Clinical Pharmacokinetics of Fingolimod
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Fingolimod (FTY720), a sphingosine 1-phosphate receptor modulator, is the first in a new class of therapeutic compounds and is the first oral therapy approved for the treatment of relapsing forms of multiple sclerosis (MS). Fingolimod is a structural analogue of endogenous sphingosine and undergoes phosphorylation to produce fingolimod phosphate, the active moiety. Fingolimod targets MS via effects on the immune system, and evidence from animal models indicates that it may also have actions in the central nervous system. In phase III studies in patients with relapsing-remitting MS, fingolimod has demonstrated efficacy superior to that of an approved first-line therapy, intramuscular interferon-β-1a, as well as placebo, with benefits extending across clinical and magnetic resonance imaging measures.
The pharmacokinetic profiles of fingolimod and fingolimod phosphate have been extensively investigated in studies in healthy volunteers, renal transplant recipients (the indication for which fingolimod was initially under clinical development, but the development was subsequently discontinued) and MS patients. Results from these studies have demonstrated that fingolimod is efficiently absorbed, with an oral bioavailability of >90%, and its absorption is unaffected by dietary intake, therefore it can be taken without regard to meals. Fingolimod and fingolimod phosphate have a half-life of 6–9 days, and steady-state pharmacokinetics are reached after 1–2 months of daily dosing. The long half-life of fingolimod, together with its slow absorption, means that fingolimod has a flat concentration profile over time with once-daily dosing. Fingolimod and fingolimod phosphate show dose-proportional exposure in single- and multiple-dose studies over a range of 0.125–5 mg; hence, there is a predictable relationship between dose and systemic exposure. Furthermore, fingolimod and fingolimod phosphate exhibit low to moderate intersubject pharmacokinetic variability.
Fingolimod is extensively metabolized, with biotransformation occurring via three main pathways: (i) reversible phosphorylation to fingolimod phosphate; (ii) hydroxylation and oxidation to yield a series of inactive carboxylic acid metabolites; and (iii) formation of non-polar ceramides. Fingolimod is largely cleared through metabolism by cytochrome P450 (CYP) 4F2. Since few drugs are metabolized by CYP4F2, fingolimod would be expected to have a relatively low potential for drug-drug interactions. This is supported by data from in vitro studies indicating that fingolimod and fingolimod phosphate have little or no capacity to inhibit and no capacity to induce other major drug-metabolizing CYP enzymes at therapeutically relevant steady-state blood concentrations. Population pharmacokinetic evaluations indicate that CYP3A inhibitors and CYP3A inducers have no effect or only a weak effect on the pharmacokinetics of fingolimod and fingolimod phosphate. However, blood concentrations of fingolimod and fingolimod phosphate are increased moderately when fingolimod is coadministered with ketoconazole, an inhibitor of CYP4F2. The pharmacokinetics of fingolimod are unaffected by renal impairment or mild-to-moderate hepatic impairment. However, exposure to fingolimod is increased in patients with severe hepatic impairment. No clinically relevant effects of age, sex or ethnicity on the pharmacokinetics of fingolimod have been observed.
Fingolimod is thus a promising new therapy for eligible patients with MS, with a predictable pharmacokinetic profile that allows effective once-daily oral dosing.
KeywordsMultiple Sclerosis Multiple Sclerosis Patient Hepatic Impairment Renal Transplant Recipient Fingolimod
All authors are employees of Novartis and have no other conflicts of interest. The research described here was funded by Novartis, and the sponsor was involved in the design and conduct of the studies, collection of data, and analysis and interpretation of the data. The authors thank Markus Zollinger, Hans-Peter Gschwind and Yi Jin (Drug Metabolism and Pharmacokinetics, Novartis) for managing the preclinical development of fingolimod, and François Mercier, Heinz Schmidli and Marina Savelieva-Praz (Modelling and Simulation, Novartis) for conducting the population pharmacokinetics analyses of fingolimod. The authors take full responsibility for the content of the paper and thank Rowena Hughes and Sarah Griffiths of Oxford PharmaGenesis™ Ltd for editorial assistance, collating and incorporating comments from all authors, and editing the final manuscript. The editorial support was funded by Novartis.
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