PMID- 26525450
OWN - NLM
STAT- MEDLINE
DCOM- 20170109
LR  - 20170110
IS  - 1742-7843 (Electronic)
IS  - 1742-7835 (Linking)
VI  - 118
IP  - 5
DP  - 2016 May
TI  - Effect of Hepatic or Renal Impairment on the Pharmacokinetics, Safety, and 
      Tolerability of Ponesimod, a Selective S1P1 Receptor Modulator.
PG  - 356-68
LID - 10.1111/bcpt.12516 [doi]
AB  - Ponesimod, a selective S1P1 receptor modulator, is a potential therapeutic agent 
      for autoimmune disorders. The impact of hepatic or renal impairment on the 
      pharmacokinetics, safety and tolerability of ponesimod and its inactive 
      metabolites, ACT-204426 and ACT-338375, was evaluated. Two separate 
      single-centre, open-label studies with 32 (hepatic study) and 24 (renal study) 
      male and female individuals were conducted. Hepatic impairment was based on the 
      Child-Pugh classification, and renal impairment was determined by creatinine 
      clearance using the Cockcroft-Gault equation. Individuals with severe hepatic or 
      renal impairment were to be matched (sex and body mass index) with healthy 
      individuals. All individuals received a single dose of 10 mg ponesimod. For 
      ponesimod, the ratio of geometric means of AUC0-infinity for individuals with severe 
      hepatic impairment versus healthy individuals was 3.07 (90% CI: 2.19, 4.32). For 
      severely renally impaired individuals versus healthy individuals, this ratio was 
      1.14 (0.82, 1.58). Cmax and tmax values of ponesimod were comparable across all 
      groups in both studies. Exposure to metabolites was increased in individuals with 
      moderate or severe hepatic impairment as compared to healthy individuals. During 
      the course of these studies, there were no clinically relevant abnormalities 
      related to vital signs, 12-lead electrocardiograms and clinical laboratory 
      values. Sixteen adverse events (AEs) were reported, 12 of them of mild intensity. 
      No AEs were considered to be treatment related. Overall, ponesimod was well 
      tolerated. In individuals with renal function impairment, dose adjustment is not 
      warranted, whereas the dose should be reduced in individuals with moderate and 
      severe hepatic impairment.
CI  - (c) 2015 Nordic Association for the Publication of BCPT (former Nordic 
      Pharmacological Society).
FAU - Guerard, Nicolas
AU  - Guerard N
AD  - Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, 
      Switzerland.
FAU - Zwingelstein, Christian
AU  - Zwingelstein C
AD  - Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, 
      Switzerland.
FAU - Hoch, Matthias
AU  - Hoch M
AD  - Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, 
      Switzerland.
FAU - Dingemanse, Jasper
AU  - Dingemanse J
AD  - Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, 
      Switzerland.
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151210
PL  - England
TA  - Basic Clin Pharmacol Toxicol
JT  - Basic & clinical pharmacology & toxicology
JID - 101208422
RN  - 0 (ACT-204426)
RN  - 0 (Receptors, Lysosphingolipid)
RN  - 0 (Thiazoles)
RN  - 0 (Thiazolidines)
RN  - 5G7AKV2MKP (ponesimod)
SB  - IM
MH  - Adult
MH  - Area Under Curve
MH  - Case-Control Studies
MH  - Female
MH  - Humans
MH  - Liver Diseases/*complications
MH  - Male
MH  - Middle Aged
MH  - Receptors, Lysosphingolipid/*antagonists & inhibitors
MH  - Renal Insufficiency/*complications
MH  - Severity of Illness Index
MH  - Thiazoles/*administration & dosage/adverse effects/pharmacokinetics
MH  - Thiazolidines/pharmacokinetics
EDAT- 2015/11/04 06:00
MHDA- 2017/01/10 06:00
CRDT- 2015/11/04 06:00
PHST- 2015/08/07 00:00 [received]
PHST- 2015/10/20 00:00 [accepted]
PHST- 2015/11/04 06:00 [entrez]
PHST- 2015/11/04 06:00 [pubmed]
PHST- 2017/01/10 06:00 [medline]
AID - 10.1111/bcpt.12516 [doi]
PST - ppublish
SO  - Basic Clin Pharmacol Toxicol. 2016 May;118(5):356-68. doi: 10.1111/bcpt.12516. 
      Epub 2015 Dec 10.