Pharmacokinetics of Prednisolone at Steady State in Young Patients With Systemic Lupus Erythematosus on Prednisone Therapy: An Open-Label, Single-Dose Study

Abstract

Background Current prednisone dosing in the treatment of young patients with childhood-onset systemic lupus erythematosus (cSLE) is largely based on achieving balance between therapeutic efficacy and toxicity, with weight-based dosing a common clinical practice. Despite the widespread use of prednisone, few attempts have been made to improve its clinical dosing regimen and response to prednisone therapy remains variable. Objectives To characterize the pharmacokinetics (PK) of prednisolone, the metabolite of the prodrug prednisone, in cSLE patients and explore the relationship between PK and cSLE disease activity. Methods Blood samples were taken 1 hour before the morning prednisone dose and at 20, 40, 60, 90 minutes, and 2, 3, 4, 6, and 9 hours from 8 patients (age 12–28 years) after an 8-hour fast. Average weight-adjusted daily prednisone dose, stable at least 30 days pre-study, was 0.29 mg/kg/day. PK analysis of prednisolone was performed using non-compartmental analysis with WinNonlin®. cSLE disease activity was measured using the British Isles Lupus Assessment Group (BILAG) index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Results Mean total prednisolone area under the curve (AUC0-9), apparent oral clearance of prednisone at steady state, and half-life were 1094 (range: 467–2404) ng*hr/mL, 11 (range: 6.7–13.7) L/hr, and 2.6 (range: 1.3–3.9) hours. Mean total prednisolone AUC0-9 normalized to prednisone dose by weight was 4361 (range: 1136 – 9580) ng*hr/mL/mg/kg. Mean total prednisolone Cmax normalized to prednisone dose by weight was 1097 (range: 301 – 2211) ng/mL/mg/kg at 1.84 (range: 0.48 – 4) hours (Tmax). Patients on prednisone had inter-individual variability in prednisolone AUC0-9 (coefficient of variation, CV: 61%) and dose-adjusted AUC0-9 (CV: 58%). Conclusions Inter-individual variability in systemic exposure to prednisolone in cSLE patients was observed.

The Use of Gene Ontology Term and KEGG Pathway Enrichment for Analysis of Drug Half-Life

“…KEGG pathways enriched in drugs with half-lives less than one hour included the systemic lupus erythematosus pathway ( hsa05322 ). Drugs used to treat systemic lupus erythematosus such as prednisone, also have a very short half-life (plasma half-life of less than 1 hour) [64], which is consistent with our results.…”

Monitoring Prednisolone and Prednisone in Saliva

“…1,6,30 The concentration upswing of PLN was rapid, followed by a slower washout phase. 12,30,[32][33][34] Similar or larger values of IIV were reported in more distinct populations that included adults and/or children with immunemediated diseases. 24,31 Equilibrium of PLN between different media was reached rapidly as there was no observable delay, consistent with fast binding of PLN to transport proteins.…”

Exposure–effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis

“…The analyses evaluated drug exposures in relation to treatment response since starting MPA and drugrelated adverse events. [7][8][9][10][11][12][13][14][15][16][17][18][19] was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023). …”

“…Prednisolone is generally considered to have a wide therapeutic index and consequently, it is also normally given in a standard regimen without drug concentration measurements. However, substantial between‐subject variability in total prednisolone pharmacokinetics has been observed in childhood‐onset systemic lupus erythematosus (SLE) and transplant recipients . Based on limited data, there is a possible relationship between total prednisolone exposure and SLE disease activity as well as the occurrence of some drug‐related side effects .…”

“…However, substantial between-subject variability in total prednisolone pharmacokinetics has been observed in childhood-onset systemic lupus erythematosus (SLE) [9] and transplant recipients [10][11][12]. Based on limited data, there is a possible relationship between total prednisolone exposure and SLE disease activity as well as the occurrence of some drug-related side effects [9].…”