Clinical pharmacokinetics of fingolimod

Clinical Pharmacokinetics

Volumn 51, Issue 1, 2012, Pages 15-28

  David, Olivier J ^a   Kovarik, John M ^a   Schmouder, Robert L ^b  

^a NOVARTIS PHARMA AG   (Switzerland)

^b NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

Fingolimod; Multiple sclerosis; Pharmacokinetics; Sphingosine 1 phosphate receptor modulators

Indexed keywords

ATENOLOL; CARBAMAZEPINE; CYCLOSPORIN A; CYTOCHROME P450; CYTOCHROME P450 4F2; DILTIAZEM; FINGOLIMOD; FLUOXETINE; ISOPRENALINE; KETOCONAZOLE; ORAL CONTRACEPTIVE AGENT; PAROXETINE; PLACEBO; UNCLASSIFIED DRUG;

ANALYTIC METHOD; AREA UNDER THE CURVE; BRADYCARDIA; DIETARY INTAKE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENTIATION; DRUG TARGETING; ETHNICITY; FOOD; FOOD DRUG INTERACTION; HUMAN; HYPERTENSION; KIDNEY FAILURE; LIVER FAILURE; MAXIMUM PLASMA CONCENTRATION; MULTIPLE SCLEROSIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN BINDING; PSORIASIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW;

ANIMALS; BLOOD PROTEINS; DRUG INTERACTIONS; HUMANS; IMMUNOSUPPRESSIVE AGENTS; KIDNEY DISEASES; LIVER DISEASES; MULTIPLE SCLEROSIS; PROPYLENE GLYCOLS; PROTEIN BINDING; SPHINGOSINE;

EID: 83455173447     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.2165/11596550-000000000-00000     Document Type: Review

References (31)

1. Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002; 277 (24): 21453-7 (Pubitemid 34952287)
2. Adachi K, Chiba K. FTY720 story: its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology. Perspect Medicin Chem 2007; 1: 11-23
3. Gilenyä(fingolimod hydrochloride tablets):USprescribing information [online]. Available from URL: www.accessdata.fda.gov/drugsatfdädocs/label/ 2011/022527s002lbl.pdf [Accessed 2011 Nov 9]
4. European Medicines Agency. Gilenya (fingolimod): summary of product characteristics [online]. Available from URL: http://www.ema.europa.eu/docs/en- GB/document-library/EPAR-Product-Information/human/002202/WC500104528.pdf [Accessed 2011 Mar 30]
5. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 2010; 33 (2): 91-101
6. Brinkmann V. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol 2009; 158 (5): 1173-82
7. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362 (5): 402-15
8. Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362 (5): 387-401
9. Center for Drug Evaluation and Research [CDER]. Application number: 22-Clinical pharmacology and biopharmaceutics review(s) [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfdädocs/nda/2010/ 022527Orig1s000clinpharmr.pdf [Accessed 2011 Nov 9]
10. Kovarik JM, Schmouder R, Barilla D, et al. Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br J Clin Pharmacol 2004; 57 (5): 586-91 (Pubitemid 38582178)
11. Zollinger M, Gschwind HP, Jin Y, et al. Absorption and disposition of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in healthy volunteers: a case of xenobiotic biotransformation following endogenous metabolic pathways. Drug Metab Dispos 2011; 39 (2): 199-207
12. Jin Y, Zollinger M, Borell H, et al. CYP4F enzymes are responsible for the elimination of fingolimod (FTY720), a novel treatment of relapsing multiple sclerosis. Drug Metab Dispos 2011; 39 (2): 191-8
13. Kovarik JM, Slade A, Voss B, et al. Ethnic sensitivity study of fingolimod in White and Asian subjects. Int J Clin Pharmacol Ther 2007; 45 (2): 98-109 (Pubitemid 46344141)
14. Kovarik JM, Schmouder RL, Serra D, et al. FTY720 pharmacokinetics in mild to moderate hepatic impairment. J Clin Pharmacol 2005; 45 (4): 446-52 (Pubitemid 40490417)
15. Kovarik JM, Schmouder RL, Hartmann S, et al. Fingolimod (FTY720) in severe hepatic impairment: pharmacokinetics and relationship to markers of liver function. J Clin Pharmacol 2006; 46 (2): 149-56 (Pubitemid 43146445)
16. Zimmerlin AG, Patten CJ. Role of CYP4F in the metabolic clearance of FTY720: prediction of low drug to drug interaction potential [abstract]. Transplantation 2000; 69 Suppl.: S191
17. Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71 (3): 115-21 (Pubitemid 34271114)
18. Budde K, Schmouder RL, Brunkhorst R, et al. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol 2002; 13 (4): 1073-83 (Pubitemid 34274106)
19. Kahan BD, Karlix JL, Ferguson RM, et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation 2003; 76 (7): 1079-84 (Pubitemid 37280837)
20. Kovarik JM, Schmouder R, Barilla D, et al. Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J Clin Pharmacol 2004; 44 (5): 532-7 (Pubitemid 38509722)
21. Kovarik JM, Hartmann S, Bartlett M, et al. Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects. Biopharm Drug Dispos 2007; 28 (2): 97-104 (Pubitemid 46455770)
22. Kovarik JM, Schmouder RL, Barilla D, et al. FTY720 and cyclosporine: evaluation for a pharmacokinetic interaction. Ann Pharmacother 2004; 38 (7-8): 1153-8 (Pubitemid 38802151)
23. Schmouder R, Boulton C, Wang N, et al. An exploratory, randomized, doubleblind, placebo controlled, parallel group, multiple dose study to assess the pharmacodynamic effect of fingolimod on antibody response following multiple immunizations in healthy volunteers. Cambridge: LCG Bioscience, 2010. (Data on file)
24. Ettenger R, Schmouder R, Kovarik JM, et al. Pharmacokinetics, pharmacodynamics, safety and tolerability of single-dose fingolimod (FTY720) in adolescents with stable renal transplants. Pediatr Transplant 2011; 15 (4): 406-13
25. Kovarik JM, Tedesco-Silva H, Lorber MI, et al. Exposure-efficacy relationships of a fingolimod-everolimus regimen in kidney transplant patients at risk for delayed graft function. Transplant Proc 2006; 38 (10): 3479-82 (Pubitemid 44908468)
26. Kovarik JM, Dole K, Riviere GJ, et al. Ketoconazole increases fingolimod blood levels in a drug interaction via CYP4F2 inhibition. J Clin Pharmacol 2009; 49 (2): 212-8
27. Collins W, Francis G, Koren G, et al. Lack of interaction between fingolimod (FTY720) and oral contraceptives, and pregnancy experience in the clinical program of fingolimod in multiple sclerosis [abstract]. Neurology 2011; 76: P07.184
28. Kovarik JM, Lu M, Riviere GJ, et al. The effect on heart rate of combining single-dose fingolimod with steady-state atenolol or diltiazem in healthy subjects. Eur J Clin Pharmacol 2008; 64 (5): 457-63
29. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355 (11): 1124-40 (Pubitemid 44394919)
30. Kovarik JM, Riviere GJ, Neddermann D, et al. A mechanistic study to assess whether isoproterenol can reverse the negative chronotropic effect of fingolimod. J Clin Pharmacol 2008; 48 (3): 303-10 (Pubitemid 351257776)
31. Kovarik JM, Slade A, Riviere GJ, et al. The ability of atropine to prevent and reverse the negative chronotropic effect of fingolimod in healthy subjects. Br J Clin Pharmacol 2008; 66 (2): 199-206