Gilenia

Absorption

Fingolimod is slowly but efficiently absorbed in the gastrointestinal tract. AUC varies greatly, depending on the patient, and pharmacokinetic studies demonstrate a range of AUC values for fingolimod. The Tmax of fingolimod ranges between 12-16 hours and its bioavailability is 90-93%. Steady-state concentrations of fingolimod are achieved within 1-2 months after initiation when it is administered in a single daily dose.

Toxicity

The LD50 of fingolimod in rats ranges from 300-600 mg/kg.
Prescribing information for fingolimod does not mention symptoms or management of an overdose , however, a case report of an intentional overdose with 14mg of fingolimod and 2g phenoxymethylpenicillin resulted in hypotension in bradycardia, resolved by administering atropine. Since fingolimod has been associated with cardiotoxicity, it would be reasonable to expect cardiac effects such as bradycardia and heart block in the case of an overdose.

Chemical properties

white solid

The Uses of Gilenia

Prophylaxis of organ rejection in patients receiving allogenic renal transplants (sphingosine-1-phosphate receptor).

The Uses of Gilenia

Fingolimod is a novel immune modulator that prolongs allograft transplant survival in numerous models by inhibiting lymphocyte emigration from lymphoid organs.

Background

Multiple sclerosis, or MS, is a devastating inflammatory disease that often progresses and causes severe neurological, physical, and cognitive effects. Fingolimod is a sphingosine 1-phosphate receptor modulator for the treatment of relapsing-remitting multiple sclerosis. It was developed by Novartis and initially approved by the FDA in 2010. Fingolimod was also studied for the treatment of COVID-19, the disease caused by infection with the SARS-CoV-2 virus.

Indications

Fingolimod is indicated for the treatment of patients aged 10 and above with relapsing forms of multiple sclerosis, which may include clinically isolated syndrome, relapsing-remitting disease, as well as active secondary progressive disease.

Definition

ChEBI: An aminodiol that consists of propane-1,3-diol having amino and 2-(4-octylphenyl)ethyl substituents at the 2-position. It is a sphingosine 1-phosphate receptor modulator used for the treatment of relapsing-remitting multiple sclerosis. A prodrug, fingolimo is phosphorylated by sphingosine kinase to active metabolite fingolimod-phosphate, a structural analogue of sphingosine 1-phosphate.

Pharmacokinetics

In multiple sclerosis, fingolimod binds to sphingosine receptors, reducing its associated neuroinflammation.In COVID-19, it may reduce lung inflammation and improve the clinical outcomes of patients with this disease.
Fingolimod causes a transient reduction in heart rate and AV conduction during treatment initiation. It has the potential to prolong the QT interval.

Clinical Use

Sphingosine 1-phosphate receptor modulator:
Treatment of highly active relapsing-remitting multiple sclerosis

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: possible increased risk of bradycardia with amiodarone, disopyramide and dronedarone.
Antifungals: concentration increased by ketoconazole.
Beta-blockers: possibly increased risk of bradycardia.
Calcium channel blockers: possible increased risk of bradycardia with diltiazem and verapamil.

Metabolism

Sphingosine kinase metabolizes fingolimod to an active metabolite, fingolimod phosphate. Fingolimod metabolism occurs via 3 major metabolic pathways: firstly, phosphorylation of the (S)-enantiomer of fingolimod-phosphate (pharmacologically active), secondly, oxidation by cytochrome P450 4F2 (CYP4F2), and thirdly, fatty acid-like metabolism to various inactive metabolites. The formation of inactive non-polar ceramide analogs of fingolimod also occurs during its metabolism.

Metabolism

Transformed by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod phosphate. It is eliminated by oxidative biotransformation mainly via the cytochrome P450 4F2 isoenzyme and subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive non-polar ceramide analogues of fingolimod. The main enzyme involved in the metabolism of fingolimod is partially identified and may be either CYP4F2 or CYP3A4. 81% excreted as inactive metabolites in the urine and <2.5% in the faeces as metabolites and unchanged drug.