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

doi:10.1016/j.semarthrit.2010.05.007

Seminars in Arthritis and Rheumatism

Volume 40, Issue 4, February 2011, Pages 307-313

https://doi.org/10.1016/j.semarthrit.2010.05.007 Get rights and content

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 (AUC_0-12)] 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 AUC_0-12 and 10 IMPDH activity profiles were included in the analysis. Large interpatient variability in MPA exposure (AUC_0-12) was observed (mean ± SE: 32 ± 4.2 mg h/L; coefficient of variation: 57%). Maximum MPA serum concentrations coincided with maximum IMPDH inhibition. AUC_0-12 and weight-adjusted MMF dosing were only moderately correlated (r = 0.56, P = 0.01). An AUC_0-12 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 AUC_0-12 of at least 30 mg h/L is required for cSLE improvement.

Section snippets

Patients

With approval of the institutional review boards of the participating sites, patients diagnosed with cSLE (26) (ie, SLE with diagnosis before or at age 16 years) were studied prospectively after consent and assent had been obtained. To be included in the study, patients were required to have stable renal function, receive MMF at a stable oral dose for at least 3 weeks, and be on stable doses of other medications for at least 30 days before the study visits. The patients included in this study

Patients

Data on 19 cSLE patients (18 females, 1 male; 58% African-American, 42% Caucasian, 79% Non-Hispanic) with a mean ± SD age of 16.9 ± 4 years were available for analysis. Patients' demographics and clinical characteristics at the time of the first study visit are summarized in Table 1. The average ± SD disease duration of cSLE was 3.3 ± 3 years. The mean ± SD duration of MMF treatment was 1.5 ± 1.4 years (range: 0.14-6.4 years). Indications for starting MMF therapy were lupus nephritis (n = 16)

Discussion

We observed significant interindividual variability in both pharmacokinetics and pharmacodynamics of MPA. Additionally, we present initial evidence that personalized cSLE disease control may be related to sufficient exposure to MMF. Both statements support the notion that personalized MMF regimens, based on MPA-PK and/or MPA-PD, may be preferable to the current weight-based approach of MMF dosing in cSLE patients.

Weight-adjusted MMF dosing only moderately correlated with patients' actual

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Children-onset lupus nephritis (cLN) occurs > 50 % of patients with systemic lupus erythematosus. Mycophenolic acid (MPA) is the first-line agent for the induction and maintenance treatment of LN. This study was to explore the predictors of renal flare in cLN.
Data from 90 patients were included in population pharmacokinetic (PK) models to predict MPA exposure. Cox regression models and restricted cubic spline were performed in 61 patients to identify the risk factors for renal flare, baseline clinical characteristics and MPA exposures as potential covariates.
PK best fitted a two-compartment model of first-order absorption and linear elimination, with delayed absorption. Clearance increased with weight and immunoglobulin G (IgG), but decreased with albumin and serum creatinine. During follow-up of 1040 (658–1359) days, 18 patients experienced a renal flare, after a median time of 932.5 (663.5–1316) days. Each 1-mg·h/L increase of MPA-AUC was associated with a 6 % decreased risk of an event (HR = 0.94; 95 % CI: 0.90–0.98), while IgG significantly increased this risk (HR = 1.17; 95 % CI: 1.08–1.26). ROC analysis showed that MPA-AUC_0-12h < 35 mg·h/L and IgG > 17.6 g/L had a good prediction of renal flare. Of restricted cubic spline, the risk of renal flares decreased with higher MPA exposure but reached a plateau when AUC_0-12h > 55 mg·h/L, while substantially increases when IgG is > 18.2 g/L.
Monitoring MPA exposure together with IgG could be very useful during clinical practice to identify patients with a potential high risk of renal flare. This early risk assessment would allow for the treat-to-target and tailored medicine.
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An estimated 15%–20% of all systemic lupus erythematosus (SLE) is diagnosed during childhood (childhood-onset systemic lupus erythematosus [cSLE]). This chapter focuses on the unique features of cSLE, including clinical presentation and manifestations, treatment, and outcomes, highlighting differences from adult-onset disease. Perhaps the most striking difference is the more severe phenotype that occurs with earlier age of onset. Monogenic causes of SLE are rare in adult-onset disease but are increasingly recognized as mechanistic drivers of disease in the youngest patients. Treatment considerations unique to pediatric patients include the effects of medicine on growth and development, as well as a more limited evidence base to guide treatment, as clinical trials rarely focus on cSLE patients. Clinicians, patients, and families also face challenges in medical decision-making trying to balance the long-term effects of medication with projected disease damage based on limited data, due to the difficulty of studying long-term outcomes after patients transition to adult care.
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Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil (MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases (UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s (CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate (GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid (GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.

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: The study is supported by a NIAMS P60-AR047884 grant, the CCHMC Translational Research Initiative, and the Center for Clinical and Translational Research UL1-RR026314. Drs. Vinks and Fukuda are supported by NIH Grant 5U10HD037249. Dr. Vinks is supported by NIH Grant 5K24HD050387. Drs. Wiers and Sherwin are supported by a NIAMS T32 AR007594 grant. Dr. Wiers is supported by the NIH Loan Repayment Program.

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

Objectives

Methods

Results

Conclusion

Section snippets

Patients

Patients

Discussion

Immunopharmacology

Transplant Proc

Kidney Int

Am J Transplant

Transplant Proc

Clin Biochem

Clin Ther

Transplant Proc

Mycophenolic acid morpholinoethylester (RS-61443) is a new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of T- and B-cell purine synthesis

Transplant Proc

Preferential suppression of lymphocyte proliferation by mycophenolic acid and predicted long-term effects of mycophenolate mofetil in transplantation

Transplant Proc

Mechanism of action of mycophenolate mofetil

Ther Drug Monit

The immunosuppressor mycophenolic acid kills activated lymphocytes by inducing a nonclassical actin-dependent necrotic signal

J Immunol

Mycophenolate mofetil as a treatment for autoimmune haemolytic anaemia in patients with systemic lupus erythematosus and antiphospholipid syndrome

Lupus

Refractory immune thrombocytopenia in systemic lupus erythematosus: response to mycophenolate mofetil

Lupus

Successful treatment of subacute cutaneous lupus erythematosus with mycophenolate mofetil

Br J Dermatol

Mycophenolate mofetil for the treatment of systemic lupus erythematosus: an open pilot trial

Lupus

Mycophenolate mofetil (MMF) for the treatment of juvenile onset systemic lupus erythematosus

Pediatr Rheumatol

Mycophenolate mofetil promotes prolonged improvement of renal dysfunction after pediatric liver transplantation: experience of a single center

Pediatr Transplant

Five-year outcome in pediatric patients with mycophenolate mofetil-based renal transplantation

Transplantation

Maintenance immunosuppression with mycophenolate mofetil and corticosteroids in pediatric kidney transplantation: temporary benefit but not without risk

Transplantation

Mycophenolate mofetil in pediatric renal transplantation: non-induction vs. induction with basiliximab

Pediatr Transplant

Pharmacokinetics of mycophenolate mofetil in stable pediatric liver transplant recipients receiving mycophenolate mofetil and cyclosporine

Liver Transpl

Mycophenolate mofetil suspension in pediatric renal transplantation: three-year data from the tricontinental trial

Pediatr Transplant

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