WO2021148314A1

WO2021148314A1 - Accelerated elimination of (s)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol

Info

Publication number: WO2021148314A1
Application number: PCT/EP2021/050777
Authority: WO
Inventors: Jasper Dingemanse; Elise JACOB; Pierre-Eric JUIF; Christopher Kohl
Original assignee: Idorsia Pharmaceuticals Ltd
Priority date: 2020-01-20
Filing date: 2021-01-15
Publication date: 2021-07-29
Also published as: TW202140048A

Abstract

The present invention relates to the use of charcoal in an accelerated elimination procedure of (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-5 ethyl-6-methyl-phenoxy}-propane-1,2-diol.

Description

Accelerated Elimination of (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)- [1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol

The present invention relates to charcoal for use in an accelerated elimination procedure of (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl- phenoxy}-propane-1 ,2-diol (hereinafter also referred to as “COMPOUND” or “cenerimod”). Such use is especially indicated in an emergency situation.

The preparation of (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]- 2-ethyl-6-methyl-phenoxy}-propane-1 ,2-diol and the medicinal use thereof is described in the published POT applications WO 2011/007324, WO 2013/175397 and WO 2016/184939.

COMPOUND is a potent, selective modulator of the sphingosine-1-phosphate 1 (S1Pi) receptor (Piali et al. Pharmacol Res Perspect. 2017, e00370).

Sphingosin 1 (S1P) is the natural ligand of the five sphingosine-1 -phosphate receptors SIP1-5. The S1P/S1Pi axis plays a central role in the control of lymphocyte trafficking. The concentration of S1P is low within the lymph node parenchyma but very high in the adjacent efferent lymphatic circulation, two compartments separated by lymphatic endothelium. Lymphocytes are able to sense a concentration gradient of S1P and migrate towards higher S1P concentration. Lymphocyte egress from primary and secondary lymphoid organs is dependent on S1P1 receptor expression in lymphocytes. In the presence of an S1Pi receptor agonist, cell-surface S1Pi receptors are rapidly and efficiently internalized by endocytosis and lymphocytes lose their ability to sense S1P concentration gradients. As a consequence, S1Pi receptor agonists block lymphocyte migration out of lymphoid tissue into the lymphatic and vascular circulation and thus lower the number of circulating lymphocytes in a subject treated with an S1Pi receptor agonist. Following withdrawal of an S1P1 receptor agonist, the functional lymphocytes return to the circulation from their sites of sequestration.

Due to this mode of action, S1Pi receptor agonists can be used as immunomodulatory drugs in the treatment of autoimmune diseases and other diseases where an immunosuppressive activity is essential, as for instance rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus.

With regard to the rejection of transplanted organs, Brinkmann et al. report and reference the ability of the S1P modulator FTY720 (fingolimod) to prevent lymphocytes from reacting and migrating to inflammatory chemokines at graft sites in relevant mouse models of transplant and Chiyo et al. use an alternative method for silencing S1P1 receptors and describe prevention of rejection pathology and lowering of local levels of IFN-gamma post adoptive transfer in a lung model (Brinkmann, Yonsei Med J, 2004, Vol 45, 991-7, Chiyo et al., Am. J. Transplant, 2008, Vol 8, 537-46); in addition, the S1P receptor modulator FTY720 was utilized in a murine model of cornea transplant which effectively prolong the corneal allograft survival providing evidence for the use of S1P1 modulators in cornea transplant (Gao et al., PLoS One, 2014, Vol 9,e105693). Huu et al. demonstrated the efficacy of FTY720 in a murine model of Graft-versus-Host Diseases (GvHD) by showing that FTY720 promoted the expansion of regulatory cells and reduced vascular damage and infiltration of immune cells into the skin (Huu et al., Arthritis Rheum., 2013, Vol 65,1624- 35). In a murine model, COMPOUND suppressed the infiltration of CD4, CD8, and CD11b cells into the inflamed skin, increased the frequency of regulatory T cells in the spleen and skin of GvHD mice supporting efficacy of COMPOUND in the model (Kano et al., Sci Rep. 2019, 9(1):658). Lessard et al. demonstrated in human patients a strong link of the risk loci associated which highlights the importance of the adaptive immune system in Sjogren's Syndrome and which can be dampened by S1P1 modulators (Lessard et al., Nat Genet, 2013, Vol 45, 1284-92 (doi:10.1038/ng.2792)). Ankylosing spondylitis has been shown to be a chronic inflammatory autoimmune disease with the adaptive immune system contributing significantly to its pathology (Shamji et al., Neurosurg Focus, 2008, Vol 24, E3); and suppression of the adaptive immune system by targeting of B cells and T cells has been shown to be an effective treatment in patients suffering from Ankylosing spondylitis (reviewed in Song et al, Current Op Rheum, 2011 , Vol23, 346-351). Piali et al. showed in murine models of rheumatoid and juvenile arthritis, an S1P1 modulator, ponesimod, reduced swelling and joint inflammation through a reduction in lymphocytes (Piali et al., J Pharmacol Exp Ther, 2011 , Vol.337, 547-56). In a well-established murine model of Lupus nephritis and systemic lupus erythematosus (SLE), MRL/lpr which recapitulates many aspects of human pathology, Wenderfer et al. demonstrate that treatment of diseased animals with KRP-203, a selective agonist of the S1Pi receptor, lead to significant increase in survival and reduced tubulointerstitial disease and a 4- to 8- fold fewer infiltrating CD4+ and CD8+ T-cells (Wenderfer et al., Kidney Int., 2008, Vol. 74, 1319-26). In systemic- and diffuse cutaneous systemic sclerosis Huu et al. demonstrated that an S1Pi modulator was beneficial in reducing vascular damage and infiltration of immune cells into the skin (Huu et al., Arthritis Rheum., 2013, Vol 65,1624-35). In vasculitis it has been shown that perivascular cuffing and intraluminal accumulation of mononuclear leukocytes, markers of coronary vasculitis, are attenuated using FTY720, reviewed in Behjati et al (Behjati., et al, Iran J. Neurol., 2014, Vol 13, 119-26); furthermore, Hao et al. demonstrated that plasma levels of circulating S1P was significantly higher in patients with ANCA associated Vasculitis with active disease compared with patients in remission and blocking S1Pi attenuated the activation of neutrophils in vitro from human cells (Hao et al., Arthritis Res. Ther., 2014, Vol 16, R142). T cell involvement in vasculitic disease such as Giant-cell arteritis (GCA) has shown to be important. Brack et al. demonstrated that in implanted inflamed temporal arteries from patients with GCA into severe combined immunodeficiency (SCID) mice vascular lesions were T cell-dependent indicating that a reduction in these cells could prove beneficial in treating Giant-cell arteritis (Brack et al., Mol. Med, 1997, Vol. 3, 530-43). Treatment with an S1Pi receptor modulator leads to lymphocyte depletion in man. Lockwood et al demonstrated in a clinical trial of patients suffering from Behcet’s disease treated with an anti-CD52 antibody (CAMPATH-1H) which, like S1P1 modulators also depletes lymphocytes, by six months 72% had entered remission and steroid treatment could be reduced suggesting a beneficial outcome for patients (Lockwood et al., Rheumatology, 2003, Vol. 42, 1539-44). With regard to non-infectious uveitis, Commodaro et al. showed that treatment in vivo with FTY720 was able to suppress Experimental Autoimmune Uveitis in mice. (Commodaro et al., Invest Ophthalmol Vis Sci. , 2010, Vol. 51 , 2568-74). The sphingosine-1-phosphate receptor agonist FTY720 was shown to prevent the development of anti-glomerular basement membrane Glomerulonephritis in a murine mouse model by Sui et al, demonstrating the potential for such compounds in the treatment of Goodpasture syndrome (Sui et al., Mol. Biol. Rep., 2012, Vo. 39, 389-97). Regarding primary biliary cirrhosis, Li et al. showed that S1P levels in liver tissue were markedly up- regulated in a mouse model of cholestasis-induced liver fibrosis and administration of an S1P modulator clearly ameliorated bile duct ligation-induced hepatic fibrosis, as demonstrated by attenuated deposition of collagen type I and III, reduced smooth muscle alpha-actin expression and decreased total hydroxyproline content (Li et al., Am. J. Pathol., 2009, Vol.175, 1464-72). Yin et al. showed that FTY720, a S1P modulator is able to improve several markers of Con A-induced liver injury, a model for autoimmune hepatitis, in mice, including serum ALT, serum AST, TNF-alpha, and NF-kappaB, which provides evidence for utilizing an S1Pi modulator in autoimmune hepatitis (Yin XD et al., Curr. Ther. Res. Clin. Exp, 2012, Vol. 73, 140-9). There is compelling evidence that vitiligo is a lymphocyte driven autoimmune disease and specifically CD8+ cytotoxic T lymphocytes play a pivotal role in depigmentation (Lili et al, PLoS One, 2012, Vol 7 e37513). Therefore, based on the mode of action of S1Pi modulators there is strong reason to expect S1Pi modulation could prove beneficial to patients suffering from vitiligo (Ongenae et al., Pigment Cell Res, 2003, Vol. 16, 90-100). Alopecia areata is an autoimmune disorder with lymphocytic activity strongly contributing to pathology and where a reduction in lymphocyte activity is targeted to manage disease, reviewed in Suhail et al. (Suhail et al., J. Saudi Society of Dermatology & Dermatologic Surgery, 2013 Vol. 17, 37-45). Cytotoxic T lymphocytes seem to play a major part in the pathogenesis of Rasmussen’s encephalitis and case reports in patients have demonstrated that both T cell and B cell depletion can be efficacious in treatment as reviewed in Varadkar et al. Further, there is strong rationale to believe that reduction in cytotoxic T lymphocytes with an S1P modulator would ameliorate the disease (Varadkar et al., The Lancet Neurology, 2014 Vol.13, 195-205). The non- selective S1P receptor modulator, fingolimod, and the selective S1Pi receptor modulator, siponimod, are currently used to treat patients for multiple sclerosis (Kappos et al, 2010, NEJM, vol.362, 387-401 ; Kappos et al., 2018, Lancet, Vol391(10127): 1263-1273). Other S1Pi receptor modulator, such as ozanimod, are being investigated in MS patients and showed promising data (Rasche and Paul, Expert Opin Pharmacother. 2018, 19(18):2073- 2086). Amiselimod inhibited the relapse of experimental autoimmune encephalomyelitis (EAE) during treatment and reduced demyelination as well as infiltration of immune cells within the CNS and in particular in the spinal cord suggesting efficacy in MS (Kataoka H, ECTRIMS: Mult Scler. 2015 Oct 8; 115138:Abstract EP1317). In a murine dextran sodium sulfate (DSS) model of colitis, Sanada et al. showed that a Sphingosine-1 -Phosphate Receptor Agonist W-061 resulted in improvement of DSS-induced colitis, and significantly reduced the number of CD4+ T cells in the colonic lamina propria (Sanada et al., PLoS One, 2011 , Vol.6, e23933). In patients with ulcerative colitis, treatment with ozanimod resulted in a slightly higher rate of clinical remission (Sandborn et al, NEJM 2016; 374(18): 1754-62). Animal models of contact dermatitis are described in Japtok et al. and Kohno et al. Japtok et al. describe effects of S1P on modulating proliferation of both lymphocytes and keratinocytes which leads to an improved outcome. Kohno et al demonstrate that treatment with FTY720 prevented dermatitis in a murine NC/Nga model of dermatitis. Clinical trials in psoriasis reviewed by Ambrosio et al. and performed with S1Pi modulators provide evidence that treatment with S1P modulators is connected with an antiinflammatory action providing evidence for a novel approach for the treatment of atopic dermatitis and psoriasis with an S1Pi modulator (Japtok et al., Allergo J. Int., 2014, Vol.23, 54-59; Kohno et al., Biol. Pharm. Bull., 2004, Vol. 27, 1392-6, D’Ambrosio et al, Therapeutic Advances Chronic Disease, 2016, Vol 7(1) 18-33). In a murine model of type I diabetes chronic oral ponesimod treatment (an S1Pi modulator) efficiently prevented autoimmune diabetes in 6, 10 and 16 week-old pre-diabetic NOD mice (You et al., PLos One, 2013, Vol.8, e77296). Ando et al. use BXSB mice, a genetic model of systemic lupus erythematosus (SLE) reflecting human pathology, to show treatment with FTY720 lead to a survival advantage and improved renal function as measured by decreased proteinuria. Histological analysis revealed that FTY720 suppressed mesangial cell proliferation and inflammatory cell infiltration and a marked decrease in lymphocytes. These results suggest that FTY720 ameliorates systemic lupus erythematosus manifested in the kidney as lupus nephritis by inhibiting the end-stage inflammatory process following IC deposition in glomeruli. (Ando et al., Biochem. Biophys. Res. Commun, 2010, Vol. 394, 804-10). Hermann et al. concluded from a clinical phase II study that cenerimod, a selective sphingosine-1 -phosphate 1 (S1Pi) receptor modulator, has the potential to be a new therapeutic approach for patients with SLE (Hermann et al., First Use of Cenerimod, a Selective sphingosine-1 -phosphate 1 (S1Pi) Receptor Modulator, for the Treatment of Systemic Lupus Erythematosus: A Double-Blind, Randomised, Placebo-Controlled, Phase II, Proof-of-Concept Study [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10); Hermann V, et al., First use of cenerimod, a selective S1Pi receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study. Lupus Science & Medicine 2019;6:e000354. doi:10.1136/lupus-2019-000354).

Fingolimod, a non-selective S1P receptor modulator, and siponomod, a selective S1P receptor modulator, are approved in the US for the treatment of relapsing forms of multiple sclerosis.

Teriflunomide ((Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide) is an immunomodulatory drug inhibiting pyrimidine de novo synthesis that is approved in the US as well as in Europe for the treatment of patients with relapsing forms of multiple sclerosis. The exact mechanism by which teriflunomide exerts its therapeutic effect is unknown but may involve a reduction in the number of activated lymphocytes in the central nervous system (CNS). Teriflunomide has a median half-life (ti ₂) of approximately 18 and 19 days after repeated doses of 7 mg and 14 mg respectively and is thus slowly eliminated from plasma (U.S. Food & Drug Administration, NDA 202992 (Aubagio), Labeling-Package Insert, November 29, 2016). After discontinuation of teriflunomide treatment it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. Mechanistically, this slow elimination is based on an enterohepatic recycling. It can become problematic in certain clinical situations, such as in females who become pregnant or plan to become pregnant while on teriflunomide, due to the potential teratogenic effect (Robertson et al. Expert Rev. Clin. Pharm. 2017, 10(12), 1403-1407). An accelerated elimination procedure has thus been developed for teriflunomide. It was found that both, the administration of colestyramine (also named “cholestyramine”) 8 g every 8 hours for 11 days or the administration of 50 g oral activated charcoal powder every 12 hours for 11 days successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations (U.S. Food & Drug Administration, NDA 202992 (Aubagio), Labeling-Package Insert, November 29, 2016). However, these agents are restricted by side effects and limited routes and frequencies of dosing. Side effects of colestyramine include constipation, abdominal discomfort, nausea, emesis, diarrhea, anorexia, steatorrhea, or bleeding tendencies. Activated charcoal side effects can include abdominal discomfort, diarrhea, constipation, emesis, Gl obstruction, or fecal impaction (Robertson et al. Expert Rev. Clin. Pharm. 2017, 10(12), 1403-1407). In a clinical study in healthy volunteers, Robertson et al. have thus investigated colestipol hydrochloride as an alternative for colestyramine since it has potential advantages in ease of administration (available in an oral tablet formulation, whereas colestyramine is supplied as an oral powder for suspension) and less frequent dosing (twice daily, whereas colestyramine is dosed as three times daily). The administration of colestipol HCI (8 g twice daily for 15 days) was sufficient to reduce plasma teriflunomide concentrations by >96%. Despite the fact that colestipol HCI did not completely eliminate teriflunomide with the same effectiveness as colestyramine or activated charcoal and that caution should thus be exercised for certain circumstances, the authors concluded: Although colestipol HCI did not completely eliminate teriflunomide with the same effectiveness as colestyramine, it may offer an alternative for accelerated elimination of teriflunomide with potentially improved tolerability and more favourable dosing and administration options. In addition, Lunven et al. investigated the use of colesevelam hydrochlorid for accelerated elimination of teriflunomide in healthy volunteers (Lunven et al. J. Clin. Pharmacol. 2017, 57(6), 747-750). The administration of four 625 mg tablets in the morning plus three 625 mg tablets in the evening for 11 days resulted in a reduction of teriflunomide plasma concentrations by >96% on average. The authors concluded: Colesevelam HCI may offer an additional effective and well-tolerated AEP [accelerated elimination procedure] methodology to colestyramine and activated charcoal when rapid elimination of teriflunomide is required.

Other drugs that are used in the treatment of multiple sclerosis and that have a long half- life are for instance fingolimod and natalizumab. The reason for the long half-life of fingolimod is its large volume of distribution in combination with its moderate clearance (Zollinger et al. Drug Metab. Dispos. 2011 , 39(2), 199-207) whilst the monocolonal antibody natalizumab undergoes target mediated drug disposition and is cleared by physiological clearance mechanisms of IgG proteins (Khatri et al. Neurology 2009, 72(5), 402-409). Adsorbentia such as colestyramine, charcoal, colestipol HCI and colesevelam HCI are administered orally and may only bind drug present in the gastrointestinal tract. Consequently, adsorbentia will not affect or accelerate the elimination of fingolimod and natalizumab, as they act locally in the gastrointestinal tract and not systemically.

In a phase I clinical trial, when administered once daily for 35 days at doses of 0.5, 1 , 2, and 4 mg to healthy subjects, COMPOUND let to a gradual, dose-dependent reduction in lymphocyte count that reached a plateau 20 to 23 days after first dose. The maximum (%) change from baseline (mean ± SD) was -33.6 ± 15.0% (Day 36, p = 0.0002 vs. baseline), -50.1 ± 4.4% (Day 35, p = 0.0009 vs. baseline), -64.1 ± 8.7% (Day 23, p < 0.0001 vs. baseline), and -56.3 ± 7.0% (Day 36, p < 0.0001 vs. baseline) following doses of 0.5, 1 , 2 and 4 mg, respectively (Juif et al. Int. J. Mol. Sci. 2017, 18, 2636).

The binding of COMPOUND to plasma proteins is >99.9% in different animal species and in man (Juif et al. Int. J. Mol. Sci. 2017, 18, 2636). In a pharmacokinetic / pharmacodynamic study in healthy subjects it was shown that COMPOUND has a terminal half-life of 415 hours and 539 hours after once daily administration of 2 mg and 4 mg COMPOUND for 35 days and that COMPOUND accumulates substantially over the 35 days of administration: steady-state concentrations are reached after 20 to 32 days. Juif et al. concluded: Based on the present data and its lipophilic properties, it is plausible that cenerimod accumulates in several tissues. Especially in emergency situations an accelerated elimination of COMPOUND from the body of a patient is preferable.

In-vitro experiments revealed that COMPOUND (16 mg/L) binds to activated charcoal (4 g/L to 200 g/L) to 99% or higher. This is surprisingly in contrast to the much lower binding of COMPOUND to colestyramine (16 g/L, 32 g/L, and 64 g/L resulting in 62%, 57% and 64% binding, respectively), colesevelam HCI (8 g/L, 16 g/L, and 32 g/L resulting in 89%, 74% and 76% binding, respectively), and colestipol HCI (32 g/L resulting in 19% binding). Description of the Invention

1) A first embodiment of the invention relates to activated charcoal for use in an accelerated elimination of COMPOUND from blood plasma of a subject.

2) A further embodiment of the invention relates to activated charcoal for use in a method of accelerating the elimination of COMPOUND from blood plasma of a subject, comprising administering to the subject in need thereof an effective amount of activated charcoal. 3) A further embodiment of the invention relates to a method of accelerating the elimination of COMPOUND from blood plasma of a subject, comprising administering to the subject in need thereof an effective amount of activated charcoal.

4) A further embodiment of the invention relates to a use of activated charcoal in an accelerated elimination of COMPOUND from blood plasma of a subject.

5) A further embodiment of the invention relates to a use of activated charcoal in the preparation of a pharmaceutical composition for an accelerated elimination of COMPOUND from blood plasma of a subject.

6) A further embodiment of the invention relates to a pharmaceutical composition comprising activated charcoal for use in an accelerated elimination of COMPOUND from blood plasma of a subject. 7) A further embodiment of the invention relates to a pharmaceutical composition comprising activated charcoal as an active agent for an accelerated elimination of COMPOUND from blood plasma of a subject.

8) A further embodiment of the invention relates to activated charcoal for use in accelerating the increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND, or a pharmaceutically acceptable salt thereof.

9) A further embodiment of the invention relates to activated charcoal for use in a method of accelerating the increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND, or a pharmaceutically acceptable salt thereof.

10) A further embodiment of the invention relates to a method of accelerating the increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND, or a pharmaceutically acceptable salt thereof, comprising administering to the subject in need thereof an effective amount of activated charcoal.

11) A further embodiment of the invention relates to a use of activated charcoal for accelerating the increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND, or a pharmaceutically acceptable salt thereof.

12) A further embodiment of the invention relates to a use of activated charcoal in the preparation of a pharmaceutical composition for accelerating the increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND, or a pharmaceutically acceptable salt thereof.

13) A further embodiment of the invention relates to a pharmaceutical composition comprising activated charcoal for use in accelerating the increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND, or a pharmaceutically acceptable salt thereof.

14) A further embodiment of the invention relates to a pharmaceutical composition comprising activated charcoal as an active agent for accelerating the increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND, or a pharmaceutically acceptable salt thereof.

15) A further embodiment of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with an activated immune system, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, activated charcoal is to be administered. 16) A further embodiment of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder associated with an activated immune system, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, the elimination of COMPOUND is to be accelerated by administration of activated charcoal.

17) A further embodiment of the present invention relates to a method of treating a disease or disorder associated with an activated immune system, comprising administering to a subject in need thereof a pharmaceutically active amount of COMPOUND, or of a pharmaceutically acceptable salt thereof, wherein in case an accelerated elimination of

COMPOUND from blood plasma of a subject is indicated, the elimination of COMPOUND is to be accelerated by administration of an effective amount of activated charcoal. 18) A further embodiment of the invention relates to a use of COMPOUND, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder associated with an activated immune system, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, the elimination of COMPOUND is to be accelerated by administration of activated charcoal.

19) A further embodiment of the invention relates to a use of COMPOUND, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for the treatment of a disease or disorder associated with an activated immune system, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, the elimination of COMPOUND is to be accelerated by administration of activated charcoal.

20) A further embodiment of the invention relates to a pharmaceutical composition comprising COMPOUND for use in the treatment of a disease or disorder associated with an activated immune system, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, the elimination of COMPOUND is to be accelerated by administration of activated charcoal.

21) A further embodiment of the invention relates to a pharmaceutical composition comprising COMPOUND as an active agent for the treatment of a disease or disorder associated with an activated immune system, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, the elimination of COMPOUND is to be accelerated by administration of activated charcoal.

22) A further embodiment of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, activated charcoal is to be administered.

23) A further embodiment of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, the elimination of COMPOUND is to be accelerated by administration of activated charcoal.

24) A further embodiment of the present invention relates to a method of treating a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, comprising administering to a subject in need thereof a pharmaceutically active amount of COMPOUND, or of a pharmaceutically acceptable salt thereof, wherein in case an accelerated elimination of COMPOUND from blood plasma of a patient is indicated, the elimination of COMPOUND is to be accelerated by administration of activated charcoal.

25) A further embodiment of the invention relates to a use of COMPOUND, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, the elimination of COMPOUND is to be accelerated by administration of activated charcoal.

26) A further embodiment of the invention relates to a use of COMPOUND, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, the elimination of COMPOUND is to be accelerated by administration of activated charcoal.

27) A further embodiment of the invention relates to a pharmaceutical composition comprising COMPOUND for use in the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, the elimination of COMPOUND is to be accelerated by administration of activated charcoal.

28) A further embodiment of the invention relates to a pharmaceutical composition comprising COMPOUND as an active agent for the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an accelerated elimination of COMPOUND from blood plasma of a subject is indicated, the elimination of COMPOUND is to be accelerated by administration of activated charcoal.

29) A further embodiment of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with an activated immune system, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

30) A further embodiment of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder associated with an activated immune system, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

31) A further embodiment of the present invention relates to a method of treating a disease or disorder associated with an activated immune system, comprising administering to a subject in need thereof a pharmaceutically active amount of COMPOUND, or of a pharmaceutically acceptable salt thereof, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

32) A further embodiment of the invention relates to a use of COMPOUND, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder associated with an activated immune system, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

33) A further embodiment of the invention relates to a use of COMPOUND, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for the treatment of a disease or disorder associated with an activated immune system, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

34) A further embodiment of the invention relates to a pharmaceutical composition comprising COMPOUND for use in the treatment of a disease or disorder associated with an activated immune system, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

35) A further embodiment of the invention relates to a pharmaceutical composition comprising COMPOUND as an active agent for the treatment of a disease or disorder associated with an activated immune system, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

36) A further embodiment of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

37) A further embodiment of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

38) A further embodiment of the present invention relates to a method of treating a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, comprising administering to a subject in need thereof a pharmaceutically active amount of COMPOUND, or of a pharmaceutically acceptable salt thereof, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

39) A further embodiment of the invention relates to a use of COMPOUND, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered. 40) A further embodiment of the invention relates to a use of COMPOUND, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

41) A further embodiment of the invention relates to a pharmaceutical composition comprising COMPOUND for use in the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

42) A further embodiment of the invention relates to a pharmaceutical composition comprising COMPOUND as an active agent for the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated, the treatment with COMPOUND is to be discontinued and activated charcoal is to be administered.

43) A further embodiment of the invention relates to any one of embodiments 1) to 42), wherein the activated charcoal is in essentially pure form.

44) A further embodiment of the invention relates to any one of embodiments 1) to 42), wherein the activated charcoal is in form of a composition or is used as a composition, the composition comprising at least 40 %w/w (preferably at least 60 %w/w, and most preferably at least 80 %w/w) activated charcoal and at least one excipient.

45) A further embodiment of the invention relates to any one of embodiments 1) to 42), wherein the activated charcoal is in form of a composition or is used as a composition, the composition comprising at least 40 %w/w (preferably at least 60 %w/w, and most preferably at least 80 %w/w) activated charcoal, a C_3-6-polyol selected from glycerol (1 ,2,3- propanetriol) and sorbitol and optionally additional excipients.

The term “optionally” means that the composition may comprise only activated charcoal and a C_3-6-polyol, or may comprise activated charcoal, a C_3.6-polyol and one or more (up to a maximum of 10, preferably up to a maximum of 6, and more preferably up to a maximum of 3) additional excipients.

46) A further embodiment of the invention relates to any one of embodiments 1) to 45), wherein the activated charcoal is to be administered at least once per day for a period between 2 and 24 days (preferably between 6 and 15 days and more preferably between 9 and 12 days).

47) A further embodiment of the invention relates to any one of embodiments 1) to 46), wherein the activated charcoal is to be administered between one and six times per day (preferably between one and three times per day and more preferably two or three times per day). 48) A further embodiment of the invention relates to any one of embodiments 1) to 47), wherein the amount of activated charcoal to be administered is between 1 g and 100 g activated charcoal per administration (preferably between 25 g and 75 g and more preferably between 40 g and 60 g).

It is to be understood that the above “amount of activated charcoal” refers to the actual amount of activated charcoal present in the respective composition without considering the amounts of excipients in the composition.

49) A further embodiment of the invention relates to any one of embodiments 1) to 48), wherein the activated charcoal is used as a powder or as granules.

50) A further embodiment of the invention relates to any one of embodiments 1) to 49), wherein the activated charcoal is to be administered orally as a suspension in water or in a water-based liquid.

The term “water-based liquid” refers to a liquid comprising at least 80 %w/w (preferably at least 90 %w/w) water and taste-modifying ingredients. Examples are juices, such as fruit juices, soft dinks and other beverages.

51) A further embodiment of the invention relates to any one of embodiments 1) to 49), wherein the activated charcoal is to be administered orally as a suspension in water.

52) A further embodiment of the invention relates to any one of embodiments 1) to 51), wherein the treatment of the subject with COMPOUND, or a pharmaceutically acceptable salt thereof, is to be discontinued after the first administration of activated charcoal to the subject.

It is preferred that the subject receives the last administration of COMPOUND, or of a pharmaceutically acceptable salt thereof, less than 24 h (preferably less than 12 h) before a first administration of activated charcoal and that the subject receives no further administration of COMPOUND, or of a pharmaceutically acceptable salt thereof, after a first administration of activated charcoal.

It is further preferred that a treatment of the subject with COMPOUND, or a pharmaceutically acceptable salt thereof, is not resumed before the cause for an accelerated elimination procedure is resolved.

53) A further embodiment of the invention relates to any one of embodiments 1) to 52), wherein the time required to reduce the concentration of COMPOUND in blood plasma of a subject by 90% relative to the concentration of COMPOUND five hours after the last administration of COMPOUND, or of a pharmaceutically acceptable salt thereof, is reduced by at least 10% due to administration of activated charcoal.

54) A further embodiment of the invention relates to any one of embodiments 1) to 52), wherein the time required to reduce the concentration of COMPOUND in blood plasma of a subject by 90% relative to the concentration of COMPOUND five hours after the last administration of COMPOUND, or of a pharmaceutically acceptable salt thereof, is reduced by at least 50% due to administration of activated charcoal.

55) A further embodiment of the invention relates to any one of embodiments 1) to 52), wherein the time required to reduce the concentration of COMPOUND in blood plasma of a subject by 90% relative to the concentration of COMPOUND five hours after the last administration of COMPOUND, or of a pharmaceutically acceptable salt thereof, is reduced by at least 80% due to administration of activated charcoal.

56) A further embodiment of the invention relates to any one of embodiments 1) to 52), wherein the time required to reduce the concentration of COMPOUND in blood plasma of a subject by 95% relative to the concentration of COMPOUND five hours after the last administration of COMPOUND, or of a pharmaceutically acceptable salt thereof, is reduced by at least 50% due to administration of activated charcoal.

57) A further embodiment of the invention relates to any one of embodiments 1) to 52), wherein the time required to reduce the concentration of COMPOUND in blood plasma of a subject by 95% relative to the concentration of COMPOUND five hours after the last administration of COMPOUND, or of a pharmaceutically acceptable salt thereof, is reduced by at least 80% due to administration of activated charcoal.

58) A further embodiment of the invention relates to any one of embodiments 1) to 52), wherein the time required to reduce the concentration of COMPOUND in blood plasma of a subject by 98% relative to the concentration of COMPOUND five hours after the last administration of COMPOUND, or of a pharmaceutically acceptable salt thereof, is reduced by at least 50% due to administration of activated charcoal.

59) A further embodiment of the invention relates to any one of embodiments 1) to 52), wherein the time required to reduce the concentration of COMPOUND in blood plasma of a subject by 98% relative to the concentration of COMPOUND five hours after the last administration of COMPOUND, or of a pharmaceutically acceptable salt thereof, is reduced by at least 80% due to administration of activated charcoal.

60) A further embodiment of the invention relates to any one of embodiments 1) to 7), 15) to 28) and 43) to 59), wherein the elimination of COMPOUND from the body of the subject is accelerated.

61) A further embodiment of the invention relates to any one of embodiments 1) to 60), wherein the subject is a mammal.

62) A further embodiment of the invention relates to any one of embodiments 1) to 60), wherein the subject is a human.

63) A further embodiment of the invention relates to any one of embodiments 1) to 62), wherein the subject is a patient (notably a human patient).

64) A further embodiment of the invention relates to any one of embodiments 1) to 63), wherein the subject is a subject (especially a human and notably a human patient) in need of an accelerated elimination of COMPOUND.

65) A further embodiment of the invention relates to any one of embodiments 1) to 63), wherein the subject is a subject (especially a human and notably a human patient) in need of an accelerated increase of the lymphocyte count in the blood (notably the peripheral blood) of the subject.

66) A further embodiment of the invention relates to any one of embodiments 22) to 28) and 36) to 65), wherein the disease or disorder is selected from the group consisting of multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus.

67) A further embodiment of the invention relates to any one of embodiments 22) to 28) and 36) to 65), wherein the disease or disorder is systemic lupus erythematosus.

68) A further embodiment of the invention relates to any one of embodiments 1) to 67), wherein a 20% increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND is reached faster with than without administration of activated charcoal to the subject.

69) A further embodiment of the invention relates to any one of embodiments 1) to 67), wherein a 40% increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND is reached faster with than without administration of activated charcoal to the subject.

70) A further embodiment of the invention relates to any one of embodiments 1) to 67), wherein a 60% increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND is reached faster with than without administration of activated charcoal to the subject.

71) A further embodiment of the invention relates to any one of embodiments 68) to 70), wherein the increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND is reached at least two times faster with than without administration of activated charcoal to the subject.

72) A further embodiment of the invention relates to any one of embodiments 68) to 70), wherein the increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND is reached at least three times faster with than without administration of activated charcoal to the subject.

73) A further embodiment of the invention relates to any one of embodiments 68) to 70), wherein the increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject after discontinuation of the treatment of the subject with COMPOUND is reached at least four times faster with than without administration of activated charcoal to the subject.

Based on the dependencies of the different embodiments 1) to 73) as disclosed hereinabove, the following embodiments are thus especially intended and herewith specifically disclosed in individualised form:

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43+1, 43+2, 43+5, 43+8, 43+9, 43+12, 43+15, 43+16, 43+19, 43+22, 43+23, 43+26, 43+29, 43+30, 43+33, 43+36, 43+37, 43+40, 44+1, 44+2, 44+5, 44+8, 44+9, 44+12, 44+15, 44+16, 44+19, 44+22, 44+23, 44+26, 44+29, 44+30, 44+33, 44+36, 44+37, 44+40, 46+1, 46+2, 46+5, 46+8, 46+9, 46+12, 46+15, 46+16, 46+19, 46+22, 46+23, 46+26, 46+29, 46+30, 46+33, 46+36, 46+37, 46+40, 46+43+1, 46+43+2, 46+43+5, 46+43+8, 46+43+9, 46+43+12, 46+43+15, 46+43+16, 46+43+19, 46+43+22, 46+43+23, 46+43+26, 46+43+29, 46+43+30, 46+43+33, 46+43+36, 46+43+37, 46+43+40, 46+44+1, 46+44+2, 46+44+5, 46+44+8, 46+44+9, 46+44+12, 46+44+15, 46+44+16, 46+44+19, 46+44+22, 46+44+23, 46+44+26, 46+44+29, 46+44+30, 46+44+33, 46+44+36, 46+44+37, 46+44+40, 47+1, 47+2, 47+5, 47+8, 47+9, 47+12, 47+15, 47+16, 47+19, 47+22, 47+23, 47+26, 47+29, 47+30, 47+33, 47+36, 47+37, 47+40, 47+43+1, 47+43+2, 47+43+5, 47+43+8, 47+43+9, 47+43+12, 47+43+15, 47+43+16, 47+43+19, 47+43+22, 47+43+23, 47+43+26, 47+43+29, 47+43+30, 47+43+33, 47+43+36, 47+43+37, 47+43+40, 47+44+1, 47+44+2, 47+44+5, 47+44+8, 47+44+9, 47+44+12, 47+44+15, 47+44+16, 47+44+19, 47+44+22, 47+44+23, 47+44+26, 47+44+29, 47+44+30, 47+44+33, 47+44+36, 47+44+37, 47+44+40, 47+46+1, 47+46+2, 47+46+5, 47+46+8, 47+46+9, 47+46+12, 47+46+15, 47+46+16, 47+46+19, 47+46+22, 47+46+23, 47+46+26, 47+46+29, 47+46+30, 47+46+33, 47+46+36, 47+46+37, 47+46+40, 47+46+43+1, 47+46+43+2, 47+46+43+5, 47+46+43+8, 47+46+43+9, 47+46+43+12, 47+46+43+15, 47+46+43+16, 47+46+43+19, 47+46+43+22, 47+46+43+23, 47+46+43+26, 47+46+43+29, 47+46+43+30, 47+46+43+33, 47+46+43+36, 47+46+43+37, 47+46+43+40, 47+46+44+1, 47+46+44+2, 47+46+44+5, 47+46+44+8, 47+46+44+9, 47+46+44+12, 47+46+44+15, 47+46+44+16, 47+46+44+19, 47+46+44+22, 47+46+44+23, 47+46+44+26, 47+46+44+29, 47+46+44+30, 47+46+44+33, 47+46+44+36, 47+46+44+37, 47+46+44+40, 48+1, 48+2, 48+5, 48+8, 48+9, 48+12, 48+15, 48+16, 48+19, 48+22, 48+23, 48+26, 48+29, 48+30, 48+33, 48+36, 48+37, 48+40, 48+43+1, 48+43+2, 48+43+5, 48+43+8, 48+43+9, 48+43+12, 48+43+15, 48+43+16, 48+43+19, 48+43+22, 48+43+23, 48+43+26, 48+43+29, 48+43+30, 48+43+33, 48+43+36, 48+43+37, 48+43+40, 48+44+1, 48+44+2, 48+44+5, 48+44+8, 48+44+9, 48+44+12, 48+44+15, 48+44+16, 48+44+19, 48+44+22, 48+44+23, 48+44+26, 48+44+29, 48+44+30, 48+44+33, 48+44+36, 48+44+37, 48+44+40, 48+46+1, 48+46+2, 48+46+5, 48+46+8, 48+46+9, 48+46+12, 48+46+15, 48+46+16, 48+46+19, 48+46+22, 48+46+23, 48+46+26, 48+46+29, 48+46+30, 48+46+33, 48+46+36, 48+46+37, 48+46+40, 48+46+43+1, 48+46+43+2, 48+46+43+5, 48+46+43+8,

48+46+43+9, 48+46+43+12, 48+46+43+15, 48+46+43+16, 48+46+43+19, 48+46+43+22, 48+46+43+23, 48+46+43+26, 48+46+43+29, 48+46+43+30, 48+46+43+33, 48+46+43+36, 48+46+43+37, 48+46+43+40, 48+46+44+1, 48+46+44+2, 48+46+44+5, 48+46+44+8, 48+46+44+9, 48+46+44+12, 48+46+44+15, 48+46+44+16, 48+46+44+19, 48+46+44+22, 48+46+44+23, 48+46+44+26, 48+46+44+29, 48+46+44+30, 48+46+44+33, 48+46+44+36, 48+46+44+37, 48+46+44+40, 48+47+1, 48+47+2, 48+47+5, 48+47+8, 48+47+9, 48+47+12, 48+47+15, 48+47+16, 48+47+19, 48+47+22, 48+47+23, 48+47+26, 48+47+29, 48+47+30, 48+47+33, 48+47+36, 48+47+37, 48+47+40, 48+47+43+1, 48+47+43+2, 48+47+43+5, 48+47+43+8,

48+47+43+9, 48+47+43+12, 48+47+43+15, 48+47+43+16, 48+47+43+19, 48+47+43+22, 48+47+43+23, 48+47+43+26, 48+47+43+29, 48+47+43+30, 48+47+43+33, 48+47+43+36, 48+47+43+37, 48+47+43+40, 48+47+44+1, 48+47+44+2, 48+47+44+5, 48+47+44+8, 48+47+44+9, 48+47+44+12, 48+47+44+15, 48+47+44+16, 48+47+44+19, 48+47+44+22, 48+47+44+23, 48+47+44+26, 48+47+44+29, 48+47+44+30, 48+47+44+33, 48+47+44+36, 48+47+44+37, 48+47+44+40, 48+47+46+1, 48+47+46+2, 48+47+46+5, 48+47+46+8, 48+47+46+9, 48+47+46+12, 48+47+46+15, 48+47+46+16, 48+47+46+19, 48+47+46+22, 48+47+46+23, 48+47+46+26, 48+47+46+29, 48+47+46+30, 48+47+46+33, 48+47+46+36, 48+47+46+37, 48+47+46+40, 48+47+46+43+1, 48+47+46+43+2, 48+47+46+43+5, 48+47+46+43+8, 48+47+46+43+9, 48+47+46+43+12, 48+47+46+43+15, 48+47+46+43+16, 48+47+46+43+19, 48+47+46+43+22, 48+47+46+43+ 23, 48+47+46+43+26, 48+47+46+43+29, 48+47+46+43+30, 48+47+46+43+33, 48+47+46+43+36, 48+47+46+ 43+37, 48+47+46+43+40, 48+47+46+44+1, 48+47+46+44+2, 48+47+46+44+5, 48+47+46+44+8, 48+47+46+ 44+9, 48+47+46+44+12, 48+47+46+44+15, 48+47+46+44+16, 48+47+46+44+19, 48+47+46+44+22, 48+47+ 46+44+23, 48+47+46+44+26, 48+47+46+44+29, 48+47+46+44+30, 48+47+46+44+33, 48+47+46+44+36, 48+47+46+44+37, 48+47+46+44+40, 51+1, 51+2, 51+5, 51+8, 51+9, 51+12, 51+15, 51+16, 51+19, 51+22, 51+23, 51+26, 51+29, 51+30, 51+33, 51+36, 51+37, 51+40, 51+43+1, 51+43+2, 51+43+5, 51+43+8, 51+43+9, 51+43+12, 51+43+15, 51+43+16, 51+43+19, 51+43+22, 51+43+23, 51+43+26, 51+43+29, 51+43+30,

51+43+33, 51+43+36, 51+43+37, 51+43+40, 51+44+1, 51+44+2, 51+44+5, 51+44+8, 51+44+9, 51+44+12, 51+44+15, 51+44+16, 51+44+19, 51+44+22, 51+44+23, 51+44+26, 51+44+29, 51+44+30, 51+44+33,

51+44+36, 51+44+37, 51+44+40, 51+46+1, 51+46+2, 51+46+5, 51+46+8, 51+46+9, 51+46+12, 51+46+15, 51+46+16, 51+46+19, 51+46+22, 51+46+23, 51+46+26, 51+46+29, 51+46+30, 51+46+33, 51+46+36,

51+46+37, 51+46+40, 51+46+43+1, 51+46+43+2, 51+46+43+5, 51+46+43+8, 51+46+43+9, 51+46+43+12, 51+46+43+15, 51+46+43+16, 51+46+43+19, 51+46+43+22, 51+46+43+23, 51+46+43+26, 51+46+43+29, 51+46+43+30, 51+46+43+33, 51+46+43+36, 51+46+43+37, 51+46+43+40, 51+46+44+1, 51+46+44+2,

51+46+44+5, 51+46+44+8, 51+46+44+9, 51+46+44+12, 51+46+44+15, 51+46+44+16, 51+46+44+19,

51+46+44+22, 51+46+44+23, 51+46+44+26, 51+46+44+29, 51+46+44+30, 51+46+44+33, 51+46+44+36, 51+46+44+37, 51+46+44+40, 51+47+1, 51+47+2, 51+47+5, 51+47+8, 51+47+9, 51+47+12, 51+47+15, 51+47+16, 51+47+19, 51+47+22, 51+47+23, 51+47+26, 51+47+29, 51+47+30, 51+47+33, 51+47+36,

51+47+37, 51+47+40, 51+47+43+1, 51+47+43+2, 51+47+43+5, 51+47+43+8, 51+47+43+9, 51+47+43+12, 51+47+43+15, 51+47+43+16, 51+47+43+19, 51+47+43+22, 51+47+43+23, 51+47+43+26, 51+47+43+29, 51+47+43+30, 51+47+43+33, 51+47+43+36, 51+47+43+37, 51+47+43+40, 51+47+44+1, 51+47+44+2,

51+47+44+5, 51+47+44+8, 51+47+44+9, 51+47+44+12, 51+47+44+15, 51+47+44+16, 51+47+44+19,

51+47+44+22, 51+47+44+23, 51+47+44+26, 51+47+44+29, 51+47+44+30, 51+47+44+33, 51+47+44+36, 51+47+44+37, 51+47+44+40, 51+47+46+1, 51+47+46+2, 51+47+46+5, 51+47+46+8, 51+47+46+9,

51+47+46+12, 51+47+46+15, 51+47+46+16, 51+47+46+19, 51+47+46+22, 51+47+46+23, 51+47+46+26, 51+47+46+29, 51+47+46+30, 51+47+46+33, 51+47+46+36, 51+47+46+37, 51+47+46+40, 51+47+46+43+1, 51+47+46+43+2, 51+47+46+43+5, 51+47+46+43+8, 51+47+46+43+9, 51+47+46+43+12, 51+47+46+43+15, 51+47+46+43+16, 51+47+46+43+19, 51+47+46+43+22, 51+47+46+43+23, 51+47+46+43+26, 51+47+46+43+ 29, 51+47+46+43+30, 51+47+46+43+33, 51+47+46+43+36, 51+47+46+43+37, 51+47+46+43+40, 51+47+46+ 44+1, 51+47+46+44+2, 51+47+46+44+5, 51+47+46+44+8, 51+47+46+44+9, 51+47+46+44+12, 51+47+46+ 44+15, 51+47+46+44+16, 51+47+46+44+19, 51+47+46+44+22, 51+47+46+44+23, 51+47+46+44+26, 51+47+ 46+44+29, 51+47+46+44+30, 51+47+46+44+33, 51+47+46+44+36, 51+47+46+44+37, 51+47+46+44+40, 51+48+1, 51+48+2, 51+48+5, 51+48+8, 51+48+9, 51+48+12, 51+48+15, 51+48+16, 51+48+19, 51+48+22, 51+48+23, 51+48+26, 51+48+29, 51+48+30, 51+48+33, 51+48+36, 51+48+37, 51+48+40, 51+48+43+1, 51+48+43+2, 51+48+43+5, 51+48+43+8, 51+48+43+9, 51+48+43+12, 51+48+43+15, 51+48+43+16, 51+48+43+19, 51+48+43+22, 51+48+43+23, 51+48+43+26, 51+48+43+29, 51+48+43+30, 51+48+43+33, 51+48+43+36, 51+48+43+37, 51+48+43+40, 51+48+44+1, 51+48+44+2, 51+48+44+5, 51+48+44+8, 51+48+44+9, 51+48+44+12, 51+48+44+15, 51+48+44+16, 51+48+44+19, 51+48+44+22, 51+48+44+23, 51+48+44+26, 51+48+44+29, 51+48+44+30, 51+48+44+33, 51+48+44+36, 51+48+44+37, 51+48+44+40, 51+48+46+1, 51+48+46+2, 51+48+46+5, 51+48+46+8, 51+48+46+9, 51+48+46+12, 51+48+46+15, 51+48+46+16, 51+48+46+19, 51+48+46+22, 51+48+46+23, 51+48+46+26, 51+48+46+29, 51+48+46+30, 51+48+46+33, 51+48+46+36, 51+48+46+37, 51+48+46+40, 51+48+46+43+1, 51+48+46+43+2,

51+48+46+43+5, 51+48+46+43+8, 51+48+46+43+9, 51+48+46+43+12, 51+48+46+43+15, 51+48+46+43+16, 51+48+46+43+19, 51+48+46+43+22, 51+48+46+43+23, 51+48+46+43+26, 51+48+46+43+29, 51+48+46+ 43+30, 51+48+46+43+33, 51+48+46+43+36, 51+48+46+43+37, 51+48+46+43+40, 51+48+46+44+1, 51+48+ 46+44+2, 51+48+46+44+5, 51+48+46+44+8, 51+48+46+44+9, 51+48+46+44+12, 51+48+46+44+15, 51+48+ 46+44+16, 51+48+46+44+19, 51+48+46+44+22, 51+48+46+44+23, 51+48+46+44+26, 51+48+46+44+29, 51+48+46+44+30, 51+48+46+44+33, 51+48+46+44+36, 51+48+46+44+37, 51+48+46+44+40, 51+48+47+1, 51+48+47+2, 51+48+47+5, 51+48+47+8, 51+48+47+9, 51+48+47+12, 51+48+47+15, 51+48+47+16, 51+48+47+19, 51+48+47+22, 51+48+47+23, 51+48+47+26, 51+48+47+29, 51+48+47+30, 51+48+47+33, 51+48+47+36, 51+48+47+37, 51+48+47+40, 51+48+47+43+1, 51+48+47+43+2, 51+48+47+43+5, 51+48+ 47+43+8, 51+48+47+43+9, 51+48+47+43+12, 51+48+47+43+15, 51+48+47+43+16, 51+48+47+43+19, 51 + 48+47+43+22, 51+48+47+43+23, 51+48+47+43+26, 51+48+47+43+29, 51+48+47+43+30, 51+48+47+43+33, 51+48+47+43+36, 51+48+47+43+37, 51+48+47+43+40, 51+48+47+44+1, 51+48+47+44+2, 51+48+47+44+5, 51+48+47+44+8, 51+48+47+44+9, 51+48+47+44+12, 51+48+47+44+15, 51+48+47+44+16, 51+48+47+44+19, 51+48+47+44+22, 51+48+47+44+23, 51+48+47+44+26, 51+48+47+44+29, 51+48+47+44+30, 51+48+47+ 44+33, 51+48+47+44+36, 51+48+47+44+37, 51+48+47+44+40, 51+48+47+46+1, 51+48+47+46+2,

51+48+47+46+5, 51+48+47+46+8, 51+48+47+46+9, 51+48+47+46+12, 51+48+47+46+15, 51+48+47+46+16, 51+48+47+46+19, 51+48+47+46+22, 51+48+47+46+23, 51+48+47+46+26, 51+48+47+46+29, 51+48+47+ 46+30, 51+48+47+46+33, 51+48+47+46+36, 51+48+47+46+37, 51+48+47+46+40, 51+48+47+46+43+1, 51+48+47+46+43+2, 51+48+47+46+43+5, 51+48+47+46+43+8, 51+48+47+46+43+9, 51+48+47+46+43+12, 51+48+47+46+43+15, 51+48+47+46+43+16, 51+48+47+46+43+19, 51+48+47+46+43+22, 51+48+47+46+ 43+23, 51+48+47+46+43+26, 51+48+47+46+43+29, 51+48+47+46+43+30, 51+48+47+46+43+33, 51+48+47+ 46+43+36, 51+48+47+46+43+37, 51+48+47+46+43+40, 51+48+47+46+44+1, 51+48+47+46+44+2, 51+48+ 47+46+44+5, 51+48+47+46+44+8, 51+48+47+46+44+9, 51+48+47+46+44+12, 51+48+47+46+44+15, 51+48+ 47+46+44+16, 51+48+47+46+44+19, 51+48+47+46+44+22, 51+48+47+46+44+23, 51+48+47+46+44+26, 51 + 48+47+46+44+29, 51+48+47+46+44+30, 51+48+47+46+44+33, 51+48+47+46+44+36, 51+48+47+46+44+37, 51+48+47+46+44+40, 52+1, 52+2, 52+5, 52+8, 52+9, 52+12, 52+15, 52+16, 52+19, 52+22, 52+23, 52+26, 52+29, 52+30, 52+33, 52+36, 52+37, 52+40, 52+43+1, 52+43+2, 52+43+5, 52+43+8, 52+43+9, 52+43+12, 52+43+15, 52+43+16, 52+43+19, 52+43+22, 52+43+23, 52+43+26, 52+43+29, 52+43+30, 52+43+33,

52+43+36, 52+43+37, 52+43+40, 52+44+1, 52+44+2, 52+44+5, 52+44+8, 52+44+9, 52+44+12, 52+44+15, 52+44+16, 52+44+19, 52+44+22, 52+44+23, 52+44+26, 52+44+29, 52+44+30, 52+44+33, 52+44+36,

52+44+37, 52+44+40, 52+46+1, 52+46+2, 52+46+5, 52+46+8, 52+46+9, 52+46+12, 52+46+15, 52+46+16, 52+46+19, 52+46+22, 52+46+23, 52+46+26, 52+46+29, 52+46+30, 52+46+33, 52+46+36, 52+46+37,

52+46+40, 52+46+43+1, 52+46+43+2, 52+46+43+5, 52+46+43+8, 52+46+43+9, 52+46+43+12, 52+46+43+15, 52+46+43+16, 52+46+43+19, 52+46+43+22, 52+46+43+23, 52+46+43+26, 52+46+43+29, 52+46+43+30, 52+46+43+33, 52+46+43+36, 52+46+43+37, 52+46+43+40, 52+46+44+1, 52+46+44+2, 52+46+44+5,

52+46+44+8, 52+46+44+9, 52+46+44+12, 52+46+44+15, 52+46+44+16, 52+46+44+19, 52+46+44+22, 52+46+44+23, 52+46+44+26, 52+46+44+29, 52+46+44+30, 52+46+44+33, 52+46+44+36, 52+46+44+37, 52+46+44+40, 52+47+1, 52+47+2, 52+47+5, 52+47+8, 52+47+9, 52+47+12, 52+47+15, 52+47+16, 52+47+19, 52+47+22, 52+47+23, 52+47+26, 52+47+29, 52+47+30, 52+47+33, 52+47+36, 52+47+37, 52+47+40,

52+47+43+1, 52+47+43+2, 52+47+43+5, 52+47+43+8, 52+47+43+9, 52+47+43+12, 52+47+43+15, 52+47+43+16, 52+47+43+19, 52+47+43+22, 52+47+43+23, 52+47+43+26, 52+47+43+29, 52+47+43+30, 52+47+43+33, 52+47+43+36, 52+47+43+37, 52+47+43+40, 52+47+44+1, 52+47+44+2, 52+47+44+5,

52+47+44+8, 52+47+44+9, 52+47+44+12, 52+47+44+15, 52+47+44+16, 52+47+44+19, 52+47+44+22, 52+47+44+23, 52+47+44+26, 52+47+44+29, 52+47+44+30, 52+47+44+33, 52+47+44+36, 52+47+44+37, 52+47+44+40, 52+47+46+1, 52+47+46+2, 52+47+46+5, 52+47+46+8, 52+47+46+9, 52+47+46+12, 52+47+46+15, 52+47+46+16, 52+47+46+19, 52+47+46+22, 52+47+46+23, 52+47+46+26, 52+47+46+29, 52+47+46+30, 52+47+46+33, 52+47+46+36, 52+47+46+37, 52+47+46+40, 52+47+46+43+1, 52+47+46+43+2, 52+47+46+43+5, 52+47+46+43+8, 52+47+46+43+9, 52+47+46+43+12, 52+47+46+43+15, 52+47+46+43+16, 52+47+46+43+19, 52+47+46+43+22, 52+47+46+43+23, 52+47+46+43+26, 52+47+46+43+29, 52+47+46+ 43+30, 52+47+46+43+33, 52+47+46+43+36, 52+47+46+43+37, 52+47+46+43+40, 52+47+46+44+1, 52+47+ 46+44+2, 52+47+46+44+5, 52+47+46+44+8, 52+47+46+44+9, 52+47+46+44+12, 52+47+46+44+15, 52+47+ 46+44+16, 52+47+46+44+19, 52+47+46+44+22, 52+47+46+44+23, 52+47+46+44+26, 52+47+46+44+29, 52+47+46+44+30, 52+47+46+44+33, 52+47+46+44+36, 52+47+46+44+37, 52+47+46+44+40, 52+48+1, 52+48+2, 52+48+5, 52+48+8, 52+48+9, 52+48+12, 52+48+15, 52+48+16, 52+48+19, 52+48+22, 52+48+23, 52+48+26, 52+48+29, 52+48+30, 52+48+33, 52+48+36, 52+48+37, 52+48+40, 52+48+43+1, 52+48+43+2, 52+48+43+5, 52+48+43+8, 52+48+43+9, 52+48+43+12, 52+48+43+15, 52+48+43+16, 52+48+43+19, 52+48+43+22, 52+48+43+23, 52+48+43+26, 52+48+43+29, 52+48+43+30, 52+48+43+33, 52+48+43+36, 52+48+43+37, 52+48+43+40, 52+48+44+1, 52+48+44+2, 52+48+44+5, 52+48+44+8, 52+48+44+9, 52+48+44+12, 52+48+44+15, 52+48+44+16, 52+48+44+19, 52+48+44+22, 52+48+44+23, 52+48+44+26, 52+48+44+29, 52+48+44+30, 52+48+44+33, 52+48+44+36, 52+48+44+37, 52+48+44+40, 52+48+46+1, 52+48+46+2, 52+48+46+5, 52+48+46+8, 52+48+46+9, 52+48+46+12, 52+48+46+15, 52+48+46+16, 52+48+46+19, 52+48+46+22, 52+48+46+23, 52+48+46+26, 52+48+46+29, 52+48+46+30, 52+48+46+33, 52+48+46+36, 52+48+46+37, 52+48+46+40, 52+48+46+43+1, 52+48+46+43+2, 52+48+46+43+5,

52+48+46+43+8, 52+48+46+43+9, 52+48+46+43+12, 52+48+46+43+15, 52+48+46+43+16, 52+48+46+43+19, 52+48+46+43+22, 52+48+46+43+23, 52+48+46+43+26, 52+48+46+43+29, 52+48+46+43+30,

52+48+46+43+33, 52+48+46+43+36, 52+48+46+43+37, 52+48+46+43+40, 52+48+46+44+1, 52+48+46+44+2, 52+48+46+44+5, 52+48+46+44+8, 52+48+46+44+9, 52+48+46+44+12, 52+48+46+44+15, 52+48+46+44+16, 52+48+46+44+19, 52+48+46+44+22, 52+48+46+44+23, 52+48+46+44+26, 52+48+46+44+29, 52+48+46+ 44+30, 52+48+46+44+33, 52+48+46+44+36, 52+48+46+44+37, 52+48+46+44+40, 52+48+47+1, 52+48+47+2, 52+48+47+5, 52+48+47+8, 52+48+47+9, 52+48+47+12, 52+48+47+15, 52+48+47+16, 52+48+47+19, 52+48+ 47+22, 52+48+47+23, 52+48+47+26, 52+48+47+29, 52+48+47+30, 52+48+47+33, 52+48+47+36, 52+48+ 47+37, 52+48+47+40, 52+48+47+43+1, 52+48+47+43+2, 52+48+47+43+5, 52+48+47+43+8, 52+48+47+43+9, 52+48+47+43+12, 52+48+47+43+15, 52+48+47+43+16, 52+48+47+43+19, 52+48+47+43+22, 52+48+47+ 43+23, 52+48+47+43+26, 52+48+47+43+29, 52+48+47+43+30, 52+48+47+43+33, 52+48+47+43+36,

52+48+47+43+37, 52+48+47+43+40, 52+48+47+44+1, 52+48+47+44+2, 52+48+47+44+5, 52+48+47+44+8, 52+48+47+44+9, 52+48+47+44+12, 52+48+47+44+15, 52+48+47+44+16, 52+48+47+44+19, 52+48+47+ 44+22, 52+48+47+44+23, 52+48+47+44+26, 52+48+47+44+29, 52+48+47+44+30, 52+48+47+44+33,

52+48+47+44+36, 52+48+47+44+37, 52+48+47+44+40, 52+48+47+46+1, 52+48+47+46+2, 52+48+47+46+5, 52+48+47+46+8, 52+48+47+46+9, 52+48+47+46+12, 52+48+47+46+15, 52+48+47+46+16, 52+48+47+46+19, 52+48+47+46+22, 52+48+47+46+23, 52+48+47+46+26, 52+48+47+46+29, 52+48+47+46+30, 52+48+47+ 46+33, 52+48+47+46+36, 52+48+47+46+37, 52+48+47+46+40, 52+48+47+46+43+1, 52+48+47+46+43+2, 52+48+47+46+43+5, 52+48+47+46+43+8, 52+48+47+46+43+9, 52+48+47+46+43+12, 52+48+47+46+43+15, 52+48+47+46+43+16, 52+48+47+46+43+19, 52+48+47+46+43+22, 52+48+47+46+43+23, 52+48+47+46+43+ 26, 52+48+47+46+43+29, 52+48+47+46+43+30, 52+48+47+46+43+33, 52+48+47+46+43+36, 52+48+47+46+ 43+37, 52+48+47+46+43+40, 52+48+47+46+44+1, 52+48+47+46+44+2, 52+48+47+46+44+5, 52+48+47+46+ 44+8, 52+48+47+46+44+9, 52+48+47+46+44+12, 52+48+47+46+44+15, 52+48+47+46+44+16, 52+48+47+ 46+44+19, 52+48+47+46+44+22, 52+48+47+46+44+23, 52+48+47+46+44+26, 52+48+47+46+44+29, 52+48+ 47+46+44+30, 52+48+47+46+44+33, 52+48+47+46+44+36, 52+48+47+46+44+37, 52+48+47+46+44+40, 52+51+1, 52+51+2, 52+51+5, 52+51+8, 52+51+9, 52+51+12, 52+51+15, 52+51+16, 52+51+19, 52+51+22, 52+51+23, 52+51+26, 52+51+29, 52+51+30, 52+51+33, 52+51+36, 52+51+37, 52+51+40, 52+51+43+1, 52+51+43+2, 52+51+43+5, 52+51+43+8, 52+51+43+9, 52+51+43+12, 52+51+43+15, 52+51+43+16, 52+51+43+19, 52+51+43+22, 52+51+43+23, 52+51+43+26, 52+51+43+29, 52+51+43+30, 52+51+43+33, 52+51+43+36, 52+51+43+37, 52+51+43+40, 52+51+44+1, 52+51+44+2, 52+51+44+5, 52+51+44+8, 52+51+44+9, 52+51+44+12, 52+51+44+15, 52+51+44+16, 52+51+44+19, 52+51+44+22, 52+51+44+23, 52+51+44+26, 52+51+44+29, 52+51+44+30, 52+51+44+33, 52+51+44+36, 52+51+44+37, 52+51+44+40, 52+51+46+1, 52+51+46+2, 52+51+46+5, 52+51+46+8, 52+51+46+9, 52+51+46+12, 52+51+46+15, 52+51+46+16, 52+51+46+19, 52+51+46+22, 52+51+46+23, 52+51+46+26, 52+51+46+29, 52+51+46+30, 52+51+46+33, 52+51+46+36, 52+51+46+37, 52+51+46+40, 52+51+46+43+1, 52+51+46+43+2, 52+51+46+ 43+5, 52+51+46+43+8, 52+51+46+43+9, 52+51+46+43+12, 52+51+46+43+15, 52+51+46+43+16, 52+51+46+ 43+19, 52+51+46+43+22, 52+51+46+43+23, 52+51+46+43+26, 52+51+46+43+29, 52+51+46+43+30, 52+51 + 46+43+33, 52+51+46+43+36, 52+51+46+43+37, 52+51+46+43+40, 52+51+46+44+1, 52+51+46+44+2, 52+51+46+44+5, 52+51+46+44+8, 52+51+46+44+9, 52+51+46+44+12, 52+51+46+44+15, 52+51+46+44+16, 52+51+46+44+19, 52+51+46+44+22, 52+51+46+44+23, 52+51+46+44+26, 52+51+46+44+29,

52+51+46+44+30, 52+51+46+44+33, 52+51+46+44+36, 52+51+46+44+37, 52+51+46+44+40, 52+51+47+1, 52+51+47+2, 52+51+47+5, 52+51+47+8, 52+51+47+9, 52+51+47+12, 52+51+47+15, 52+51+47+16, 52+51+47+19, 52+51+47+22, 52+51+47+23, 52+51+47+26, 52+51+47+29, 52+51+47+30, 52+51+47+33, 52+51+47+36, 52+51+47+37, 52+51+47+40, 52+51+47+43+1, 52+51+47+43+2, 52+51+47+43+5, 52+51 + 47+43+8, 52+51+47+43+9, 52+51+47+43+12, 52+51+47+43+15, 52+51+47+43+16, 52+51+47+43+19, 52+51+47+43+22, 52+51+47+43+23, 52+51+47+43+26, 52+51+47+43+29, 52+51+47+43+30, 52+51+47+ 43+33, 52+51+47+43+36, 52+51+47+43+37, 52+51+47+43+40, 52+51+47+44+1, 52+51+47+44+2, 52+51 + 47+44+5, 52+51+47+44+8, 52+51+47+44+9, 52+51+47+44+12, 52+51+47+44+15, 52+51+47+44+16, 52+51 + 47+44+19, 52+51+47+44+22, 52+51+47+44+23, 52+51+47+44+26, 52+51+47+44+29, 52+51+47+44+30, 52+51+47+44+33, 52+51+47+44+36, 52+51+47+44+37, 52+51+47+44+40, 52+51+47+46+1, 52+51+47+46+2, 52+51+47+46+5, 52+51+47+46+8, 52+51+47+46+9, 52+51+47+46+12, 52+51+47+46+15, 52+51+47+46+16, 52+51+47+46+19, 52+51+47+46+22, 52+51+47+46+23, 52+51+47+46+26, 52+51+47+46+29, 52+51+47+ 46+30, 52+51+47+46+33, 52+51+47+46+36, 52+51+47+46+37, 52+51+47+46+40, 52+51+47+46+43+1, 52+51+47+46+43+2, 52+51+47+46+43+5, 52+51+47+46+43+8, 52+51+47+46+43+9, 52+51+47+46+43+12, 52+51+47+46+43+15, 52+51+47+46+43+16, 52+51+47+46+43+19, 52+51+47+46+43+22, 52+51+47+46+ 43+23, 52+51+47+46+43+26, 52+51+47+46+43+29, 52+51+47+46+43+30, 52+51+47+46+43+33, 52+51+47+ 46+43+36, 52+51+47+46+43+37, 52+51+47+46+43+40, 52+51+47+46+44+1, 52+51+47+46+44+2, 52+51 + 47+46+44+5, 52+51+47+46+44+8, 52+51+47+46+44+9, 52+51+47+46+44+12, 52+51+47+46+44+15, 52+51 + 47+46+44+16, 52+51+47+46+44+19, 52+51+47+46+44+22, 52+51+47+46+44+23, 52+51+47+46+44+26, 52+51+47+46+44+29, 52+51+47+46+44+30, 52+51+47+46+44+33, 52+51+47+46+44+36, 52+51+47+46+ 44+37, 52+51+47+46+44+40, 52+51+48+1, 52+51+48+2, 52+51+48+5, 52+51+48+8, 52+51+48+9, 52+51 + 48+12, 52+51+48+15, 52+51+48+16, 52+51+48+19, 52+51+48+22, 52+51+48+23, 52+51+48+26, 52+51 + 48+29, 52+51+48+30, 52+51+48+33, 52+51+48+36, 52+51+48+37, 52+51+48+40, 52+51+48+43+1, 52+51 + 48+43+2, 52+51+48+43+5, 52+51+48+43+8, 52+51+48+43+9, 52+51+48+43+12, 52+51+48+43+15, 52+51 + 48+43+16, 52+51+48+43+19, 52+51+48+43+22, 52+51+48+43+23, 52+51+48+43+26, 52+51+48+43+29, 52+51+48+43+30, 52+51+48+43+33, 52+51+48+43+36, 52+51+48+43+37, 52+51+48+43+40, 52+51+48+ 44+1, 52+51+48+44+2, 52+51+48+44+5, 52+51+48+44+8, 52+51+48+44+9, 52+51+48+44+12, 52+51+48+ 44+15, 52+51+48+44+16, 52+51+48+44+19, 52+51+48+44+22, 52+51+48+44+23, 52+51+48+44+26, 52+51 + 48+44+29, 52+51+48+44+30, 52+51+48+44+33, 52+51+48+44+36, 52+51+48+44+37, 52+51+48+44+40, 52+51+48+46+1, 52+51+48+46+2, 52+51+48+46+5, 52+51+48+46+8, 52+51+48+46+9, 52+51+48+46+12, 52+51+48+46+15, 52+51+48+46+16, 52+51+48+46+19, 52+51+48+46+22, 52+51+48+46+23, 52+51+48+ 46+26, 52+51+48+46+29, 52+51+48+46+30, 52+51+48+46+33, 52+51+48+46+36, 52+51+48+46+37, 52+51 + 48+46+40, 52+51+48+46+43+1, 52+51+48+46+43+2, 52+51+48+46+43+5, 52+51+48+46+43+8, 52+51+48+ 46+43+9, 52+51+48+46+43+12, 52+51+48+46+43+15, 52+51+48+46+43+16, 52+51+48+46+43+19, 52+51 + 48+46+43+22, 52+51+48+46+43+23, 52+51+48+46+43+26, 52+51+48+46+43+29, 52+51+48+46+43+30, 52+51+48+46+43+33, 52+51+48+46+43+36, 52+51+48+46+43+37, 52+51+48+46+43+40, 52+51+48+46+44+ 1, 52+51+48+46+44+2, 52+51+48+46+44+5, 52+51+48+46+44+8, 52+51+48+46+44+9, 52+51+48+46+44+ 12, 52+51+48+46+44+15, 52+51+48+46+44+16, 52+51+48+46+44+19, 52+51+48+46+44+22, 52+51+48+46+ 44+23, 52+51+48+46+44+26, 52+51+48+46+44+29, 52+51+48+46+44+30, 52+51+48+46+44+33, 52+51+48+ 46+44+36, 52+51+48+46+44+37, 52+51+48+46+44+40, 52+51+48+47+1, 52+51+48+47+2, 52+51+48+47+5, 52+51+48+47+8, 52+51+48+47+9, 52+51+48+47+12, 52+51+48+47+15, 52+51+48+47+16, 52+51+48+47+19, 52+51+48+47+22, 52+51+48+47+23, 52+51+48+47+26, 52+51+48+47+29, 52+51+48+47+30, 52+51+48+ 47+33, 52+51+48+47+36, 52+51+48+47+37, 52+51+48+47+40, 52+51+48+47+43+1, 52+51+48+47+43+2, 52+51+48+47+43+5, 52+51+48+47+43+8, 52+51+48+47+43+9, 52+51+48+47+43+12, 52+51+48+47+43+15, 52+51+48+47+43+16, 52+51+48+47+43+19, 52+51+48+47+43+22, 52+51+48+47+43+23, 52+51+48+47+ 43+26, 52+51+48+47+43+29, 52+51+48+47+43+30, 52+51+48+47+43+33, 52+51+48+47+43+36, 52+51 + 48+47+43+37, 52+51+48+47+43+40, 52+51+48+47+44+1, 52+51+48+47+44+2, 52+51+48+47+44+5, 52+51+48+47+44+8, 52+51+48+47+44+9, 52+51+48+47+44+12, 52+51+48+47+44+15, 52+51+48+47+44+ 16, 52+51+48+47+44+19, 52+51+48+47+44+22, 52+51+48+47+44+23, 52+51+48+47+44+26, 52+51+48+47+ 44+29, 52+51+48+47+44+30, 52+51+48+47+44+33, 52+51+48+47+44+36, 52+51+48+47+44+37, 52+51+48+ 47+44+40, 52+51+48+47+46+1, 52+51+48+47+46+2, 52+51+48+47+46+5, 52+51+48+47+46+8, 52+51+48+ 47+46+9, 52+51+48+47+46+12, 52+51+48+47+46+15, 52+51+48+47+46+16, 52+51+48+47+46+19, 52+51 + 48+47+46+22, 52+51+48+47+46+23, 52+51+48+47+46+26, 52+51+48+47+46+29, 52+51+48+47+46+30, 52+ 51+48+47+46+33, 52+51+48+47+46+36, 52+51+48+47+46+37, 52+51+48+47+46+40, 52+51+48+47+46+ 43+1, 52+51+48+47+46+43+2, 52+51+48+47+46+43+5, 52+51+48+47+46+43+8, 52+51+48+47+46+43+9, 52+51+48+47+46+43+12, 52+51+48+47+46+43+15, 52+51+48+47+46+43+16, 52+51+48+47+46+43+19, 52+ 51+48+47+46+43+22, 52+51+48+47+46+43+23, 52+51+48+47+46+43+26, 52+51+48+47+46+43+29, 52+51 + 48+47+46+43+30, 52+51+48+47+46+43+33, 52+51+48+47+46+43+36, 52+51+48+47+46+43+37, 52+51+48+ 47+46+43+40, 52+51+48+47+46+44+1, 52+51+48+47+46+44+2, 52+51+48+47+46+44+5, 52+51+48+47+46+ 44+8, 52+51+48+47+46+44+9, 52+51+48+47+46+44+12, 52+51+48+47+46+44+15, 52+51+48+47+46+44+ 16, 52+51+48+47+46+44+19, 52+51+48+47+46+44+22, 52+51+48+47+46+44+23, 52+51+48+47+46+44+26, 52+51+48+47+46+44+29, 52+51+48+47+46+44+30, 52+51+48+47+46+44+33, 52+51+48+47+46+44+36, 52+51 +48+47+46+44+37, 52+51 +48+47+46+44+40.

In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas “+” indicates the dependency from another embodiment. The different individualised embodiments are separated by commas. In other words, “46+43+1 ” for example refers to embodiment 46) depending on embodiment 43), depending on embodiment 1), i.e. embodiment “46+43+1 ” corresponds to embodiment 1) further characterised by the features of the embodiments 43) and 46).

Definitions provided herein are intended to apply uniformly to the subject matter as defined in any one of embodiments 1) to 73), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term or expression defines and may replace the respective term or expression independently of (and in combination with) any definition or preferred definition of any or all other terms or expressions as defined herein.

Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a dose is described to be between 1 g and 100 g, this means that the end points 1 g and 100 g are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1 , 2, 3, or 4.

Unless used regarding temperatures, the term “about” (or alternatively “around”) placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term “about” (or alternatively “around”) placed before a temperature Ύ” refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C. Besides, the term “room temperature” as used herein refers to a temperature of about 25°C.

Whenever the phrase “the elimination is to be accelerated” is used in relation to the elimination of COMPOUND, the phrase means “the elimination is to be accelerated and/or the elimination is accelerated and/or the accelerated elimination is to be achieved and/or the accelerated elimination is achieved”, and preferably “the elimination is to be accelerated and/or the elimination is accelerated”. In one embodiment the phrase “the elimination is to be accelerated” is used in the specific sense “the elimination is to be accelerated”. In another embodiment the phrase “the elimination is to be accelerated” is used in the specific sense “the elimination is accelerated”. In another embodiment the phrase “the elimination is to be accelerated” is used in the specific sense “the accelerated elimination is to be achieved”. In still another embodiment the phrase “the elimination is to be accelerated” is used in the specific sense “the accelerated elimination is achieved”.

Whenever the phrase “is to be administered” is used in relation to activated charcoal, the phrase means “is to be administered and/or is intended to be administered and/or is administered”, and preferably “is to be administered and/or is administered”. In one embodiment the phrase “is to be administered” is used in the specific sense “is to be administered”. In another embodiment the phrase “is to be administered” is used in the specific sense “is intended to be administered”. In still another embodiment the phrase “is to be administered” is used in the specific sense “is administered”.

Whenever the phrase “is to be discontinued” is used in relation to COMPOUND, the phrase means “is to be discontinued and/or is intended to be discontinued and/or is discontinued”, and preferably “is to be discontinued and/or is discontinued”. In one embodiment the phrase “is to be discontinued” is used in the specific sense “is to be discontinued”. In another embodiment the phrase “is to be discontinued” is used in the specific sense “is intended to be discontinued”. In still another embodiment the phrase “is to be discontinued” is used in the specific sense “is discontinued”.

With regard to the term “indicated” it is to be understood that “an accelerated elimination of COMPOUND from blood plasma of a subject is indicated”, if an accelerated elimination procedure is beneficial and/or necessary for the well-being and/or the health of the subject (as for instance diagnosed by a health care provider); examples are the diagnosis by a health care provider of a serious infection, a pregnancy, an occurrence of an adverse event/effect or another emergency situation in a subject; or the wish of a female subject to become pregnant.

In analogy, it is to be understood that “an acceleration of the increase in the lymphocyte count in the blood (notably the peripheral blood) of a subject is indicated”, if such an accelerated increase in the lymphocyte count is beneficial and/or necessary for the wellbeing and/or the health of the subject (as for instance diagnosed by a health care provider); examples are the diagnosis by a health care provider of a serious infection, a pregnancy, an occurrence of an adverse event/effect or another emergency situation in a subject; or the wish of a female subject to become pregnant.

The term “activated charcoal” refers to activated charcoal (also called “activated carbon”) suitable for human use. The activated charcoal may be used in essentially pure form or in form of a composition comprising at least one additional excipient. Preferably the activated charcoal is used as powder or as granules. Preferably the activated charcoal is to be administered as a suspension for oral administration.

The term "essentially pure" is understood in the context of the present invention to mean especially that the activated charcoal consists in an amount of at least 95 per cent, and notably of at least 99 per cent, by weight of activated charcoal. The term “accelerated elimination procedure” refers to any procedure that is suitable for (or used for) an accelerated elimination of COMPOUND from blood plasma of a subject by administration of activated charcoal to the subject. An accelerated elimination procedure may be initiated for any reason requiring an accelerated increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject having a reduced lymphocyte count that is caused by treatment with COMPOUND, or a pharmaceutically acceptable salt thereof. Such reason may be for instance a serious infection, a pregnancy, an occurrence of an adverse event/effect or another emergency situation. Such reason may also be related to the life circumstances of the treated subject, for instance if females wish to become pregnant.

The term “accelerated elimination” (or in analogy: “accelerating the elimination” and the like) as used for instance in “accelerated elimination of COMPOUND” means that the elimination of COMPOUND from blood plasma (or from the body) of a subject is to be accelerated by a discontinuation of the treatment with COMPOUND together with an administration of activated charcoal (as compared to a discontinuation of the treatment with COMPOUND alone). Especially, the term “accelerated elimination” (or in analogy: “accelerating the elimination” and the like) as used for instance in “accelerated elimination of COMPOUND” means that the elimination of COMPOUND from blood plasma of a subject is to be accelerated by a discontinuation of the treatment with COMPOUND together with an administration of an effective amount of activated charcoal (as compared to a discontinuation of the treatment with COMPOUND alone). Notably, the elimination is accelerated if the time required to reduce the concentration of COMPOUND in blood plasma of a subject by 90% (especially by 95% and notably by 98%) relative to the concentration of COMPOUND five hours after the last administration of COMPOUND, or of a pharmaceutically acceptable salt thereof, is reduced by at least 10% (especially at least 50% and notably at least 80%) due to administration of activated charcoal.

Preferably, the accelerated elimination of COMPOUND from blood plasma of a subject and/or the accelerated increase of the lymphocyte count in the blood (notably the peripheral blood) of a subject is demonstrated in a clinical trial to be statistically significant.

The term “pharmaceutical composition”, if used in relation to activated charcoal, refers to a composition comprising activated charcoal suitable for use in a subject (preferably in a mammal and most preferably in a human). The composition may contain activated charcoal in essentially pure form or, preferably, the composition further comprises at least one excipient. The term “pharmaceutical composition” encompasses a final dosage form, such as a medicament. Preferably the pharmaceutical composition is to be administered to the subject as a suspension in water (preferred) or in a water-based liquid.

The term “pharmaceutical composition”, if used in relation to COMPOUND, refers to a composition comprising COMPOUND suitable for use in a subject (preferably in a mammal and most preferably in a human). Preferably the composition further comprises at least one excipient. The term “pharmaceutical composition” encompasses a final dosage form, such as a medicament. Preferably the pharmaceutical composition is to be administered to the subject as a tablet. Preferably the pharmaceutical composition and/or the medicament and/or the tablet comprises between about 2 mg and about 4 mg COMPOUND (and more preferably about 2 mg or about 4 mg COMPOUND).

In a preferred embodiment the pharmaceutical composition comprises COMPOUND (preferably in an amount between about 2 mg and about 4 mg) and a disintegrant (preferably crospovidone) in an amount between 2 mg and 10 mg (preferably between 3 mg and 7 mg).

In another preferred embodiment the pharmaceutical composition comprises COMPOUND in an amount between about 1 mg and about 4 mg (preferably in an amount between about 2 mg and about 4 mg), mannitol, crospovidone, hypromellose (HPMC), colloidal silicon dioxide, and magnesium stearate.

In a more preferred embodiment the pharmaceutical composition comprises

• COMPOUND in an amount of about 2 mg;

• Mannitol in an amount between 88 mg and 132 mg (preferably between 99 mg and 121 mg);

• Crospovidone in an amount between 4.22 mg and 6.34 mg (preferably between 4.75 mg and 5.81 mg);

• Hypromellose (HPMC) in an amount between 0.96 mg and 1.44 mg (preferably between 1.08 mg and 1.32 mg);

• Colloidal silicon dioxide in an amount between 0.48 mg and 0.72 mg (preferably between 0.54 mg and 0.66 mg); and

• Magnesium stearate in an amount between 0.67 mg and 1.01 mg (preferably between 0.76 mg and 0.92 mg).

In another more preferred embodiment the pharmaceutical composition comprises · COMPOUND in an amount of about 4 mg; • Mannitol in an amount between 86 mg and 130 mg (preferably between 97 mg and 119 mg);

It is preferred that the pharmaceutical composition comprises COMPOUND in the crystalline form A as described in WO 2016/184939. If COMPOUND is described in the present specification to be useful in the treatment of a disease or disorder, it is to be understood that likewise a pharmaceutical composition (preferably as described above) is useful in the treatment of the disease or disorder.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of COMPOUND and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts. For reference see for example ‘Handbook of Pharmaceutical Salts. Properties, Selection and Use.’, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008 and ‘Pharmaceutical Salts and Cocrystals’, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.

The concentration of COMPOUND in blood plasma of a subject can be measured according to Juif et al. Int. J. Mol. Sci. 2017, 18, 2636 or Juif et al. Int. J. Mol. Sci. 2019, 20, 3232 or according to the procedure given in the experimental part. The lymphocyte count in the blood (notably the peripheral blood) of a subject can be measured according to known procedures in the art or according to the procedure given in the experimental part.

(S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl- phenoxy}-propane-1 ,2-diol (COMPOUND) may be used for the prevention (prophylaxis) and/or treatment of diseases or disorders associated with an activated immune system. Diseases or disorders associated with an activated immune system are especially diseases or disorders that are responsive to a decrease of the lymphocyte count in the blood (notably the peripheral blood) of a subject (especially a patient). In a preferred embodiment, such diseases and disorders are autoimmune diseases and disorders wherein the immune system attacks healthy cells, tissues, and/or organs.

Such diseases or disorders associated with an activated immune system and to be prevented/treated with COMPOUND are selected from the group consisting of rejection of transplanted organs, tissue or cells; graft-versus-host diseases (especially: brought about by transplantation); autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; antiphospholipid syndrome; Hashimoto's thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I diabetes; uveitis; episcleritis; scleritis; Kawasaki's disease, uveo-retinitis; posterior uveitis; uveitis associated with Behcet's disease; Behcet's disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; psoriatic arthritis; atopic dermatitis; myopathy; myositis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; giant cell arteritis; erythema; cutaneous eosinophilia; acne; scleroderma; alopecia areata; Rasmussen's encephalitis; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialis corneae; corneal leukoma; ocular pemphigus; Mooren's ulcer; ulcerative keratitis; scleritis; Graves' ophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late asthma and airway hyper-responsiveness; bronchiolitis; bronchitis; endometriosis; orchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; necrotizing enterocolitis; intestinal lesions associated with thermal burns; coeliac disease; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease; ulcerative colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; cardiac infarction; aortitis syndrome; cachexia due to viral disease; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture's syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; tubulointerstitial nephritis; interstitial cystitis; multiple myositis; Guillain-Barre syndrome; Meniere's disease; polyneuritis; multiple neuritis; myelitis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; autoimmune thrombocytopenia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergic sensitivity; cutaneous T cell lymphoma; polyarteritis nodosa; Huntington's chorea; Sydenham's chorea; myocardosis; myocarditis; scleroderma; Wegener's granuloma; Sjogren's syndrome; spondylarthropathy / ankylosing spondylitis; juvenile arthritis; lupus nephritis; systemic sclerosis; diffuse cutaneous systemic sclerosis; adiposis; eosinophilic fascitis; lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis; male pattern alopecia or alopecia senilis; muscular dystrophy; pyoderma; Sezary's syndrome; hypophysitis; chronic adrenal insufficiency; Addison's disease; ischemia-reperfusion injury of organs which occurs upon preservation; endotoxin shock; pseudomembranous colitis; colitis caused by drug or radiation; ischemic acute renal insufficiency; chronic renal insufficiency; lung cancer; malignancy of lymphoid origin; acute or chronic lymphocytic leukemias; lymphoma; pulmonary emphysema; cataracta; siderosis; retinitis pigmentosa; senile macular degeneration; vitreal scarring; corneal alkali burn; dermatitis erythema; ballous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; peripheral artery disease; carcinogenesis; solid cancer tumors; metastasis of carcinoma; hypobaropathy; autoimmune hepatitis; vitiligo; primary biliary cirrhosis; sclerosing cholangitis; partial liver resection; acute liver necrosis; cirrhosis; alcoholic cirrhosis; hepatic failure; fulminant hepatic failure; late-onset hepatic failure; and "acute-on- chronic" liver failure.

Preferred diseases or disorders to be treated and/or prevented with COMPOUND are selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus. The accelerated elimination procedure (for an accelerated elimination of COMPOUND from blood plasma of a subject) may be initiated at any time after a first administration of COMPOUND to the subject. Due to the substantial accumulation of COMPOUND in blood plasma of a subject, the maximum effect of COMPOUND on lymphocyte count reduction is only reached after an initial treatment period with COMPOUND (Juif et al. Int. J. Mol. Sci. 2017, 18, 2636). In a preferred embodiment, the accelerated elimination procedure is initiated only after at least 5 days of treatment with COMPOUND. In another preferred embodiment, the accelerated elimination procedure is initiated only after at least 20 days of treatment with COMPOUND. In still another preferred embodiment, the accelerated elimination procedure is initiated only after at least 35 days of treatment with COMPOUND.

Experimental Part

The following Examples illustrate the invention in more detail. Temperatures are given in degrees Celsius.

Abbreviations as used herein: b.i.d. twice a day EDTA ethylenediaminetetraacetic acid h hour(s)

HPLC high performance liquid chromatography HPMC hydroxypropyl methylcellulose LOD loss on drying min minute(s)

PE-bag polyethylene-bag rpm revolutions per minute SD standard deviation UV ultraviolet

%(w/w) per cent (weight by weight)

Example 1

In-vitro binding of COMPOUND to different adsorbents

The binding of COMPOUND to colestyramine, colestipol hydrochloride, activated charcoal, and colesevelam hydrochloride was examined to test for an accelerated elimination due to absorption. As a reference compound, teriflunomide was included in the testing. Materials:

The compounds investigated were COMPOUND and teriflunomide. The adsorbents tested were colestyramine (Medchem Express), colestipol hydrochloride (U.S.P.C.), activated charcoal (Norit®, Fluka), and colesevelam hydrochloride (Key Organics). FaSSIF version 1 (later named as FaSSIF) was prepared according to the procedure described by Biorelevant.com (UK). In practice, the buffer pH 6.5 was prepared by dissolving 0.42 g of sodium hydroxide pellets (Sigma-Aldrich, Germany), 3.95 g of sodium phosphate monobasic monohydrate (Sigma-Aldrich, Germany), and 6.19 g of sodium chloride (Sigma- Aldrich, Germany) in approximately 0.9 L of 18.2 MQ.cm reverse-osmosis water (Purelab Flex, ELGA labwater, Unity Lab Service, Switzerland) at room temperature in a 1 L volumetric flask. The pH of the solution was checked and adjusted to 6.5 with sodium hydroxide 1M (Fluka, Germany) or hydrochloric acid 1M (Fluka, Germany) if needed, prior to making it up to 1 L volume with 18.2 MQ.cm reverse-osmosis water. Then, FaSSIF was prepared by dissolving 2.24 g of FaSSIF/FeSSIF/FaSSGF powder (Biorelevant.com, UK) in approximately 0.9 L of buffer pH 6.5 at room temperature in a 1 L volumetric flask. After dissolution, buffer pH 6.5 was added up to volume and the solution was let to stand for 2 hours before use. Acetonitrile and water used for the mobile phases were obtained from Honeywell Riedel-de Haen, Germany. Trifluoroacetic acid was obtained from Sigma- Aldrich, Germany. A Stuart SB2 rotator from Bibby Sterilin, UK, was put in a Binder constant climate chamber (Germany) at 37°C for the equilibration step. Centrifuges 5417R with rotor F45-30-11 and 581 OR with rotor A-4-62 from Eppendorf, Switzerland, were used for the separation step. Samples were prepared in HPLC vials from Shimadzu, Switzerland, and transferred to 0.5 mL Multiply-Pro cups from Sarstedt, Germany, for second step of centrifugation with activated charcoal.

The samples were analyzed by high performance liquid chromatography coupled to UV detection. A Nexera X2 HPLC from Shimadzu, Switzerland, equipped with an auto-sampler SIL-30AC MP set at 25°C, a photo-diode array detector SPD-M30A, an on-line degassing unit DGU-20A5R, two solvent delivery units LC-30AD, a column oven CTO-20A set at 50°C, and a system controller CBM-20A was used. Separation was achieved with a

Kinetex 2.6 pm EVO C18 100 A 50 x 2.1 mm column from Phenomenex, Switzerland. The mobile phases consisted of 0.05% (v/v) of Trifluoroacetic acid in water (mobile phase A) and 0.05% (v/v) of Trifluoroacetic acid in acetonitrile (mobile phase B). A gradient was applied from 5% B to 95% B during 2 min, a plateau was maintained at 95% B during 0.2 min before coming back to 5% B in 0.01 min, which was maintained during 0.29 min for a total run time of 2.5 min. The flow rate was set at 1.5 mL/min. The volume of samples injected was between 0.5 mI_ and 5.0 mI_.

Method:

The binding of COMPOUND and teriflunomide to the different adsorbents was determined by the following procedure. The study was designed to reflect physiological conditions expected in the body on standard dosing (4 mg in 250 mL for COMPOUND giving 16 pg/mL; 14 mg and 70 mg in 250 mL for teriflunomide giving 56 pg/mL and 280 pg/mL respectively; 4 g, 8 g and 16 g in 250 mL of colestyramine giving 16 mg/mL, 32 mg/mL and 64 mg/mL respectively; 8 g in 250 mL of colestipol hydrochloride giving 32 mg/mL; 1 g, 4 g and 50 g in 250 mL of activated charcoal giving 4 mg/mL, 16 mg/mL and 200 mg/mL respectively; 2 g, 4 g and 8 g in 250 mL of colesevelam hydrochloride giving 8 mg/mL, 16 mg/mL and 32 mg/mL respectively). FaSSIF at 37°C was used as medium with 4 hours equilibration time.

A stock solution of COMPOUND in FaSSIF was prepared at a concentration of 16 ± 1 pg/mL ( stock solution 1) (target was 16 pg/mL) at 37°C. The following amounts of the adsorbents tested were weighed in HPLC glass vials in duplicates: 16 mg, 32 mg and 64 mg of colestyramine; 32 mg of colestipol hydrochloride; 4 mg, 16 mg and 200 mg of activated charcoal; 8 mg, 16 mg and 32 mg of colesevelam hydrochloride. Suspensions were prepared by adding 1 mL of stock solution 1 to each vial at time zero. In parallel, 1 mL of stock solution 1 was added in duplicates to two empty vials at time zero, used as references.

Similarly, stock solutions of teriflunomide in FaSSIF were prepared at a concentration of 50 ± 4 pg/mL ( stock solution 2) (target was 56 pg/mL) and of 275 ± 1 pg/mL ( stock solution 3) (target was 280 pg/mL) at 37°C. For stock solution 2 the following amounts of the adsorbents tested were weighed in HPLC glass vials in duplicates: 32 mg of colestyramine; 32 mg of colestipol hydrochloride; 200 mg of activated charcoal; 8 mg, 16 mg and 32 mg of colesevelam hydrochloride. Suspensions were prepared by adding 1 mL of stock solution 2 to each vial at time zero. For stock solution 3 16 mg of colesevelam hydrochloride were weighed in HPLC glass vials in duplicates. Suspensions were prepared by adding 1 mL of stock solution 3 to each vial at time zero. In parallel, 1 mL of stock solution 2 and 1 mL of stock solution 3 were added in duplicates to four empty vials at time zero, used as references.

All vials were equilibrated during approximatively 3h20 on a rotating wheel placed in a climate chamber set at 37°C. They were then centrifuged at 3220 g and 37°C during 20 min. 200 pL of the supernatants of the samples containing activated charcoal were transferred in 0.5 mL Multiply-Pro cup and further centrifuged at 18200 g and 25°C during 20 min. Binding of the compounds to the Multiply-Pro cup was checked and showed no significant binding. After centrifugation (4h after time zero), the supernatants were diluted 1 :1 with acetonitrile (1 :9 for samples with stock solution 3) and analyzed by HPLC-UV. Quantification of the compounds was done with calibration samples in acetonitrile from 0.4 pg/mL to 25 pg/mL for COMPOUND and from 0.05 pg/mL to 50 pg/mL for teriflunomide. Detection was carried out at 270 nm for COMPOUND and at 285 nm for teriflunomide. Extent of binding was calculated as following: total compound added — free compound recovered in FaSSIF

% bound = - _* 100 total compound added Results:

The extent of COMPOUND and teriflunomide binding to the various adsorbents after 4 h at 37°C in FaSSIF is shown in Table 1 giving the average of the duplicates in % bound.

Table 1 :

^Concentration of COMPOUND in the reference was 16.0 ± 0.1 pg/mL. * Concentration of teriflunomide in the reference was 53.8 ± 0.1 pg/mL. Concentration of teriflunomide in the reference was 46.9 ± 0.3 pg/mL. "Concentration of teriflunomide in the reference was 275 ± 1 pg/mL. No free COMPOUND was measurable in the samples containing 16 mg/ml_ and 32 mg/ml_ of activated charcoal.

In vitro experiments revealed that the percentage of COMPOUND bound was approximately 60% with 16 mg/ml_, 32 mg/ml_ and 64 mg/ml_ of colestyramine; 20% with 32 mg/ml_ of colestipol hydrochloride; >99% with 4 mg/ml_, 16 mg/ml_ and 200 mg/ml_ of activated charcoal; 90% with 8 mg/ml_ of colesevelam hydrochloride and 75% with 16 mg/ml_ and 32 mg/ml_ of colesevelam hydrochloride with a dose of 4 mg. The percentage of Teriflunomide bound was 100% with 32 mg/ml_ of Colestyramine; 85% with 32 mg/ml_ of Colestipol hydrochloride; 100% with 200 mg/ml_ of activated charcoal; 99% with 8 mg/ml_, 16 mg/ml_ and 32 mg/ml_ of colesevelam hydrochloride with a dose of 14 mg. The percentage of Teriflunomide bound was 99% with 16 mg/ml_ of Colesevelam hydrochloride with a dose of 70 mg.

These values were independent of adsorbent concentrations tested, except for COMPOUND and 8 mg/ml_ of colesevelam hydrochloride. While it is possible that the binding characteristics differ outside the ranges investigated, the study was designed to reflect physiological conditions expected in the body on standard dosing.

Example 2

Clinical evaluation of the effect of activated charcoal on the pharmacokinetics of COMPOUND in healthy male and female subjects

Study Design:

In a single-center, double-blind, placebo-controlled study, 66 healthy male and female subjects are randomized to one of the following treatment groups according to a 1 :1 :1 ratio: (i) COMPOUND 0.5 mg (film-coated tablets; see example 3) once daily in the morning for 50 days (Day 7 to Day 56 after a screening period of 6 days); (ii) COMPOUND 4 mg (film- coated tablets; see example 3) once daily in the morning for 50 days (Day 7 to Day 56 after a screening period of 6 days); and (iii) matching placebo once daily for 50 days (Day 7 to Day 56 after a screening period of 6 days). From Day 57, out of the 66 subjects who will have received placebo or cenerimod, 33 subjects are confined to the clinic for 12 days (i.e., until the morning of Day 68) and receive 50 g of charcoal every 12 h (Accelerated Elimination Procedure, AEP) from Day 57 to Day 67. The 33 remaining subjects do not receive any medication (non-AEP), remain in the clinic for 4 days (i.e., until the morning of Day 60) and return for an ambulatory visit on Day 68. All subjects randomized to the cenerimod or placebo groups return for ambulatory visits on Days 81 (±2), 95 (±2), 109 (±2), 123 (±2), 137 (±2), 151 (±2), 165 (±2), 179 (±2), and 193 (±2). Charcoal is administered as an oral suspension containing 50 g activated charcoal b.i.d. (i.e., every 12 h) to subjects randomized to the AEP part from Day 51 to Day 61. A commercially available formulation of activated charcoal (Carbomix®) is used, that is available as granules for oral suspension containing 50 g of charcoal to be reconstituted with 240 mL of water.

Pharmacokinetic Assessment:

Blood sampling for pharmacokinetic assessment of COMPOUND is taken on Day 6, on Days 7, 14, 21 , 35, and 56 prior to administration of COMPOUND and 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 and 12 hours thereafter. In the AEP group, additional blood sampling is taken 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264 and 276 hours after the last administration of COMPOUND. In the non-AEP group, additional blood sampling is taken 24, 36, 48, 60, 72, 84 and 96 hours after the last administration of COMPOUND. In both groups, AEP and non-AEP, further blood sampling is taken on Day 68, 81 , 95, 109, 123, 137, 151 , 165, 179, and 193.

For determination of COMPOUND, 2.7 mL of blood is collected by direct venipuncture or via an i.v. catheter placed in an antecubital vein in the arm in Monovette® or equivalent tubes containing ethylene diamine tetra-acetic acid. The indwelling catheter is inserted in the arm before the start of blood sampling and is kept patent by rinsing with saline and purging before each sampling. The indwelling catheter is periodically inspected by a qualified staff member. Immediately following collection of the required blood volume, the Monovettes® is slowly tilted backwards and forwards (no shaking) to bring the anticoagulant into solution, and immediately cooled on ice. Within 30 min of collection, the Monovettes® is centrifuged at approximately 1500 g for 10 min at 4 °C. The plasma is transferred into one labeled polypropylene tube to avoid carry-over of erythrocytes. All samples are stored in an upright position at < -20 (± 5) °C.

The analysis of COMPOUND in plasma is performed using a validated liquid chromatography coupled to tandem mass spectrometry assay. Concentrations are calculated by interpolation from a calibration curve. Quality control (QC) samples are analyzed throughout the study. Their measured concentrations are used to determine between-run and overall precision and accuracy of the analysis.

Example 3

Table 2: Tablets containing 0.5 mg, 2 mg, and 4 mg of COMPOUND

Tablets containing COMPOUND in different amounts (e.g. an amount of COMPOUND in the range of 0.50 mg and 4.00 mg) can be obtained by keeping the total of COMPOUND and mannitol at 112.08 mg.

Description of manufacturing process:

1.1 Preparation of the granulation solution

The binder concentration is set to 2.6%.

The granulation solution is prepared with an overage of 20%.

The binder is added to the water and mixed with a propeller stirrer until the powder is fully dissolved.

1.2 Weighing and sieving of COMPOUND

The amount of COMPOUND is adjusted based on assay for use with an overage of 20%.

The COMPOUND is sieved through a cone mill (e.g. Bohle Turbo Sieve 200 (BTS200)) with a 0.8 mm screen at a speed rate of 150-200 rpm.

The required amount of sieved COMPOUND is weighted for blending with the excipients of the inner phase.

1.3 Mixing of the powder blend

Mannitol and half of the Crospovidone are weighted and passed through a cone mill (e.g. BTS 200) sieve with a 1.0 mm screen and speed rate of 150-200 rpm.

The excipients are transferred into a blending bin (e.g. a MC40 bin) and blended for 3 minutes at 20 rpm using the Bohle free-fall blender for bin layering.

Half of the blend is discharged into a PE-bag or a stainless-steel bowl. The sieved COMPOUND is added to the MC40 bin.

The discharged half of the blend is transferred into the MC40 bin and blended for 10 minutes at 20 rpm using the Bohle free-fall blender. nulation

A spray rate of 90 g/min is applied.

The spray rate is adapted to achieve a product temperature of approximately 25°C within the first 10 to 20 min (the spray rate is reduced to approximately 80 g/min). Once a LOD < 1.0% is reached, the drying process is stopped, and a confirmative sample is taken directly from the vessel.

Drying of granulate is continued if residual moisture is > 1.0% after sieving.

Sieve screen of 1.0 mm is maintained for sieving of granules. ransfer

The fluidized bed granulator (FBD) is loaded by transfer tube.

Inlet air volume: 400 m³/h.

Filter cleaning interval: 20 sec. reheating

Inlet air temperature: 50 °C.

Inlet air volume: 200 nfVh.

Target product temperature: 40° C.

Filter cleaning interval: 20 sec. praying

Inlet air temperature: 55 °C.

Inlet air volume: 200 nfVh.

The spray rate of 90 g/min is applied.

The spray rate is adapted to achieve a product temperature of approximately 25°C within the first 10 to 20 minutes.

Once a product temperature of 25°C is reached, the spray rate is reduced to approximately 80 g/min.

Spray pressure: 2 bar.

Filter cleaning interval: 20 sec. rying

Inlet air temperature: 60 °C.

Inlet air volume: 200 nfVh.

Filter cleaning interval: 20 sec.

Keep target LOD after drying of <1.0% to keep the granules mixture as dry as possible. The last LOD sample will be taken from the granules directly from the vessel for confirmation.

Additional drying of granulate if residual moisture is > 1.0% after sieving (LOD monitoring every 5 min to avoid over-drying).

1.5 Blending of granules

The dried granules are discharged manually.

The granules are sieved through a cone mill (e.g. BTS 200) with a 1.0 mm screen and a speed rate of 150-200 rpm into a blending bin (e.g. a MC40 bin).

If the LOD is >1% after sieving additional drying is applied.

1.6 Mixing of final blend

The outer phase (colloidal silicon dioxide and the other half of crospovidone but without Magnesium stearate) is sieved through a 0.5 mm hand screen and added to the granules.

The granules and the outer phase are blended for 10 minutes at 20 rpm using the Bohle free-fall blender.

Magnesium stearate is sieved through a 0.5 mm hand screen and added to the mix. The final blend is blended for 5 minutes at 20 rpm using the Bohle free-fall blender.

1.7 Tabletinq

Tableting on Fette 102i with 20 punches.

1.8 Coating

The Coating suspension is prepared with 12% solid content (AquaPolish P Orange) in a beaker with a motor stirrer.

Coating is performed until a weight gain of 3% is achieved.

Example 4

Measurement of the lymphocyte count in peripheral blood

To assess lymphocyte count, whole blood samples are collected using routine venepuncture techniques. The samples are collected in 1.2, 3.7 or 10ml blood collection tubes that contain EDTA as anticoagulant. Blood samples are processed within 8 hours of venepuncture; alternatively, blood samples are refrigerated between 1°C and 7°C and allowed to equilibrate to room temperature within 15-20 minutes on a roller mixer before processing. The analysis is performed using a cell counter.

Claims

1. Activated charcoal for use in an accelerated elimination of (S)-3-{4-[5-(2-cyclopentyl-6- methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1 ,2-diol from blood plasma of a subject.

2. Activated charcoal for use in accelerating the increase of the lymphocyte count in the blood of a subject after discontinuation of the treatment of the subject with (S)-3-{4-[5-(2- cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}- propane-1 , 2-diol.

3. Activated charcoal for use according to any one of claims 1 or 2, wherein the activated charcoal is in essentially pure form.

4. Activated charcoal for use according to any one of claims 1 or 2, wherein the activated charcoal is in form of a composition or is used as a composition, the composition comprising at least 40 %w/w activated charcoal and at least one excipient.

5. Activated charcoal for use according to any one of claims 1 to 4, wherein the activated charcoal is to be administered orally as a suspension in water.

6. (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl- phenoxy}-propane-1 , 2-diol, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with an activated immune system, wherein in case an accelerated elimination of (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)- [1 , 2, 4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1 , 2-diol from blood plasma of a subject is indicated, activated charcoal is to be administered.

7. (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl- phenoxy}-propane-1 , 2-diol, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an accelerated elimination of (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin- 4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1 ,2-diol from blood plasma of a subject is indicated, activated charcoal is to be administered.

8. (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl- phenoxy}-propane-1 ,2-diol, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with an activated immune system, wherein in case an acceleration of the increase in the lymphocyte count in the blood of a subject is indicated, the treatment with (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)- [1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1 ,2-diol is to be discontinued and activated charcoal is to be administered.

9. (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl- phenoxy}-propane-1 ,2-diol, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from the group consisting of rejection of transplanted organs selected from kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease; autoimmune syndromes selected from Sjogren's syndrome, spondylarthropathy / ankylosing spondylitis, juvenile arthritis, lupus nephritis, systemic sclerosis, diffuse cutaneous systemic sclerosis, vasculitis, giant cell arteritis, Behcet disease, non-infectious uveitis, Goodpasture syndrome, primary biliary cirrhosis, autoimmune hepatitis, vitiligo, alopecia areata, Rasmussen's encephalitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis; atopic dermatitis; type I diabetes; and systemic lupus erythematosus, wherein in case an acceleration of the increase in the lymphocyte count in the blood of a subject is indicated, the treatment with (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)- [1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1 ,2-diol is to be discontinued and activated charcoal is to be administered.

10. Activated charcoal for use according to any one of claims 1 to 5, or (S)-3-{4-[5-(2- cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}- propane-1 ,2-diol, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 6 to 9, wherein the treatment of the subject with (S)-3-{4-[5-(2-cyclopentyl-6- methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1 ,2-diol, or a pharmaceutically acceptable salt thereof, is to be discontinued after the first administration of activated charcoal to the subject.

11. Activated charcoal for use according to any one of claims 1 to 5 or 10, or (S)-3-{4-[5-(2- cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}- propane-1 ,2-diol, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 6 to 10, wherein the time required to reduce the concentration of (S)-3-{4-[5- (2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}- propane-1 ,2-diol in blood plasma of a subject by 90% relative to the concentration of (S)-3- {4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl- phenoxy}-propane-1 ,2-diol five hours after the last administration of (S)-3-{4-[5-(2- cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}- propane-1 ,2-diol, or of a pharmaceutically acceptable salt thereof, is reduced by at least 10% due to administration of activated charcoal.

12. Activated charcoal for use according to any one of claims 1 to 5 or 10 to 11 , or (S)-3-{4- [5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}- propane-1 ,2-diol, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 6 to 11 , wherein the subject is a human.

13. (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6- methyl-phenoxy}-propane-1 ,2-diol, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 7 or 9 to 12, wherein the disease or disorder is systemic lupus erythematosus.

14. Activated charcoal for use according to any one of claims 1 to 5 or 10 to 12, or (S)-3-{4- [5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}- propane-1 ,2-diol, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 6 to 13, wherein a 20% increase of the lymphocyte count in the blood of a subject after discontinuation of the treatment of the subject with (S)-3-{4-[5-(2-cyclopentyl- 6-methoxy-pyridin-4-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1 ,2-diol is reached at least two times faster with than without administration of activated charcoal to the subject.