Development of Improved Dosing Regimens for Mycophenolate Mofetil Based on Population Pharmacokinetic Analyses in Adults with Lupus Nephritis

Azrin N. Abd Rahman, Susan E. Tett, Abdul Halim Abdul Gafor, Brett C. McWhinney, Christine E. Staatz

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background and Objective: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim of this study was to develop a population pharmacokinetic model of MPA and its metabolite, 7-O-MPA-β-glucuronide (MPAG), to identify important covariate influences and better predict patient dosing requirements. Methods: MPA and MPAG concentration–time profiles were collected from 25 patients receiving mycophenolate mofetil (MMF) with or without cyclosporine (CsA) co-therapy. Samples were collected pre-dose and at 1, 2, 4, 6 and 8 h post-dose on one or two occasions. Results: A total of 225 and 226 concentration–time measurements of MPA and MPAG, respectively, were used to develop the model, utilizing NONMEM® software. A two-compartment model with first-order absorption and elimination for MPA and a one-compartment model with first-order elimination and enterohepatic circulation (EHC) for MPAG best described the data. Apparent clearance of MPAG (CL/FMPAG) significantly decreased with reducing renal function and extent of EHC was reduced with concomitant CsA use. Simulations using the final model showed that a 70-kg subject with a creatinine clearance of 90 mL/min receiving concomitant CsA would require 1.25 g of MMF twice daily while a similar subject who did not receive concomitant CsA would require 0.75 g twice daily to achieve a MPA area under the concentration–time curve from 0 to 12 h (AUC0–12) of 45 mg·h/L. Conclusion: A ‘tiered’ dosing approach considering patient renal function and CsA co-therapy, rather than a ‘one dose fits all’ approach, would help individualize MMF therapy in adult lupus nephritis patients to ensure more patients have optimal MPA exposure.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalEuropean Journal of Drug Metabolism and Pharmacokinetics
DOIs
Publication statusAccepted/In press - 23 May 2017

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Mycophenolic Acid
Lupus Nephritis
Pharmacokinetics
Population
Glucuronides
Enterohepatic Circulation
Kidney
Therapeutics
Cyclosporine
Area Under Curve
Creatinine
Software

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Development of Improved Dosing Regimens for Mycophenolate Mofetil Based on Population Pharmacokinetic Analyses in Adults with Lupus Nephritis. / Abd Rahman, Azrin N.; Tett, Susan E.; Abdul Gafor, Abdul Halim; McWhinney, Brett C.; Staatz, Christine E.

In: European Journal of Drug Metabolism and Pharmacokinetics, 23.05.2017, p. 1-12.

Research output: Contribution to journalArticle

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abstract = "Background and Objective: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim of this study was to develop a population pharmacokinetic model of MPA and its metabolite, 7-O-MPA-β-glucuronide (MPAG), to identify important covariate influences and better predict patient dosing requirements. Methods: MPA and MPAG concentration–time profiles were collected from 25 patients receiving mycophenolate mofetil (MMF) with or without cyclosporine (CsA) co-therapy. Samples were collected pre-dose and at 1, 2, 4, 6 and 8 h post-dose on one or two occasions. Results: A total of 225 and 226 concentration–time measurements of MPA and MPAG, respectively, were used to develop the model, utilizing NONMEM{\circledR} software. A two-compartment model with first-order absorption and elimination for MPA and a one-compartment model with first-order elimination and enterohepatic circulation (EHC) for MPAG best described the data. Apparent clearance of MPAG (CL/FMPAG) significantly decreased with reducing renal function and extent of EHC was reduced with concomitant CsA use. Simulations using the final model showed that a 70-kg subject with a creatinine clearance of 90 mL/min receiving concomitant CsA would require 1.25 g of MMF twice daily while a similar subject who did not receive concomitant CsA would require 0.75 g twice daily to achieve a MPA area under the concentration–time curve from 0 to 12 h (AUC0–12) of 45 mg·h/L. Conclusion: A ‘tiered’ dosing approach considering patient renal function and CsA co-therapy, rather than a ‘one dose fits all’ approach, would help individualize MMF therapy in adult lupus nephritis patients to ensure more patients have optimal MPA exposure.",
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AB - Background and Objective: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim of this study was to develop a population pharmacokinetic model of MPA and its metabolite, 7-O-MPA-β-glucuronide (MPAG), to identify important covariate influences and better predict patient dosing requirements. Methods: MPA and MPAG concentration–time profiles were collected from 25 patients receiving mycophenolate mofetil (MMF) with or without cyclosporine (CsA) co-therapy. Samples were collected pre-dose and at 1, 2, 4, 6 and 8 h post-dose on one or two occasions. Results: A total of 225 and 226 concentration–time measurements of MPA and MPAG, respectively, were used to develop the model, utilizing NONMEM® software. A two-compartment model with first-order absorption and elimination for MPA and a one-compartment model with first-order elimination and enterohepatic circulation (EHC) for MPAG best described the data. Apparent clearance of MPAG (CL/FMPAG) significantly decreased with reducing renal function and extent of EHC was reduced with concomitant CsA use. Simulations using the final model showed that a 70-kg subject with a creatinine clearance of 90 mL/min receiving concomitant CsA would require 1.25 g of MMF twice daily while a similar subject who did not receive concomitant CsA would require 0.75 g twice daily to achieve a MPA area under the concentration–time curve from 0 to 12 h (AUC0–12) of 45 mg·h/L. Conclusion: A ‘tiered’ dosing approach considering patient renal function and CsA co-therapy, rather than a ‘one dose fits all’ approach, would help individualize MMF therapy in adult lupus nephritis patients to ensure more patients have optimal MPA exposure.

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