PMID- 22131101
OWN - NLM
STAT- MEDLINE
DCOM- 20120713
LR  - 20220310
IS  - 1529-0131 (Electronic)
IS  - 0004-3591 (Linking)
VI  - 64
IP  - 5
DP  - 2012 May
TI  - Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod 
      (ABR-215757), a new quinoline-3-carboxamide derivative: studies in lupus-prone 
      mice and a multicenter, randomized, double-blind, placebo-controlled, 
      repeat-dose, dose-ranging study in patients with systemic lupus erythematosus.
PG  - 1579-88
LID - 10.1002/art.33493 [doi]
AB  - OBJECTIVE: To assess the efficacy of paquinimod, a new immunomodulatory small 
      molecule, in a murine lupus model, and to evaluate its pharmacokinetics and 
      tolerability in systemic lupus erythematosus (SLE) patients at doses predicted to 
      be efficacious and safe and determine the maximum tolerated dose. METHODS: The 
      efficacy of paquinimod was studied in lupus-prone MRL-lpr/lpr mice and compared 
      with that of established SLE treatments. Dose-response data and pharmacokinetic 
      data were used to calculate effective and safe clinical doses of paquinimod. The 
      pharmacokinetics and tolerability of paquinimod were evaluated in a phase Ib 
      double-blind, placebo controlled, dose-ranging study in which cohorts of SLE 
      patients received daily oral treatment for 12 weeks. RESULTS: Paquinimod 
      treatment resulted in disease inhibition in MRL-lpr/lpr mice, comparable to that 
      obtained with prednisolone and mycophenolate mofetil; prominent effects on 
      disease manifestations and serologic markers and a steroid-sparing effect were 
      observed. In patients with SLE, the pharmacokinetic properties of paquinimod were 
      linear and well suitable for once-daily oral treatment. The majority of the 
      adverse events (AEs) were mild or moderate, and transient. The most frequent AEs 
      were arthralgia and myalgia, reported with the highest dose levels of paquinimod 
      (4.5 mg/day and 6.0 mg/day). At the 4.5 mg/day dose level and higher, some AEs of 
      severe intensity and serious adverse events were reported. CONCLUSION: Paquinimod 
      effectively inhibited disease and had a steroid-sparing effect in experimental 
      lupus. Results from preclinical models together with pharmacokinetic data were 
      successfully translated into a safe clinical dose range, and doses of up to 3.0 
      mg/day were well tolerated in the SLE patients. Taken together, the promising 
      combined data from a murine model and human SLE support the future clinical 
      development of paquinimod.
CI  - Copyright (c) 2012 by the American College of Rheumatology.
FAU - Bengtsson, Anders A
AU  - Bengtsson AA
AD  - Lund University, Lund, Sweden. Anders.Bengtsson@med.lu.se
FAU - Sturfelt, Gunnar
AU  - Sturfelt G
FAU - Lood, Christian
AU  - Lood C
FAU - Ronnblom, Lars
AU  - Ronnblom L
FAU - van Vollenhoven, Ronald F
AU  - van Vollenhoven RF
FAU - Axelsson, Bengt
AU  - Axelsson B
FAU - Sparre, Birgitta
AU  - Sparre B
FAU - Tuvesson, Helen
AU  - Tuvesson H
FAU - Ohman, Marie Wallen
AU  - Ohman MW
FAU - Leanderson, Tomas
AU  - Leanderson T
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Quinolines)
RN  - 0 (quinoline-3-carboxamide)
RN  - 9PHQ9Y1OLM (Prednisolone)
RN  - HB76GLG27V (paquinimod)
RN  - HU9DX48N0T (Mycophenolic Acid)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Disease Models, Animal
MH  - Double-Blind Method
MH  - Female
MH  - Humans
MH  - *Immunosuppressive Agents/adverse effects/pharmacokinetics/therapeutic use
MH  - Kidney/metabolism/pathology
MH  - Lupus Erythematosus, Systemic/*drug therapy/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred MRL lpr
MH  - Middle Aged
MH  - Mycophenolic Acid/analogs & derivatives/therapeutic use
MH  - Prednisolone/therapeutic use
MH  - Quinolines/adverse effects/*chemistry/pharmacokinetics/therapeutic use
MH  - Severity of Illness Index
MH  - Treatment Outcome
MH  - Young Adult
EDAT- 2011/12/02 06:00
MHDA- 2012/07/14 06:00
CRDT- 2011/12/02 06:00
PHST- 2011/12/02 06:00 [entrez]
PHST- 2011/12/02 06:00 [pubmed]
PHST- 2012/07/14 06:00 [medline]
AID - 10.1002/art.33493 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2012 May;64(5):1579-88. doi: 10.1002/art.33493.