Development of Population PK Model with Enterohepatic Circulation for Mycophenolic Acid in Patients with Childhood-Onset Systemic Lupus Erythematosus

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Despite its increased use, the pharmacokinetics (PK) of mycophenolic acid (MPA) and the relationship between dose, plasma concentration and exposure are poorly understood, especially in children. • The PK of MPA are associated with high inter‐ and intra‐individual variability. • MPA and its metabolites, like the inactive 7‐O‐MPA‐β‐glucuronide (MPAG) undergo enterohepatic circulation (EHC), which can contribute to an increase in exposure to MPA of 40% (range 10–60%). WHAT THIS STUDY ADDS • Thisis the first report of MPA PK in adolescents with childhood‐onset systemic lupus erythematosus (cSLE). • The proposed final population PK model successfully incorporates the physiological aspects associated with MPA disposition, which includes MPA and its main metabolite MPAG, and adequately reflects the complex processes of absorption and enterohepatic circulation associated with mycophenolate mofetil (MMF) oral dosing in patients with cSLE. • This model provides a basis for further development of a model‐based Bayesian estimator for individualized MPA dosing in paediatric patients treated for cSLE. AIM This study aimed to develop a population pharmacokinetic (PK) enterohepatic recycling model for MPA in patients with childhood‐onset systemic lupus erythematosus (cSLE). METHODS MPA concentration–time data were from outpatients on stable oral mycophenolate mofetil (MMF) and collected under fasting conditions, with standardized meals (1 and 4 h post‐dose). Sampling times were pre‐dose, 20, 40 min, 1, 1.5, 2, 3, 4, 6 and 9 h, post dose. The population PK analysis simultaneously modelled MPA and 7‐O‐MPA‐β‐glucuronide (MPAG) concentrations using nonlinear mixed effect modelling. RESULTS PK analysis included 186 MPA and MPAG concentrations (mg l–1) from 19 patients. cSLE patients, age range 10–28 years, median 16.5 years were included. Mean ± SD disease duration was 3.8 ± 3.7 years. The final PK model included a gallbladder compartment for enterohepatic recycling and bile release time related to meal times, with first order absorption and single series of transit compartments. The PK estimates for MPA were CL1/F 25.3 l h–1, V3/F 20.9 l, V4/F 234 l and CL2/F 19.8 l h–1. CONCLUSION The final model fitted the complex processes of absorption and enterohepatic circulation (EHC) in those treated with MMF for cSLE and could be applied in Bayesian dose optimization algorithms

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

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. Objective The purpose of this study was to characterize the pharmacokinetic (PK) properties of prednisolone, the metabolite of the prodrug prednisone, in cSLE patients and explore the relationship between PK properties and cSLE disease activity. Methods Blood samples were taken 1 hour before the morning prednisone dose and at 20, 40, 60, and 90 minutes, and 2, 3, 4, 6, and 9 hours from 8 patients (ages 12–28 years) after an 8-hour fast. The mean weight-adjusted daily prednisone dose, stable for at least 30 days pre-study, was 0.29 mg/kg/d. PK analysis of prednisolone was performed using noncompartmental analysis with WinNonlin. cSLE disease activity was measured using the British Isles Lupus Assessment Group index and Systemic Lupus Erythematosus Disease Activity Index. Results Mean total prednisolone AUC0–9, prednisone CL/F at steady state, and half-life were 1094 (range, 467–2404) ng/h/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/h/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 interindividual variability in prednisolone AUC0–9 (61% CV) and dose-adjusted AUC0–9 (58% CV). Conclusions Interindividual variability in systemic exposure to prednisolone in cSLE patients was observed

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

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. Objective The purpose of this study was to characterize the pharmacokinetic (PK) properties of prednisolone, the metabolite of the prodrug prednisone, in cSLE patients and explore the relationship between PK properties and cSLE disease activity. Methods Blood samples were taken 1 hour before the morning prednisone dose and at 20, 40, 60, and 90 minutes, and 2, 3, 4, 6, and 9 hours from 8 patients (ages 12–28 years) after an 8-hour fast. The mean weight-adjusted daily prednisone dose, stable for at least 30 days pre-study, was 0.29 mg/kg/d. PK analysis of prednisolone was performed using noncompartmental analysis with WinNonlin. cSLE disease activity was measured using the British Isles Lupus Assessment Group index and Systemic Lupus Erythematosus Disease Activity Index. Results Mean total prednisolone AUC0–9, prednisone CL/F at steady state, and half-life were 1094 (range, 467–2404) ng/h/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/h/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 interindividual variability in prednisolone AUC0–9 (61% CV) and dose-adjusted AUC0–9 (58% CV). Conclusions Interindividual variability in systemic exposure to prednisolone in cSLE patients was observed

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

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. Objective The purpose of this study was to characterize the pharmacokinetic (PK) properties of prednisolone, the metabolite of the prodrug prednisone, in cSLE patients and explore the relationship between PK properties and cSLE disease activity. Methods Blood samples were taken 1 hour before the morning prednisone dose and at 20, 40, 60, and 90 minutes, and 2, 3, 4, 6, and 9 hours from 8 patients (ages 12–28 years) after an 8-hour fast. The mean weight-adjusted daily prednisone dose, stable for at least 30 days pre-study, was 0.29 mg/kg/d. PK analysis of prednisolone was performed using noncompartmental analysis with WinNonlin. cSLE disease activity was measured using the British Isles Lupus Assessment Group index and Systemic Lupus Erythematosus Disease Activity Index. Results Mean total prednisolone AUC0–9, prednisone CL/F at steady state, and half-life were 1094 (range, 467–2404) ng/h/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/h/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 interindividual variability in prednisolone AUC0–9 (61% CV) and dose-adjusted AUC0–9 (58% CV). Conclusions Interindividual variability in systemic exposure to prednisolone in cSLE patients was observed

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

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. Objective The purpose of this study was to characterize the pharmacokinetic (PK) properties of prednisolone, the metabolite of the prodrug prednisone, in cSLE patients and explore the relationship between PK properties and cSLE disease activity. Methods Blood samples were taken 1 hour before the morning prednisone dose and at 20, 40, 60, and 90 minutes, and 2, 3, 4, 6, and 9 hours from 8 patients (ages 12–28 years) after an 8-hour fast. The mean weight-adjusted daily prednisone dose, stable for at least 30 days pre-study, was 0.29 mg/kg/d. PK analysis of prednisolone was performed using noncompartmental analysis with WinNonlin. cSLE disease activity was measured using the British Isles Lupus Assessment Group index and Systemic Lupus Erythematosus Disease Activity Index. Results Mean total prednisolone AUC0–9, prednisone CL/F at steady state, and half-life were 1094 (range, 467–2404) ng/h/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/h/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 interindividual variability in prednisolone AUC0–9 (61% CV) and dose-adjusted AUC0–9 (58% CV). Conclusions Interindividual variability in systemic exposure to prednisolone in cSLE patients was observed

Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid and Their Relation to Response to Therapy of Childhood-Onset Systemic Lupus Erythematosus

Objectives Mycophenolic acid (MPA) is the active form of mycophenolate mofetil (MMF), which is currently used off-label as immunosuppressive therapy in childhood-onset SLE (cSLE). The objectives of this study were to (1) characterize the pharmacokinetics (MPA-PK) and pharmacodynamics (MPA-PD) of MPA and (2) explore the relationship between MPA-PK and cSLE disease activity. Methods MPA-PK [area under the curve from 0-12 hours (AUC0-12)] and MPA-PD [inosine-monophosphate dehydrogenase (IMPDH) activity] were evaluated in cSLE patients on stable MMF dosing. Change in SLE disease activity while on MMF therapy was measured using the British Isles Lupus Assessment Group (BILAG) index. Results A total of 19 AUC0-12 and 10 IMPDH activity profiles were included in the analysis. Large interpatient variability in MPA exposure (AUC0-12) was observed (mean ± SE: 32 ± 4.2 mg h/L; coefficient of variation: 57%). Maximum MPA serum concentrations coincided with maximum IMPDH inhibition. AUC0-12 and weight-adjusted MMF dosing were only moderately correlated (r = 0.56, P = 0.01). An AUC0-12 of ≥30 mg h/L was associated with decreased BILAG scores while on MMF therapy (P = 0.002). Conclusion Weight-adjusted MMF dosing alone does not reliably allow for the prediction of exposure to biologically active MPA in cSLE. Individualized dosing considering MPA-PK appears warranted as this allows for better estimation of immunologic suppression (IMPDH activity). Additional controlled studies are necessary to confirm that an MPA AUC0-12 of at least 30 mg h/L is required for cSLE improvement