Pharmacokinetics of oral fumarates in healthy subjects.
OBJECTIVE
To characterize the pharmacokinetics of fumarates in healthy subjects.


METHODS
Ten subjects received a single fumarate tablet (containing 120 mg of dimethylfumarate and 95 mg of calcium-monoethylfumarate) in the fasted state and after a standardized breakfast in randomized order. Prior to and at fixed intervals after the dose, blood samples were drawn and the concentrations of monomethylfumarate, the biologically active metabolite, as well as dimethylfumarate and fumaric acid were measured using high-performance liquid chromatography.


RESULTS
After a lag time, a transient increase in serum monomethylfumarate concentrations in the blood was observed, whereas dimethylfumarate and fumaric acid concentrations remained below the detection limit. The tlag was 240 min [range 60-603 min; 95% confidence interval (CI) 139, 471] shorter when the tablet was taken after an overnight fast (90 min; range 60-120 min; 95% CI 66, 107) than when taken with breakfast (300 min; range 180-723 min; 95% CI 0, 1002). The tmax was 241 min (range 60-1189 min, 95% CI 53, 781) shorter when the tablet was taken after an overnight fast (182 min; range 120-240 min; 95% CI 146, 211) than when taken with breakfast (361 min; range 240-1429 min; 95% CI 0, 1062). The mean Cmax for monomethylfumarate in the blood of fasting subjects was to 0.84 mg l(-1) (range 0.37-1.29 mg l(-1); 95% CI 0.52, 1.07) and did not differ from that in fed subjects (0.48 mg l(-1); range 0-1.22 mg l(-1); 95% CI 0, 5.55).


CONCLUSIONS
The pharmacokinetics of monomethylfumarate in healthy subjects after a single tablet of fumarate are highly variable, particularly after food intake. Further experiments exploring the pharmacokinetics of oral fumarates are warranted in order to elucidate the mechanisms underlying variability in response in patients.
Litjens
Nicolle H R
NH
Department of Infectious Diseases, Leiden University Medical Centre, Leiden, the Netherlands.
Burggraaf
Jacobus
J
van Strijen
Elisabeth
E
van Gulpen
Co
C
Mattie
Herman
H
Schoemaker
Rik C
RC
van Dissel
Jaap T
JT
Thio
H Bing
HB
Nibbering
Peter H
PH
D000284:Administration, Oral; D000328:Adult; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005650:Fumarates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D013607:Tablets
D016588:Anticarcinogenic Agents; D005650:Fumarates; D013607:Tablets; C032005:fumaric acid