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

Th17/1 and ex-Th17 cells are detected in patients with polyarticular juvenile arthritis and increase following treatment

Abstract Background A better understanding of the pathogenesis of polyarticular juvenile idiopathic arthritis (polyJIA) is needed to aide in the development of data-driven approaches to guide selection between therapeutic options. One inflammatory pathway of interest is JAK-STAT signaling. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s). Previous studies have demonstrated increased STAT3 activation in adult patients with rheumatoid arthritis, but less is known about STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls. Methods Blood from 17 patients with polyJIA was collected at initial diagnosis and again if remission was achieved (post-treatment). Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4 + T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Data were analyzed using Mann–Whitney U and Wilcoxon matched-pairs signed rank tests. Results Treatment-naïve polyJIA patients had increased Th17 cells (CD3 + CD4 + interleukin(IL)-17 +) compared to controls (0.15% v 0.44%, p < 0.05), but Tregs (CD3 + CD4 + CD25 + FOXP3 +) from patients did not differ from controls. Changes in STAT3 phosphorylation in CD4 + T cells following ex vivo stimulation were not significantly different in patients compared to controls. We identified dual IL-17 + and interferon (IFN)γ + expressing CD4 + T cells in patients, but not controls. Further, both Th17/1 s (CCR6 + CD161 + IFNγ + IL-17 +) and ex-Th17s (CCR6 + CD161 + IFNγ + IL-17neg) were increased in patients’ post-treatment (Th17/1: 0.3% v 0.07%, p < 0.05 and ex-Th17s: 2.3% v 1.4%, p < 0.05). The patients with the highest IL-17 expressing cells post-treatment remained therapy-bound. Conclusions Patients with polyJIA have increased baseline Th17 cells, potentially reflecting higher tonic STAT3 activation in vivo. These quantifiable immune markers may identify patients that would benefit upfront from pathway-focused biologic therapies. Our data also suggest that inflammatory CD4 + T cell subsets not detected in controls but increased in post-treatment samples should be further evaluated as a tool to stratify patients in remission on medication. Future work will explore these proposed diagnostic and prognostic biomarkers

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