Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease

Mycophenolic acid (MPA), the active drug moiety of mycophenolate, is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. An understanding of the pharmacokinetics and pharmacodynamics of mycophenolate in this population sho...

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Main Authors:	Abd. Rahman, Nurul Azrin, Tett, Susan E., Staatz, Christian E.
Format:	Article
Language:	English
Published:	Springer International Publishing AG 2013
Subjects:	R Medicine (General) RM Therapeutics. Pharmacology RS Pharmacy and materia medica
Online Access:	http://irep.iium.edu.my/30553/ http://irep.iium.edu.my/30553/ http://irep.iium.edu.my/30553/ http://irep.iium.edu.my/30553/1/Azrin_AbdRahman_2013.pdf

id	iium-30553
recordtype	eprints
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
language	English
topic	R Medicine (General) RM Therapeutics. Pharmacology RS Pharmacy and materia medica
spellingShingle	R Medicine (General) RM Therapeutics. Pharmacology RS Pharmacy and materia medica Abd. Rahman, Nurul Azrin Tett, Susan E. Staatz, Christian E. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease
description	Mycophenolic acid (MPA), the active drug moiety of mycophenolate, is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. An understanding of the pharmacokinetics and pharmacodynamics of mycophenolate in this population should assist the clinician with rational dosage decisions. This review aims to provide an overview of the published literature on the clinical pharmacokinetics of mycophenolate in autoimmune disease and a briefer summary of current pharmacodynamic knowledge, and to identify areas of potential future research in this field. A literature search was conducted using PubMed and EMBASE databases as well as bibliographies of relevant articles and ‘on-line early’ pages of key journals. Twenty-six pharmacokinetic/pharmacodynamic studies of mycophenolate in people with autoimmune disease were identified and appraised. Twenty-two of these studies used non-compartmental analysis techniques and four used population modelling methods to estimate mycophenolate pharmacokinetic parameters. Seven studies linked mycophenolate exposure to treatment outcomes. Only four studies measured free (unbound) as well as total mycophenolate exposure and only two studies characterised MPA disposition following enteric-coated mycophenolate sodium (EC-MPS) administration. Across all studies MPA displayed erratic and complex pharmacokinetics with substantial between-subject variability. Based on total drug measurement, the dose-normalised MPA area under the plasma concentration-time curve (AUC) from 0 to 12 h post-dose (AUC12) varied at least five- to ten-fold between subjects. Typical values for apparent oral clearance (CL/F) of MPA during nonlinear mixed–effects modelling ranged from 8.3 to 25.3 L/h. Patient renal function, serum albumin levels, sex, ethnicity, food intake, concurrent administration of interacting drugs such as antacids, metal-containing medications and proton pump inhibitors and polymorphisms in genes encoding uridine diphosphate glucuronosyltransferase were identified in some studies as having a significant influence on the pharmacokinetics of mycophenolate. Typical MPA CL/F values in autoimmune disease patients were generally slightly lower than values published previously in population pharmacokinetic studies involving renal allograft recipients, possibly because of usage of ciclosporin, poorer renal function or lower serum albumin levels in the renal transplant cohort. In a single crossover study involving ten subjects only, significantly higher MPA AUC12 and maximum MPA concentration (C max) and lower MPA CL/F were reported following EC-MPS administration compared to mycophenolate mofetil administration. MPA exposure correlated well with treatment efficacy in patients with autoimmune disease (response to treatment, active disease and disease markers); however the relationship between MPA exposure and adverse events (infectious episodes, haematological toxicity and gastrointestinal symptoms) was unclear. Further investigation is required in autoimmune diseases such as chronic plaque psoriasis and rheumatoid arthritis and following EC-MPS administration. The extent of within-subject variability in the pharmacokinetics of mycophenolate is largely unknown and potential covariate influences need to be confirmed in studies with large subject numbers. A relationship between MPA and MPA metabolite exposure and toxicity needs to be established. The contribution of pharmacogenetics to the pharmacokinetics and pharmacodynamics of mycophenolate warrants further investigation, as does the utility of therapeutic drug monitoring. Dosing to achieve a target MPA AUC12 >35 mg·h/L is likely to lead to better efficacy outcomes in patients with autoimmune disease (rather than just giving standard doses, which lead to a wide range of exposures). However, the relationship between mycophenolate exposure and toxicity requires further investigation to determine the upper end of a target AUC range.
format	Article
author	Abd. Rahman, Nurul Azrin Tett, Susan E. Staatz, Christian E.
author_facet	Abd. Rahman, Nurul Azrin Tett, Susan E. Staatz, Christian E.
author_sort	Abd. Rahman, Nurul Azrin
title	Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease
title_short	Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease
title_full	Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease
title_fullStr	Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease
title_full_unstemmed	Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease
title_sort	clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease
publisher	Springer International Publishing AG
publishDate	2013
url	http://irep.iium.edu.my/30553/ http://irep.iium.edu.my/30553/ http://irep.iium.edu.my/30553/ http://irep.iium.edu.my/30553/1/Azrin_AbdRahman_2013.pdf
first_indexed	2023-09-18T20:44:44Z
last_indexed	2023-09-18T20:44:44Z
_version_	1777409598936842240
spelling	iium-305532013-10-31T04:03:05Z http://irep.iium.edu.my/30553/ Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease Abd. Rahman, Nurul Azrin Tett, Susan E. Staatz, Christian E. R Medicine (General) RM Therapeutics. Pharmacology RS Pharmacy and materia medica Mycophenolic acid (MPA), the active drug moiety of mycophenolate, is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. An understanding of the pharmacokinetics and pharmacodynamics of mycophenolate in this population should assist the clinician with rational dosage decisions. This review aims to provide an overview of the published literature on the clinical pharmacokinetics of mycophenolate in autoimmune disease and a briefer summary of current pharmacodynamic knowledge, and to identify areas of potential future research in this field. A literature search was conducted using PubMed and EMBASE databases as well as bibliographies of relevant articles and ‘on-line early’ pages of key journals. Twenty-six pharmacokinetic/pharmacodynamic studies of mycophenolate in people with autoimmune disease were identified and appraised. Twenty-two of these studies used non-compartmental analysis techniques and four used population modelling methods to estimate mycophenolate pharmacokinetic parameters. Seven studies linked mycophenolate exposure to treatment outcomes. Only four studies measured free (unbound) as well as total mycophenolate exposure and only two studies characterised MPA disposition following enteric-coated mycophenolate sodium (EC-MPS) administration. Across all studies MPA displayed erratic and complex pharmacokinetics with substantial between-subject variability. Based on total drug measurement, the dose-normalised MPA area under the plasma concentration-time curve (AUC) from 0 to 12 h post-dose (AUC12) varied at least five- to ten-fold between subjects. Typical values for apparent oral clearance (CL/F) of MPA during nonlinear mixed–effects modelling ranged from 8.3 to 25.3 L/h. Patient renal function, serum albumin levels, sex, ethnicity, food intake, concurrent administration of interacting drugs such as antacids, metal-containing medications and proton pump inhibitors and polymorphisms in genes encoding uridine diphosphate glucuronosyltransferase were identified in some studies as having a significant influence on the pharmacokinetics of mycophenolate. Typical MPA CL/F values in autoimmune disease patients were generally slightly lower than values published previously in population pharmacokinetic studies involving renal allograft recipients, possibly because of usage of ciclosporin, poorer renal function or lower serum albumin levels in the renal transplant cohort. In a single crossover study involving ten subjects only, significantly higher MPA AUC12 and maximum MPA concentration (C max) and lower MPA CL/F were reported following EC-MPS administration compared to mycophenolate mofetil administration. MPA exposure correlated well with treatment efficacy in patients with autoimmune disease (response to treatment, active disease and disease markers); however the relationship between MPA exposure and adverse events (infectious episodes, haematological toxicity and gastrointestinal symptoms) was unclear. Further investigation is required in autoimmune diseases such as chronic plaque psoriasis and rheumatoid arthritis and following EC-MPS administration. The extent of within-subject variability in the pharmacokinetics of mycophenolate is largely unknown and potential covariate influences need to be confirmed in studies with large subject numbers. A relationship between MPA and MPA metabolite exposure and toxicity needs to be established. The contribution of pharmacogenetics to the pharmacokinetics and pharmacodynamics of mycophenolate warrants further investigation, as does the utility of therapeutic drug monitoring. Dosing to achieve a target MPA AUC12 >35 mg·h/L is likely to lead to better efficacy outcomes in patients with autoimmune disease (rather than just giving standard doses, which lead to a wide range of exposures). However, the relationship between mycophenolate exposure and toxicity requires further investigation to determine the upper end of a target AUC range. Springer International Publishing AG 2013 Article PeerReviewed application/pdf en http://irep.iium.edu.my/30553/1/Azrin_AbdRahman_2013.pdf Abd. Rahman, Nurul Azrin and Tett, Susan E. and Staatz, Christian E. (2013) Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease. Clinical Pharmacokinetics, 52 (5). pp. 303-331. ISSN 1179-1926 (O), 0312-5963 (P) http://link.springer.com/article/10.1007%2Fs40262-013-0039-8 10.1007/s40262-013-0039-8

Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease

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