Efficacy and Safety of Pharmacokinetically-Driven Dosing of Mycophenolate Mofetil for the Treatment of Pediatric Proliferative Lupus Nephritis-A Double-Blind Placebo Controlled Clinical Trial (The Pediatric Lupus Nephritis Mycophenolate Mofetil Study)

Anna Carmela P Sagcal-Gironella^{1

2}, Angela Merritt³, Tomoyuki Mizuno^{4

5}, Vikas R Dharnidharka⁶, Joseph McDonald⁷, Marietta DeGuzman⁸, Dawn Wahezi⁹, Beatrice Goilav¹⁰, Karen Onel¹¹, Susan Kim¹², Ellen Cody¹³, Eveline Y Wu¹⁴, Laura Cannon¹⁴, Kristen Hayward¹⁵, Daryl M Okamura¹⁶, Pooja N Patel¹⁷, Larry A Greenbaum¹⁸, Kelly A Rouster-Stevens¹⁹, Jennifer C Cooper²⁰, Natasha M Ruth²¹, Stacy Ardoin²², Kathryn Cook²³, R Ezequiel Borgia²⁴, Aimee Hersh²⁵, Bin Huang²⁶, Prasad Devarajan²⁷, Hermine Brunner³

Affiliations

¹ Division of Pediatric Rheumatology, Hackensack University Medical Center, Hackensack, New Jersey, USA.
² Department of Pediatrics, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA.
³ Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁴ Division of Translational and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁵ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
⁶ Department of Pediatric Nephrology, Washington University School of Medicine, Saint Louis, Missouri, USA.
⁷ Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.
⁸ Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
⁹ Department of Pediatric Rheumatology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, USA.
¹⁰ Pediatric Nephrology, The Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, USA.
¹¹ Department of Pediatric Rheumatology, Hospital for Special Surgery, Weill Cornell Medicine, New York, New York, USA.
¹² Department of Rheumatology, University of California, San Francisco, California, USA.
¹³ Department of Pediatric Nephrology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
¹⁴ Department of Pediatric Rheumatology, University of North Carolina, Chapel Hill, North Carolina, USA.
¹⁵ Department of Pediatric Rheumatology, University of Washington, Seattle, Washington, USA.
¹⁶ Department of Pediatric Nephrology, University of Washington, Seattle, Washington, USA.
¹⁷ Depatrment of Pediatric Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.
¹⁸ Department of Pediatric Nephrology, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
¹⁹ Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
²⁰ Department of Pediatric Rheumatology, University of Colorado, Denver, Colorado, USA.
²¹ Department of Pediatric Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA.
²² Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
²³ Division of Rheumatology, Akron Children's, Akron, Ohio, USA.
²⁴ Department of Pediatric Allergy, Immunology and Rheumatology, UH Rainbow Babies & Children's Hospital, Cleveland, Ohio, USA.
²⁵ Department of Pediatrics, Immunology and Rheumatology, University of Utah, Salt Lake City, Utah, USA.
²⁶ Department of Pediatrics, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
²⁷ Department of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

PMID: 39035447
PMCID: PMC11258879

Efficacy and Safety of Pharmacokinetically-Driven Dosing of Mycophenolate Mofetil for the Treatment of Pediatric Proliferative Lupus Nephritis-A Double-Blind Placebo Controlled Clinical Trial (The Pediatric Lupus Nephritis Mycophenolate Mofetil Study)

Anna Carmela P Sagcal-Gironella et al. J Clin Trials. 2024.

. 2024;14(4):563.

Epub 2024 May 13.

Authors

Affiliations

¹ Division of Pediatric Rheumatology, Hackensack University Medical Center, Hackensack, New Jersey, USA.
² Department of Pediatrics, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA.
³ Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁴ Division of Translational and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁵ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
⁶ Department of Pediatric Nephrology, Washington University School of Medicine, Saint Louis, Missouri, USA.
⁷ Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.
⁸ Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
⁹ Department of Pediatric Rheumatology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, USA.
¹⁰ Pediatric Nephrology, The Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, USA.
¹¹ Department of Pediatric Rheumatology, Hospital for Special Surgery, Weill Cornell Medicine, New York, New York, USA.
¹² Department of Rheumatology, University of California, San Francisco, California, USA.
¹³ Department of Pediatric Nephrology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
¹⁴ Department of Pediatric Rheumatology, University of North Carolina, Chapel Hill, North Carolina, USA.
¹⁵ Department of Pediatric Rheumatology, University of Washington, Seattle, Washington, USA.
¹⁶ Department of Pediatric Nephrology, University of Washington, Seattle, Washington, USA.
¹⁷ Depatrment of Pediatric Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.
¹⁸ Department of Pediatric Nephrology, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
¹⁹ Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
²⁰ Department of Pediatric Rheumatology, University of Colorado, Denver, Colorado, USA.
²¹ Department of Pediatric Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA.
²² Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
²³ Division of Rheumatology, Akron Children's, Akron, Ohio, USA.
²⁴ Department of Pediatric Allergy, Immunology and Rheumatology, UH Rainbow Babies & Children's Hospital, Cleveland, Ohio, USA.
²⁵ Department of Pediatrics, Immunology and Rheumatology, University of Utah, Salt Lake City, Utah, USA.
²⁶ Department of Pediatrics, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
²⁷ Department of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

PMID: 39035447
PMCID: PMC11258879

Abstract

Background: The safety and efficacy of mycophenolate mofetil (MMF) for lupus nephritis (LN) treatment is established in adults and in some children. MMF is rapidly converted to the biologically active metabolite mycophenolic acid (MPA) whose pharmacokinetics (PK) is characterized by large inter- and intra-individual variability.

Methods/design: This randomized, double-blind, active comparator, controlled clinical trial of pediatric subjects with proliferative LN compares pharmacokinetically-guided precision-dosing of MMF (MMF_PK, i.e. the dose is adjusted to the target area under the concentration-time curve (AUC_0-12h) of MPA ≥ 60-70 mg*h/L) and MMF dosed per body surface area (MMF_BSA, i.e. MMF dosed 600 mg/m² body surface area), with MMF dosage taken about 12 hours apart. At baseline, subjects are randomized 1:1 to receive blinded treatment with MMF_PK or MMF_BSA for up to 53 weeks. The primary outcome is partial clinical remission of LN (partial renal response, PRR) at week 26, and the major secondary outcome is complete renal response (CRR) at week 26. Subjects in the MMF_BSA arm with PRR at week 26 will receive MMF_PK from week 26 onwards, while subjects with CRR will continue MMF_BSA or MMF_PK treatment until week 53. Subjects who achieve PRR at week 26 are discontinued from study intervention.

Discussion: The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) study will provide a thorough evaluation of the PK of MMF in pediatric LN patients, yielding a head-to-head comparison of MMF_BSA and MMF_PK for both safety and efficacy. This study has the potential to change current treatment recommendations for pediatric LN, thereby significantly impacting childhood-onset SLE (cSLE) disease prognosis and current clinical practice.

Keywords: Childhood-onset; Lupus; Lupus nephritis; Mycophenolate mofetil; Pediatric; Pharmacokinetics; SLE.

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Figures

**Figure 1:**
Pharmacokinetic pathway of MMF and MPA. Note: MMF-mycophenolate mofetil; MPA-mycophenolic acid; MPAG-MPA-glucuronide; CES-carboxylesterases; UGT-uridine 5’-diphospho-glucuronosyltransferases.

**Figure 2:**
The PLUMM Study design. Note: R-randomization; MMF_BSA-treatment arm of MMF dosed at 600 mg/m² body surface area about 12 hours apart; MMF_PK-treatment arm of MMF dosed twice daily to achieve an area under the concentration-time curve (AUC_0–12h) of MPA ≥ 60–70 mg*h/L, CRR-complete renal response; PRR-partial renal response; NR-non-responder; CYC-cyclophosphamide.

See this image and copyright information in PMC

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Efficacy and Safety of Pharmacokinetically-Driven Dosing of Mycophenolate Mofetil for the Treatment of Pediatric Proliferative Lupus Nephritis-A Double-Blind Placebo Controlled Clinical Trial (The Pediatric Lupus Nephritis Mycophenolate Mofetil Study)

Affiliations

Efficacy and Safety of Pharmacokinetically-Driven Dosing of Mycophenolate Mofetil for the Treatment of Pediatric Proliferative Lupus Nephritis-A Double-Blind Placebo Controlled Clinical Trial (The Pediatric Lupus Nephritis Mycophenolate Mofetil Study)

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Abstract

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References

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