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Pharmacokinetics of oral fumarates in healthy subjects

DOI:10.1111/j.1365-2125.2004.02145.x Pharmacokinetics of oral fumarates in healthy subjects Nicolle H. R. Litjens, Jacobus Burggraaf,1 Elisabeth van Strijen, Co van Gulpen, Herman Mattie, Rik C. Schoemaker,1
Jaap T. van Dissel, H. Bing Thio2 & Peter H. Nibbering
Department of Infectious Diseases, Leiden University Medical Centre and 1Centre for Human Drug Research, Leiden, and 2Department of
Dermatology and Venereology, Erasmus Medical Centre, Rotterdam, the Netherlands

To characterize the pharmacokinetics of fumarates in healthy subjects.
Infectious Diseases, C5-P, Leiden University Medical Centre, 2300 RC Ten subjects received a single fumarate tablet (containing 120 mg of dimethylfuma- rate 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 weremeasured using high-performance liquid chromatography.
After a lag time, a transient increase in serum monomethylfumarate concentrations in the blood was observed, whereas dimethylfumarate and fumaric acid concentra- tions 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 anovernight fast (90 min; range 60–120 min; 95% CI 66, 107) than when taken withbreakfast (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 anovernight fast (182 min; range 120–240 min; 95% CI 146, 211) than when taken Received
with breakfast (361 min; range 240–1429 min; 95% CI 0, 1062). The mean C for monomethylfumarate in the blood of fasting subjects was to 0.84 mg l-1 (range Accepted
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).
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 reponse in patients.
be circumvented using mixtures of dimethylfumarate Psoriasis vulgaris is an autoimmune skin disease char- and monoethylfumarate in enteric-coated tablets [7–12].
acterized by epidermal hyperplasia and the presence of There is some variability in the response to these fuma- inflammatory cells in affected lesions. Current long- rates among psoriasis patients. The reason for this is term (anti-inflammatory) therapies for psoriasis cause unknown and may involve both pharmacokinetic and serious adverse effects [1–5]. Fumaric acid is effective pharmacodynamic factors. There are few data on the against psoriasis [6], but its main drawback is that it pharmacokinetics of fumarates in humans [13]. Animal causes gastric ulcers. However, this adverse affect can studies indicate that fumarates are completely absorbed from the gastrointestinal tract within 2 h after adminis- metaphosphoric acid followed by extraction with dieth- tration and that dimethylfumarate is rapidly hydrolysed ylether and pH adjustment to pH 0.5. Sodium chloride in the intestinal mucosa to monomethylfumarate. This was added before centrifugation at 12 000 ¥ g. Thereaf- bioactive intermediate is further metabolized into ter, the ether layer was transferred to a glass vial and fumaric acid, which enters the citric acid cycle (personal after evaporation the residue reconstituted in methanol: communication, Joshi et al. Fumapharm AG, Switzer- 0.1 M potassium phosphate buffer (KH2PO4/K2HPO4; land). As a first step in understanding why patients with pH 7.5) supplemented with 5 mM tetrabutylammonium psoriasis vary in their response to fumarates we have characterized the pharmacokinetics of fumarates in The HPLC instrument (Spectra SERIES P100) was healthy individuals following a single dose taken on an equipped with an Alltima C18 column (5m 5250 ¥ empty stomach as well as with a meal.
4.6 mm) and a precolumn. The mobile phase for dime-thylfumarate was methanol : water 30 : 70 (v/v) and Materials and methods
that for monomethylfumarate and fumaric acid was The Medical Ethics Committee of Leiden University methanol : potassium phosphate buffer supplemented Medical Centre approved this open, randomized, cross- with 5 mM tetrabutylammonium dihydrogen phosphate over study and all subjects gave written informed 20 : 80 (v/v). The limit of detection for all three com- consent. The study was conducted according to the prin- pounds was 0.01 mg l-1, the coefficients of variation for ciples of the Declaration of Helsinki and in compliance monomethylfumarate and dimethylfumarate were 7% with International Conference on Harmonization/Good and 9% at 0.5 mg l-1, respectively, and the recoveries Clinical Practice regulations. The study population con- of monomethylfumarate and dimethylfumarate were sisted of 10 healthy subjects (four male, six female) 75 ± 7% and 98 ± 3% (n = 6).
between 19 and 28 years with a normal weight forheight (body mass index range 18–25 kg m-2).
Data analysisThe pharmacokinetic parameters for monomethylfuma- rate were calculated by noncompartmental analysis using The subjects participated on two study days. On one day WinNonlin software (version 4; Pharsight Corp., Moun- a single tablet was taken after an overnight fast and on tain View, CA, USA). Terminal half-life (t1/2) was esti- the other day the tablet was taken with a standardized mated by log-linear regression of the terminal part of the breakfast (2060 kJ – 45% as protein, 12% as fat and concentration–time curve, where the number of points 43% as carbohydrates). The tablets (Fumaraat 120®) to be included was determined by the program. Lag-time containing 120 mg of dimethylfumarate and 95 mg of (tlag), time at which peak concentrations of monometh- calcium-monoethylfumarate were purchased from Tio- ylfumarate occurred (tmax), and peak concentrations of farma (Oud-Beijerland, Netherlands). Each study day monomethylfumarate (Cmax) are reported for all subjects.
lasted 24 h and was separated from the other days by a Where possible, clearance/F (dose/AUC0–•) was esti- mated. The nonparametric Friedman test was used to Blood was collected shortly before and at fixed inter- determine whether the descriptive pharmacokinetic vals after tablet dosing and placed in 4-ml tubes con- parameters differed between the fed and fasting state.
taining sodium fluoride and potassium oxalate asantioxidant and esterase inhibitors. Immediately after collection, the samples were vortexed, transferred onto Two subjects withdrew consent after the first study day ice for 5 min and centrifuged at 4 ∞C for 10 min at for personal reasons. The fumarate tablets were well 1500 ¥ g. The resulting supernatant was stored at tolerated by all participants, who suffered no serious adverse events. In addition, no abnormalities inhaematology, blood biochemistry and urinalysis were observed. However, peripheral vasodilatation (mainly in The concentrations of the fumarates were determined as the face and the upper part of the body) occurred after described by Litjens et al. (unpublished data). After pre- 10 (out of 18) of the doses and lasted between 1 and 3 h.
cipitation of serum proteins with acetonitrile, dimethyl- This was not accompanied by a decrease in blood pres- fumarate was analysed by high-performance liquid sure, an increase in heart rate or by any other event.
Concentrations of both dimethylfumarate and fumaric The sample preparation for monomethylfumarate and acid were below the detection limit. Serum monometh- fumaric acid required a protein precipitation step using ylfumarate concentrations vs. time profiles were similar in all eight subjects who took the drug after an overnight fumarate (Figure 1A,B) occurred. The tlag and tmax in fast (Figure 1A), whereas subjects who were fed dis- fasting subjects were 240 min shorter [range 60– played either negligible monomethylfumarate concen- 602 min; mean ± SD 305 ± 179 min; 95% confidence trations or values similar to those in fasting subjects interval (CI) 139, 471] and 241 min shorter (range 60– 1189 min; mean ± SD 417 ± 394 min; 95% CI 53, 781), The main pharmacokinetic parameters for monome- respectively (P = 0.008) than in fed subjects (Table 1).
thylfumarate are summarized in Table 1. A transient Moreover, the mean Cmax of monomethylfumarate in increase in the serum concentration of monomethyl- fasting individuals (n = 8) was 0.84 mg l-1 (range 0.37– Figure 1
Concentration–time profiles for monomethylfumarate in the serum of eight healthy subjects after a single Fumaraat® tablet in the fasting (A) and fed
(B) state
Table 1
Serum pharmacokinetic parameters for monomethylfumarate in eight healthy subjects after a single Fumaraat 120® tablet in the
fasting state and after a standardized breakfast
aOwing to undetectable concentrations of monomethylfumarate, no values could be calculated. 1.29 mg l-1; mean ± SD 0.8 ± 0.33; 95% CI 0.52, 1.07), may be useful in distinguishing patients who respond to and did not differ from that in the fed subjects (0.48 mg l-1; range 0–1.22 mg l-1; mean ± SD 0.46 ±0.47 mg l-1; 95% CI 0, 5.55) (Table 1). In four out of This study was financially supported by AstraZeneca eight subjects who took the drug with a breakfast, very R&D Charnwood, Loughborough, UK. low concentrations of monomethylfumarate wereobserved.
1 Kroesen S, Widmer AF, Tyndall A, Hasler P. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. The main finding of the present study is that intake of a Rheumatology (Oxford) 2003; 42: 617–21.
single oral dose of fumarate is followed by a transient 2 Davison SC, Bunker CB, Basarab T. Etanercept for severe psoriasis and rise in serum monomethylfumarate concentrations, psoriatic arthritis: observations on combination therapy. Br J Dermatol whereas negligible concentrations of dimethylfumarate and fumaric acid are achieved. Furthermore, intake of 3 Koo J, Lee J. Cyclosporine: what clinicians need to know. Dermatol Clin the drug with breakfast decreased the extent of absorption and increased interindividual variability in serum 4 Griffiths CE, Clark CM, Chalmers RJ, Li Wan PA, Williams HC. A monomethylfumarate concentrations. Therefore, dosing systematic review of treatments for severe psoriasis. Health Technol of fumarate to patients before meals should be advocated.
The present results are in agreement with our obser- 5 Lebwohl M. Psoriasis. Lancet 2003; 361: 1197–204.
vation that dimethylfumarate is rapidly hydrolysed to 6 Schweckendiek W. Heilung von Psoriasis vulgaris. Med Monatschr monomethylfumarate at pH 8.5, but not in an acidic 7 Altmeyer PJ, Matthes U, Pawlak F et al. Antipsoriatic effect of fumaric environment (Litjens et al., unpublished data). Assum- acid derivates; results of a multicenter double-blind study in 100 ing that uptake of fumarates occurs mainly in the small patients. J Am Acad Dermatol 1994; 30: 977–81.
intestine, the hydrolysis of dimethylfumarate to monom- 8 Mrowietz U, Christophers E, Altmeyer P. Treatment of psoriasis with ethylfumarate in this compartment explains the negligi- fumarates: results of a prospective multicentre study. German ble concentrations of dimethylfumarate in blood. Any Multicentre Study. Br J Dermatol 1998; 138: 456–60.
dimethylfumarate not hydrolysed in the small intestine 9 Nugteren-Huying WM, van der Schroeff JG, Hermans J, Suurmond D. may be rapidly converted to monomethylfumarate in the Fumaric acid therapy for psoriasis: a randomized, double-blind, circulation by esterases [14]. Further hydrolysis of this placebo-controlled study. J Am Acad Dermatol 1990; 22: 311–12.
metabolite to fumaric acid occurs inside cells, thus fuel- 10 Thio HB, van der Schroeff JG, Nugteren-Huying WM, Vermeer BJ. Long- ing their citric acid cycle, as indicated by increased CO term systemic therapy with dimethylfumarate and monoethylfumarate concentrations in the expired air of dogs injected with (Fumaderm®) in psoriasis. J Eur Acad Dermatol Venereol 1995; 4: fumarates (personal communication, Joshi 11 Hoefnagel JJ, Thio HB, Willemze R, Bouwes Bavinck JN. Long-term Drug intake after breakfast resulted in an increased safety aspects of systemic therapy with fumarates in severe psoriasis. lag-time and the occurrence of variable peak concentra- tions of monomethylfumarate compared with the fasting 12 Litjens NHR, Nibbering PH, Barrois AJ et al. Beneficial effects of state, a finding that is in agreement with those reported fumarate therapy in psoriasis vulgaris patients coincide with by Mrowietz et al. [13]. No definitive explanation for downregulation of type-1 cytokines. Br J Dermatol 2003; 148: 444– the differences in the pharmacokinetics of monomethyl- fumarate between fasting and fed subjects can be 13 Mrowietz U, Christophers E, Altmeyer P. Treatment of severe psoriasis with fumarates: scientific background and guidelines for therapeutic The present study is a first attempt to characterize the use. The German Fumaric Acid Ester Consensus Conference. Br J pharmacokinetics/dynamics of fumarates. Further exper- iments in healthy subjects as well as in psoriasis patients 14 Werdenberg D, Joshi R, Wolffram S, Merkle HP, Langguth P. are warranted. It may be of importance to measure con- Presystemic metabolism and intestinal absorption of antipsoriatic fumarates. Biopharm Drug Dispos 2003; 24: 259–73.
centrations of monoethylfumarate since the combination 15 Kolbach DN, Nieboer C. Fumaric acid therapy in psoriasis: results and of dimethylfumarate and monoethylfumarate resulted in side effects of 2 years of treatment. J Am Acad Dermatol 1992; 27: a more rapid decrease in the clinical score for psoriasis than dimethylfumarate alone [15,16]. Another question 16 Nieboer C, de Hoop D, Langendijk PN, Van Loenen AC, Gubbels J. to be answered is whether the rate and extent of appear- Fumaric acid therapy in psoriasis: a double-blind comparison between ance of monomethylfumarate in the blood determines the fumaric acid compound therapy and monotherapy with rate of response in psoriasis patients. This information dimethylfumaric acid ester. Dermatologica 1990; 181: 33–7.


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