|Year : 2022 | Volume
| Issue : 2 | Page : 124-128
Therapeutic drug monitoring of mycophenolate mofetil for the treatment of pediatric lupus nephritis: A cross-sectional study
Navamani Kirubakaran, Anu Punnen, Ratna Prabha, Indira Agarwal, Sathish Kumar
Department of Pediatrics Unit II; Department of Clinical Pharmacology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||20-Jun-2021|
|Date of Acceptance||13-Aug-2021|
|Date of Web Publication||21-May-2022|
Dr. Sathish Kumar
Department of Pediatrics, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Objectives: This study aimed to determine whether mycophenolic acid area under the curve 0–12 h (MPA AUC0–12) concentrations correlate with the disease activity in children with lupus nephritis.
Methodology: Twenty-five children who fulfilled the inclusion criteria were recruited. MPA levels were measured at specific intervals between 0 and 12 h of drug administration, including the baseline (trough) levels. Disease activity is determined by systemic lupus erythematosus disease activity index (SLEDAI) scoring along with laboratory parameters, and serological status was also compared with MPA AUC0-12 concentrations.
Results: Out of 25 children, 20 (80%) were girls and 5 (20%) were boys. Mean MPA AUC0-12 concentrations was significantly lower in patients with active disease (SLEDAI score >6) (38.46 ± 14.3 μg.h/ml) than the patients with inactive disease (SLEDAI <6) (69 ± 19.24 μg.h/ml) with a P = 0.003. MPA AUC 0-12 concentrations correlated with hemoglobin complement level (C3, C4) and SLEDAI. Multivariable analysis revealed that daily mycophenolate mofetil (MMF) doses were recognized as independent variables influencing the MPA AUC0–12 concentrations.
Conclusion: Our study strongly suggests that the dose of MMF needs to be based on the MPA AUC0–12 levels.
Keywords: Disease activity, lupus nephritis, mycophenolic acid area under curve, systemic lupus erythematosus
|How to cite this article:|
Kirubakaran N, Punnen A, Prabha R, Agarwal I, Kumar S. Therapeutic drug monitoring of mycophenolate mofetil for the treatment of pediatric lupus nephritis: A cross-sectional study. Indian J Rheumatol 2022;17:124-8
|How to cite this URL:|
Kirubakaran N, Punnen A, Prabha R, Agarwal I, Kumar S. Therapeutic drug monitoring of mycophenolate mofetil for the treatment of pediatric lupus nephritis: A cross-sectional study. Indian J Rheumatol [serial online] 2022 [cited 2022 Jun 25];17:124-8. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/2/124/345780
| Introduction|| |
In pediatric population diagnosed with systemic lupus erythematosus (SLE), 40%–75% of patients develop lupus nephritis within 5 years of diagnosis. However, in the last 20 years, the treatment including corticosteroids and the use of cytotoxic therapy has increased the 10-year survival to 80%.
Mycophenolic acid (MPA) is the active form of mycophenolate mofetil (MMF), which is an immunosuppressant that is routinely given for the treatment of acute graft rejection and prophylaxis following solid organ transplant. It acts by irreversibly inhibiting the enzyme inosine monophosphate dehydrogenase and hence selectively inhibiting the proliferation of T-cells and B cells as they require de novo synthesis of purines. Successful use of MMF in lupus nephritis has been described in various studies., There are recent studies which show that MMF is comparable with cyclophosphamide in the induction and treatment of childhood SLE., MMF is also known to produce lower rates of infection and cytopenia compared to patient who are treated with cyclophosphamide.
MPA is being increasingly used now in children with lupus nephritis. However, the optimum dose of MMF in lupus nephritis has not yet been defined. The pediatric postorgan dose of 30 mg/kg twice daily or 600 mg/m2 twice daily is being followed for the treatment of lupus nephritis. A fixed-dose of 0.5–1.5 g twice daily adjusted to the tolerance of the individual is also being followed in the treatment of lupus nephritis. Of all the pharmacokinetic parameters, MPA acid area under the curve (AUC0–12) hours is best correlated with clinical outcome in patients who have undergone solid organ transplants. The MPA pharmacokinetics in patients with SLE is different from the patients who have undergone solid organ transplants.
There is an inter-individual variability of MPA concentrations for a given dose of MMF. The MPA concentrations also depend on whether the drug is given along with other drugs such as cyclosporine or tacrolimus. The target concentrations of MPA in children treated with MMF for SLE is very important as this reflects the clinical outcome and the side effects. The factors affecting inter-individual variability were studied in transplanted individuals. Both hypoalbuminemia and renal insufficiency results in a high-free fraction of MPA and hence increased clearance of MPA., There are only very few studies, which have reported the inter-individual variability of MPA concentration in children.
In this study, we looked into the relationship between MPA AUC0–12 concentration and the disease activity in children with lupus nephritis on MMF. We also studied the inter-individual variability of MPA AUC0–12 and the factors influencing MPA AUC0–12 concentration in our population.
| Methodology|| |
We have done a cross-sectional study recruiting 25 children over a period of 8 months with lupus nephritis on MMF to determine whether MPA AUC 0–12 h (MPA AUC0-12) concentration correlates with disease activity in children as measured by the SLE disease activity index score (SLEDAI). The study was approved by Institutional Review Board (IRB) of Christian Medical College, Vellore, Tamil Nadu, India (IRB No. 7702).
Children with lupus nephritis who have been on MMF for the induction or maintenance therapy were included for the study after parental consent and child assent if they are more than 8 years. Twenty-five children who were followed up in the pediatric rheumatology clinic in Christian Medical College, Vellore, who fulfilled the inclusion criteria, were consecutively recruited over a period of 8 months for the study. Inclusion criteria were, children aged 8–16 years, diagnosed to have SLE based on the American College of Rheumatology Classification Criteria with lupus nephritis Class III and IV on renal biopsy, who were on stable dose of MMF, which was appropriately spaced throughout the day for at least 1 month before recruitment for either induction or maintenance therapy, and without intake of concomitant drugs which impairs with MPA such as antacids, cyclosporine, Tacrolimus, or Acyclovir. We used a dose of 600 mg/m2 in all our patients. An informed, written consent was obtained for each patient after a detailed one-to-one discussion with the parents/patient before the study began. Baseline data WERE collected using the questionnaire method, and the child was examined.
Blood samples from the patients were obtained on the day of sampling for complete blood count, serum creatinine, serum albumin, serum complements, anti-ds DNA, along with routine urine analysis and urine spot protein creatinine ratio. The disease activity is assessed on the same day, with the SLEDAI system and SLEDAI score of ≥6 is considered an active disease. Blood samples were taken for through MPA level and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, and 12 h after MMF administration. The specimens were then centrifuged and plasma separated into a clean Eppendorf tube. All specimens are stored at −20°C until analysis.
Plasma MPA concentrations were determined by high-performance liquid chromatography. Plasma concentration data were used to estimate the concentration-time curve (AUC0–12). The patient's AUC 0–12 concentration is determined and compared with the clinical status and the serological status. It is postulated that a high drug concentration level will correspond with a lower disease status, normal complements, and a negative ds-DNA as well as clinical remission.
The quantitative variables were presented using the mean and standard deviation (SD). All categorical variables were presented using the frequencies and percentages. Comparison of quantitative variables with disease activity was performed using Mann–Whitney U-test. Qualitative values were compared with disease activity using Fisher's exact test. Clinical and demographic variables were compared with the MPA AUC0–12 using independent t-test or Mann–Whitney U-test based on the distribution. Generalized linear models with MPA AUC 0–12 as the outcome were done with each of the variables. Data analysis was done with SPSS Version 17. Data analysis was done with SPSS (Version 17.0, SPSS Inc., IBM Corporation, USA).
| Results|| |
Twenty-five outpatients (20 girls and 5 boys) who fulfilled the inclusion criteria were recruited for the study. Out of the 25 children, 16 received 2 g/day, 7 received 1.5 g/day, and 2 received 1 g/day of MMF, respectively. Out of the 25 children, 8 were lupus nephritis Class III and 17 were lupus nephritis Class IV on renal biopsy. On the day of study, 13 patients were receiving concomitant prednisolone and 22 children were receiving hydroxychloroquine. SLEDAI scores were done on all 25 children showed that 5 patients (21%) had active disease (SLEDAI score ≥6) and 20 patients (79%) had inactive disease (SLEDAI score <6) on the day of sampling.
Baseline characteristics of children with active and inactive SLE are shown in [Table 1].
|Table 1: Baseline characteristics of patients with active and inactive systemic lupus erythematosus|
Click here to view
The active and inactive disease groups were similar in age (mean age was 15.0 ± 3.3 in the active disease group and was 14.75 ± 1.7 in the inactive disease group). The two groups were also similar in weight, height, and serum albumin levels. Hemoglobin, C3, and C4 levels were statistically significant between the two groups (P < 0.05).
MPA AUC0–12 showed wide variability with lowest level of 22.1 μg.h/ml and a highest level of 104 μg.h/ml. The mean ± SD MPA AUC0–12 of the active disease group (38.46 ± 14.3 μg.h/ml) was significantly lower than that of the inactive group (69 ± 19.24 μg.h/ml) with a P = 0.003 [Figure 1].
|Figure 1: Correlation between MPA AUC 0-12 and disease activity. The mean ± SD MPA AUC0–12 of the active disease group (38.46 ± 14.3 μg.h/ml) was significantly lower than that of the inactive group (69 ± 19.24 μg.h/ml) (P value = 0.003)|
Click here to view
A univariate and multivariate regression was done to predict the factors influencing MPA AUC0–12 levels. Factors included were sex, body surface area, dose of MMF, albumin, and C3 levels.
Parameters influencing MPA AUC0–12 shown in [Table 2].
|Table 2: The discrete variables influencing mycophenolic acid concentration|
Click here to view
A univariate and multivariate regression was done to predict the factors influencing MPA AUC0–12 levels [Table 3].
|Table 3: Continuous variables influencing mycophenolic acid area under the curve 0-12|
Click here to view
| Discussion|| |
This is the one of the few studies which was done to evaluate MMF pharmacokinetics in children with lupus nephritis. With the current treatment options like MMF, the survival rate of patients with lupus nephritis had improved significantly. Most of the data available on MMF was on solid organ transplanted patients where MPA area under the plasma concentration-time curve from 0 to 12 h has been successfully correlated with the outcome. Target concentration of MPA that is aimed at for the therapy of lupus nephritis in adults is 30–60 mg h/L. The ideal dose of MMF in children with lupus nephritis is not well described. Conventionally, a dose 2–3 g/day in divided doses is given. A dose of 900 mg/m2 has been recommended in children as against a dosage of 1200–2400 mg/m2 in patients with solid organ transplants. These dosing are derived from that recommended for solid organ transplants, and there are no randomized control trial derived doses available for the treatment of lupus nephritis. There are a number of literatures suggesting that weight or body surface area dosing of MMF is not advisable as it does not predict MPA pharmacokinetics and MPA Pharmacodynamics. In renal transplantation, therapeutic drug monitoring has been developed for the individualization of doses. There were only very few similar studies done on children with SLE in literature.
The target concentration of MPA in children treated with MMF for lupus nephritis is very important as it reflect the clinical outcome and the association with side effect. There are no studies done in the pediatric age group in Indian population till date. Twenty (80%) patients were girls and 5 (20%) were boys with a female to male ratio of 4.5:1. This was in concordance with global sex distribution of the disease, although in children, the female to male predominance is not as significant as adult. The mean age of the study population was 14.8 years. None of the children had renal insufficiencies or any comorbidities.
In our study, we have clearly shown a strong association between MPA AUC0–12 and the disease activity as assessed by scoring the disease by the SLEDAI scoring system. In Zahr et al.'s study, the MPA AUC0–12 correlated with disease activity as assessed by both the SLEDAI and BILAG scoring. In the study by Rolland, a similar finding was observed, however, unlike the current study, disease activity was not assessed by validated indices.
We found that the mean MPA AUC0–12 was significantly lower in patients with active disease than the patients with inactive disease. It is notable that the two groups (active disease with SLEDAI >6 and inactive disease with SLEDAI <6) were similar in mean age, sex distribution, similar in concomitant medications intake. We have demonstrated that MPA AUC0–12 was correlated with SLEDAI, complement level (C3, C4), and hemoglobin. Complement level being one of the two main biological markers of SLE activity. Zahr et al. found that complements, MPA AUC0–12 along with ds-DNA were associated with SLE disease activity.
In our multivariate analysis, we found that daily MMF doses were recognized as independent variables influencing the MPA AUC0–12. It is very unlikely that other factors like duration of treatment with MMF or prior treatment with other drugs could have influenced the results since all the patients were on MMF for at least more than 8 weeks. The doses were not modified in the past 8 weeks. Moreover, the frequencies of concomitant drug intake among the two groups were similar.
Therapeutic compliance is a critical issue. This may contribute to variability in the drug levels and disease activity., This was addressed at the time of recruitment itself. Only patients who were on regular medications and dosing were recruited. We have also demonstrated the inter-individual variation of drug concentration per gram of MMF which substantiates that fixed daily doses are not recommended.
Among the important limitations of our study was its cross-sectional design. Since it was a cross-sectional study, the definitive conclusion regarding the association between MPA AUC0–12 levels and the SLE activity cannot be well established and can be done only through multiple regular therapeutic drug monitoring studies.
| Conclusion|| |
In this study, we found that there was a strong association between disease activity and MPA AUC0–12 in children with lupus nephritis on MMF. The dosing of MMF needs to be based on the MPA AUC0–12 levels on an individual basis to improve the efficacy. Body surface area and weight dosing might not attain adequate drug concentration and thereby not leading to good disease control. We have also demonstrated the inter-individual variability among patients taking standard dose of MMF. In light of this, the inclusion of MPA AUC0–12 as a parameter in treating children with lupus nephritis patients on MMF is recommended. However, we need large study follow-up studies with more samples to come to more definite conclusions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Niaudet P. Treatment of lupus nephritis in children. Pediatr Nephrol 2000;14:158-66.
Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus 2005;14 Suppl 1:s2-8.
Fu YF, Liu GL. Mycophenolate mofetil therapy for children with lupus nephritis refractory to both intravenous cyclosphosphamide and cyclosporine. Clin Nephrol 2001;55:318-21.
Wallman L, Stewart G, Chapman J, O'Connell P, Fulcher D. Mycophenolate mofetil for treatment of refractory lupus nephritis: Four pilot cases. Aust N Z J Med 2000;30:712-5.
Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, et al.
Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005;353:2219-28.
Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al.
Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000;343:1156-62.
Zhu B, Chen N, Lin Y, Ren H, Zhang W, Wang W, et al.
Mycophenolate mofetil in induction and maintenance therapy of severe lupus nephritis: A meta-analysis of randomized controlled trials. Nephrol Dial Transplant 2007;22:1933-42.
Ettenger R, Cohen A, Nast C, Moulton L, Marik J, Gales B. Mycophenolate mofetil as maintenance immunosuppression in pediatric renal transplantation. Transplant Proc 1997;29:340-1.
Arns W, Cibrik DM, Walker RG, Mourad G, Budde K, Mueller EA, et al.
Therapeutic drug monitoring of mycophenolic acid in solid organ transplant patients treated with mycophenolate mofetil: Review of the literature. Transplantation 2006;82:1004-12.
Cattaneo D, Merlini S, Zenoni S, Baldelli S, Gotti E, Remuzzi G, et al.
Influence of co-medication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J Transplant 2005;5:2937-44.
Borrows R, Chusney G, James A, Stichbury J, Van Tromp J, Cairns T, et al.
Determinants of mycophenolic acid levels after renal transplantation. Ther Drug Monit 2005;27:442-50.
Neumann I, Haidinger M, Jäger H, Grützmacher H, Griesmacher A, Müller MM, et al.
Pharmacokinetics of mycophenolate mofetil in patients with autoimmune diseases compared renal transplant recipients. J Am Soc Nephrol 2003;14:721-7.
Filler G, Sharma AP, Levy DM, Yasin A. Random pharmacokinetic profiles of EC-MPS in children with autoimmune disease. Pediatr Rheumatol Online J 2010;8:1.
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al.
The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-7.
Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The committee on prognosis studies in SLE. Arthritis Rheum 1992;35:630-40.
Costedoat-Chalumeau N, Amoura Z, Hulot JS, Hammoud HA, Aymard G, Cacoub P, et al.
Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum 2006;54:3284-90.
Zahr N, Arnaud L, Marquet P, Haroche J, Costedoat-Chalumeau N, Hulot JS, et al.
Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil. Arthritis Rheum 2010;62:2047-54.
Sherwin CM, Fukuda T, Brunner HI, Goebel J, Vinks AA. The evolution of population pharmacokinetic models to describe the enterohepatic recycling of mycophenolic acid in solid organ transplantation and autoimmune disease. Clin Pharmacokinet 2011;50:1-24.
Zahr N, Amoura Z, Debord J, Hulot JS, Saint-Marcoux F, Marquet P, et al.
Pharmacokinetic study of mycophenolate mofetil in patients with systemic lupus erythematosus and design of Bayesian estimator using limited sampling strategies. Clin Pharmacokinet 2008;47:277-84.
Roland M, Barbet C, Paintaud G, Magdelaine-Beuzelin C, Diot E, Halimi JM, et al.
Mycophenolate mofetil in patients with systemic lupus erythematosus: A prospective pharmacokinetic study. Lupus 2009;18:441-7.
[Table 1], [Table 2], [Table 3]