid chromatography with tandem mass spectrometric detection. Prednisolone exposure was estimated using a limited sampling strategy. Fifty-six patients were recruited. Patients had a mean age of 54 years and median time post-transplantation of 75 months. Median prednisolone dose was 5 mg. Mean area under the plasma concentration-time curve was 2390 nmol h/L (±580) (SD) and 175 nmol h/L (±78) for total and free prednisolone, respectively. Waist to upper arm circumference ratio was positively associated with free prednisolone plasma exposure with a Spearman correlation coefficient of 0.30 (p value 0.02). The correlation coefficient was 0.24 (p value 0.08) for neck to upper arm circumference ratio and free prednisolone plasma exposure. The clinical Cushingoid phenotype as determined by the Visual Assessment of Cushing's Severity (VACS) score was associated with a reduced score relating to physical functioning on the SF-12, but there was no significant relationship between free prednisolone plasma exposure and quality-of-life scores. Lipid levels and haemoglobin A1c (HbA1c) were not associated with total or free prednisolone exposure. There is a positive correlation between free prednisolone plasma exposure and waist to upper arm circumference ratio in adult male kidney transplant recipients on low maintenance prednisolone doses. There is no significant association between total or free prednisolone plasma exposure and plasma glucose and lipid levels in the low prednisolone dose range.

Impact of CYP3A5 and ABCB1 Genotype On The Pharmacokinetics of Prednisolone in Renal Transplant Recipients.

Impact of CYP3A5 and ABCB1 Genotype On The Pharmacokinetics of Prednisolone in Renal Transplant Recipients.

A Practical Limited Sampling Strategy to Predict Free Prednisolone Exposure and Glycemia in Kidney Transplant Recipients

Despite significant interindividual variability in prednisolone pharmacokinetics and potentially serious consequences with inadequate or excessive exposure, monitoring of prednisolone levels is not employed to guide therapy. As ultrahigh-performance liquid chromatography-tandem mass spectrometry methods can now measure the active free fraction of prednisolone, this study aimed to evaluate the performance of 15 published limited sampling strategies (LSSs) for predicting free prednisolone exposure in adult kidney transplant recipients and to examine the relationship between free/total prednisolone exposure and plasma glucose. The study was performed in 11 subjects without diabetes 3-4 weeks postkidney transplantation. Area under the concentration time curve profiles of total and free prednisolone from 0 to 12 hours postdose (AUC₀₋₁₂) were determined and compared with predicted AUC₀₋₁₂ values calculated from published LSSs. Venous glucose was measured concurrently with the 13 sampling time points. The mean (±SD) age of subjects was 52 ± 12 years, 5 were men and the median (interquartile range) daily prednisolone dose was 20.0 mg (20.0-22.5). Interindividual variation in dose-adjusted free and total prednisolone exposure was 1.9- and 3.2-fold, respectively. All 15 free prednisolone LSSs exhibited good correlation (r ≥ 0.83), with bias and imprecision less than 15%. An LSS incorporating 1.25- and 3-hour samples had the highest predictive power (r = 0.97, bias 1.2%, imprecision 5.6%). Free prednisolone AUC₀₋₁₂ correlated with peak glucose levels (r = 0.65, P = 0.037), as did predicted AUC₀₋₁₂ from 14/15 LSSs. Biologically active free prednisolone exposure can be accurately predicted postkidney transplantation by LSSs incorporating 2-point concentration sampling. Peak plasma glucose concentration correlated well with prednisolone exposure.

Comparison of the Influence of Cyclosporine and Tacrolimus on the Pharmacokinetics of Prednisolone in Adult Male Kidney Transplant Recipients

Cyclosporine has been observed to precipitate cushingoid features in kidney transplant recipients already on prednisolone. Some pharmacokinetic studies have demonstrated increased prednisolone exposure in patients on cyclosporine therapy compared with azathioprine, whereas other studies have found no difference. The objective of this study was to determine whether cyclosporine impacts on prednisolone exposure as compared with tacrolimus. Adult male kidney transplant recipients treated with prednisolone and either cyclosporine or tacrolimus were recruited for pharmacokinetic blood sampling at the outpatient clinic at the Princess Alexandra Hospital, Brisbane, Australia. Prednisolone plasma concentrations were determined using ultra-high-performance liquid chromatography. Dose-adjusted area under the plasma concentration-time curve (AUC) of free and total prednisolone was estimated using a previously developed limited sampling strategy and non-compartmental analysis. A total of 55 patients were eligible for analysis; 38 % received cyclosporine and 62 % received tacrolimus co-therapy. No significant difference in mean dose-adjusted total prednisolone AUC from 0 to 6 h post-dose or mean dose-adjusted free prednisolone AUC from 0 to 12 h was observed between the cyclosporine and tacrolimus groups (449 versus 428 nmol·h/L/mg, p = 0.43, and 32 versus 30 nmol·h/L/mg, p = 0.51, respectively). Cyclosporine does not change the dose-adjusted exposure of prednisolone compared with tacrolimus. Adult kidney transplant recipients can therefore continue on their usual prednisolone dose when changing therapy between cyclosporine and tacrolimus.

Aprepitant does not alter prednisolone pharmacokinetics in patients treated with R-CHOP

Aprepitant, a neurokinin 1 receptor antagonist, is an effective antiemetic drug in the prevention of chemotherapy-induced nausea and vomiting. Aprepitant co-administration increases plasma concentrations of dexamethasone and methylprednisolone by inhibiting cytochrome P450 (CYP) 3A4 [1], whereas pharmacokinetics of cyclophosphamide, which is also metabolized by CYP enzymes including CYP3A4, is not significantly changed by aprepitant [2]. Thus, aprepitant co-administration provides different effects on pharmacokinetics of CYP substrates; however, it is unknown whether aprepitant affects pharmacokinetics of prednisolone, another CYP3A4 substrate.