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Development of Improved Dosing Regimens for Mycophenolate Mofetil Based on Population Pharmacokinetic Analyses in Adults with Lupus Nephritis.
Eur J Drug Metab Pharmacokinet. 2017 Dec; 42(6):993-1004.EJ

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/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.

Authors+Show Affiliations

School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, 20 Cornwall St, Woolloongabba, Brisbane, QLD, 4102, Australia. nurul.abdrahman@uqconnect.edu.au. School of Pharmacy, International Islamic University of Malaysia, Kuantan, Pahang, Malaysia. nurul.abdrahman@uqconnect.edu.au.School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, 20 Cornwall St, Woolloongabba, Brisbane, QLD, 4102, Australia.Nephrology Unit, Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia.Department of Chemical Pathology, Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, 20 Cornwall St, Woolloongabba, Brisbane, QLD, 4102, Australia.

Pub Type(s)

Clinical Trial
Journal Article

Language

eng

PubMed ID

28536776

Citation

Abd Rahman, Azrin N., et al. "Development of Improved Dosing Regimens for Mycophenolate Mofetil Based On Population Pharmacokinetic Analyses in Adults With Lupus Nephritis." European Journal of Drug Metabolism and Pharmacokinetics, vol. 42, no. 6, 2017, pp. 993-1004.
Abd Rahman AN, Tett SE, Abdul Gafor HA, et al. Development of Improved Dosing Regimens for Mycophenolate Mofetil Based on Population Pharmacokinetic Analyses in Adults with Lupus Nephritis. Eur J Drug Metab Pharmacokinet. 2017;42(6):993-1004.
Abd Rahman, A. N., Tett, S. E., Abdul Gafor, H. A., McWhinney, B. C., & Staatz, C. E. (2017). Development of Improved Dosing Regimens for Mycophenolate Mofetil Based on Population Pharmacokinetic Analyses in Adults with Lupus Nephritis. European Journal of Drug Metabolism and Pharmacokinetics, 42(6), 993-1004. https://doi.org/10.1007/s13318-017-0420-3
Abd Rahman AN, et al. Development of Improved Dosing Regimens for Mycophenolate Mofetil Based On Population Pharmacokinetic Analyses in Adults With Lupus Nephritis. Eur J Drug Metab Pharmacokinet. 2017;42(6):993-1004. PubMed PMID: 28536776.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development of Improved Dosing Regimens for Mycophenolate Mofetil Based on Population Pharmacokinetic Analyses in Adults with Lupus Nephritis. AU - Abd Rahman,Azrin N, AU - Tett,Susan E, AU - Abdul Gafor,Halim A, AU - McWhinney,Brett C, AU - Staatz,Christine E, PY - 2017/5/26/pubmed PY - 2018/6/26/medline PY - 2017/5/25/entrez SP - 993 EP - 1004 JF - European journal of drug metabolism and pharmacokinetics JO - Eur J Drug Metab Pharmacokinet VL - 42 IS - 6 N2 - 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. SN - 2107-0180 UR - https://www.unboundmedicine.com/medline/citation/28536776/Development_of_Improved_Dosing_Regimens_for_Mycophenolate_Mofetil_Based_on_Population_Pharmacokinetic_Analyses_in_Adults_with_Lupus_Nephritis_ L2 - https://dx.doi.org/10.1007/s13318-017-0420-3 DB - PRIME DP - Unbound Medicine ER -