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Development of Improved Dosing Regimens for Mycophenolate Mofetil Based on Population Pharmacokinetic Analyses in
Azrin N Abd Rahman1,2, Susan E Tett3, Halim A Abdul Gafor4
1School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, 20 Cornwall St, Woolloongabba, Brisbane, QLD, 4102, Australia. nurul.abdrahman@uqconnect.edu.au.
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/F MPAG) 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.
Insights
Individualizing mycophenolate mofetil (MMF) dosing for lupus nephritis patients is crucial. A population pharmacokinetic model revealed that renal function and cyclosporine (CsA) co-therapy significantly impact mycophenolic acid (MPA) exposure, necessitating a tiered dosing strategy.
Area of Science:
- Pharmacokinetics
- Nephrology
- Immunosuppression
Background:
- Mycophenolic acid (MPA) is effective for lupus nephritis.
- High pharmacokinetic variability necessitates optimized dosing.
- Standard fixed-dose therapy may not ensure optimal MPA exposure.
Purpose of the Study:
- Develop a population pharmacokinetic model for MPA and its metabolite MPAG.
- Identify key covariates influencing MPA pharmacokinetics.
- Improve prediction of patient dosing requirements for MMF.
Main Methods:
- Collected MPA and MPAG concentration-time data from 25 lupus nephritis patients on MMF, with or without CsA.
- Utilized NONMEM software for population pharmacokinetic modeling.
- Employed a two-compartment model for MPA and a one-compartment model with EHC for MPAG.
Main Results:
- MPAG clearance decreased with reduced renal function.
- Enterohepatic circulation (EHC) of MPAG was reduced by CsA co-therapy.
- Simulations demonstrated different MMF doses required based on renal function and CsA use to achieve target MPA AUC0-12.
Conclusions:
- A 'tiered' dosing approach is recommended over a 'one dose fits all' strategy.
- Individualizing MMF therapy based on renal function and CsA co-therapy ensures optimal MPA exposure.
- This approach can improve treatment outcomes for adult lupus nephritis patients.
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