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Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation-a prospective, observational study.

ABSTRACT: OBJECTIVE:Mycophenolate mofetil (MMF) is an established therapy for systemic sclerosis (SSc), but its pharmacokinetics in this disease remains unexplored. We have investigated drug exposure in MMF-treated patients with SSc in relation to clinical features of the disease and common concomitant drugs. METHODS:This study was predefined to include 35 MMF-treated SSc patients who were using MMF at a fixed dose of 0.5, 1.0 or 1.5?g twice daily since at least 3?months. The 12-h drug exposure of the active MMF metabolite mycophenolic acid (MPA) was estimated by repeated analysis of plasma MPA over a 6-h period. This 12-h drug exposure was dose normalised to a daily intake of 3?g MMF (MPA_AUC3g) in order to compare subjects using MMF at different doses. Drug exposure was analysed in reference to the clinical characteristics including body weight, renal function, autoantibodies, intestinal dysbiosis, intestinal inflammation assessed by faecal (F)-calprotectin, intestinal symptoms assessed by the University of California Los Angeles Scleroderma Trial Consortium Gastrointestinal Tract Instrument 2.0 and concomitant drug usage including proton-pump inhibitors (PPI). RESULTS:Thirty-four out of 35 study participants completed the study. The mean daily MMF dose was 2.1?g. Drug exposure expressed as MPA_AUC3g varied up to 8-fold between patients (median 115, range 27-226?mg h/L). MPA_AUC3g was inversely related to body weight (rs?=?-?0.58, p?

SUBMITTER: Andreasson K

PROVIDER: S-EPMC7539387 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation-a prospective, observational study.

Andréasson Kristofer K Neringer Karl K Wuttge Dirk M DM Henrohn Dan D Marsal Jan J Hesselstrand Roger R

Arthritis research & therapy 20201006 1

<h4>Objective</h4>Mycophenolate mofetil (MMF) is an established therapy for systemic sclerosis (SSc), but its pharmacokinetics in this disease remains unexplored. We have investigated drug exposure in MMF-treated patients with SSc in relation to clinical features of the disease and common concomitant drugs.<h4>Methods</h4>This study was predefined to include 35 MMF-treated SSc patients who were using MMF at a fixed dose of 0.5, 1.0 or 1.5 g twice daily since at least 3 months. The 12-h drug expo ...[more]

PMID: 33023643

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Project description:ObjectiveTo compare mycophenolate mofetil (MMF) with placebo for the treatment of systemic sclerosis (SSc)-related interstitial lung disease (ILD).MethodsWe included participants enrolled in the placebo arm of Scleroderma Lung Study (SLS) I and the MMF arm of SLS II. SLS I randomized participants to receive either oral cyclophosphamide (CYC) or placebo for 1 year, while SLS II randomized participants to receive either MMF for 2 years or oral CYC for 1 year followed by 1 year of placebo. Eligibility criteria for SLS I and SLS II were nearly identical. The primary outcome was % predicted forced vital capacity (FVC), and key secondary outcomes included % predicted diffusing capacity for carbon monoxide (DLco), the modified Rodnan skin thickness score (MRSS), and dyspnea. Joint models were created to evaluate the treatment effect on the course of these outcomes over 2 years.ResultsAt baseline, the MMF-treated group in SLS II (n = 69) and the placebo-treated group in SLS I (n = 79) had similar percentages of men and women and similar disease duration, SSc subtype, extent of skin disease, and % predicted FVC. MMF-treated patients in SLS II were slightly older (mean ± SD age 52.6 ± 9.7 years versus 48.1 ± 12.4 years; P = 0.0152) and had higher % predicted DLco (mean ± SD 54.0 ± 11.1 versus 46.2 ± 13.3; P = 0.0002) than placebo-treated patients in SLS I. After adjustment for baseline disease severity, treatment with MMF in comparison with placebo was associated with improved % predicted FVC (P < 0.0001), % predicted DLco (P < 0.0001), MRSS (P < 0.0001), and dyspnea (P = 0.0112) over 2 years.ConclusionAlthough there are inherent limitations in comparing participants from different trials, treatment with MMF was associated with improvements in physiologic outcomes and dyspnea compared with placebo, even after accounting for baseline disease severity. These results further substantiate the use of MMF for the treatment of SSc-related ILD.

Dataset Information

Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation-a prospective, observational study.

Publications

Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation-a prospective, observational study.

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