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

Andréasson, Kristofer LU ; Neringer, Karl ; Wuttge, Dirk M. LU ; Henrohn, Dan ; Marsal, Jan LU and Hesselstrand, Roger LU (2020) In Arthritis Research and Therapy 22(1).
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... (More)

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 (r s =-0.58, p < 0.001) and renal function (r s =-0.34, p = 0.054). Anti-Topoisomerase-1 antibodies and male sex were associated with lower MPA-AUC3g (87 vs 123 and 71 vs 141; p = 0.008 and p = 0.015, respectively). MPA-AUC3g was inversely related to the intestinal abundance of lactobacilli and to F-calprotectin (r s =-0.54, p = 0.004; r s =-0.36, p = 0.034), but not to gastrointestinal symptoms. MPA-AUC3g was inversely related to PPI usage (r s =-0.45, p = 0.007). We found no association between MPA-AUC3g and disease subtype, disease duration or disease activity. Conclusion: MMF-Treated SSc patients exhibit considerable inter-individual variation in drug exposure, and lower MPA levels were primarily found in PPI users with poor prognostic factors. Body weight, renal function, sex, serology, gastrointestinal manifestations and/or measuring individual MPA exposure should be considered when using MMF for SSc.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Dysbiosis, Mycophenolate mofetil, Scleroderma, Systemic sclerosis
in
Arthritis Research and Therapy
volume
22
issue
1
article number
230
publisher
BioMed Central (BMC)
external identifiers
  • pmid:33023643
  • scopus:85092405592
ISSN
1478-6354
DOI
10.1186/s13075-020-02323-8
language
English
LU publication?
yes
id
d1a59c39-19fb-4e88-9690-303ac1b345a6
date added to LUP
2020-11-06 08:42:47
date last changed
2024-05-01 19:28:23
@article{d1a59c39-19fb-4e88-9690-303ac1b345a6,
  abstract     = {{<p>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 (r s =-0.58, p &lt; 0.001) and renal function (r s =-0.34, p = 0.054). Anti-Topoisomerase-1 antibodies and male sex were associated with lower MPA-AUC3g (87 vs 123 and 71 vs 141; p = 0.008 and p = 0.015, respectively). MPA-AUC3g was inversely related to the intestinal abundance of lactobacilli and to F-calprotectin (r s =-0.54, p = 0.004; r s =-0.36, p = 0.034), but not to gastrointestinal symptoms. MPA-AUC3g was inversely related to PPI usage (r s =-0.45, p = 0.007). We found no association between MPA-AUC3g and disease subtype, disease duration or disease activity. Conclusion: MMF-Treated SSc patients exhibit considerable inter-individual variation in drug exposure, and lower MPA levels were primarily found in PPI users with poor prognostic factors. Body weight, renal function, sex, serology, gastrointestinal manifestations and/or measuring individual MPA exposure should be considered when using MMF for SSc. </p>}},
  author       = {{Andréasson, Kristofer and Neringer, Karl and Wuttge, Dirk M. and Henrohn, Dan and Marsal, Jan and Hesselstrand, Roger}},
  issn         = {{1478-6354}},
  keywords     = {{Dysbiosis; Mycophenolate mofetil; Scleroderma; Systemic sclerosis}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Arthritis Research and Therapy}},
  title        = {{Mycophenolate mofetil for systemic sclerosis : Drug exposure exhibits considerable inter-individual variation-a prospective, observational study}},
  url          = {{http://dx.doi.org/10.1186/s13075-020-02323-8}},
  doi          = {{10.1186/s13075-020-02323-8}},
  volume       = {{22}},
  year         = {{2020}},
}