Chemical formula: C₂₉H₃₅F₃N₂O₃ Molecular mass: 516.605 g/mol PubChem compound: 44599207
Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds selectively to two out of five G-protein-coupled receptors (GPCRs) for S1P, namely S1P1 and S1P5. By acting as a functional antagonist on S1P1 receptors on lymphocytes, siponimod prevents egress from lymph nodes. This reduces the recirculation of T cells into the central nervous system (CNS) to limit central inflammation.
Siponimod induces a dose-dependent reduction of the peripheral blood lymphocyte count within 6 hours of the first dose, due to the reversible sequestration of lymphocytes in lymphoid tissues.
With continued daily dosing, the lymphocyte count continues to decrease, reaching a nadir median (90% CI) lymphocyte count of approximately 0.560 (0.271-1.08) cells/nL in a typical CYP2C9*1*1 or *1*2 non-Japanese SPMS patient, corresponding to 20-30% of baseline. Low lymphocyte counts are maintained with daily dosing.
In the vast majority (90%) of SPMS patients, lymphocyte counts return to the normal range within 10 days of stopping therapy. After stopping siponimod treatment residual lowering effects on peripheral lymphocyte count may persist for up to 3-4 weeks after the last dose.
Siponimod causes a transient reduction in heart rate and atrioventricular conduction on treatment initiation, which is mechanistically related to the activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels via S1P1 receptor stimulation leading to cellular hyperpolarisation and reduced excitability. Due to its functional antagonism at S1P1 receptors, initial titration of siponimod successively desensitises GIRK channels until the maintenance dose is reached.
The effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod on cardiac repolarisation were investigated in a thorough QT study. The results did not suggest an arrhythmogenic potential related to QT prolongation with siponimod. Siponimod increased the placebo-corrected baseline-adjusted mean QTcF (ΔΔQTcF) by more than 5 ms, with a maximum mean effect of 7.8 ms (2 mg) and 7.2 ms (10 mg), respectively, at 3 h post-dose. The upper bound of the one-sided 95% CI for the ΔΔQTcF at all time points remained below 10 ms. Categorical analysis revealed no treatment-emergent QTc values above 480 ms, no QTc increases from baseline of more than 60 ms and no corrected or uncorrected QT/QTc value exceeded 500 ms.
Siponimod treatment with single or multiple doses for 28 days is not associated with clinically relevant increases in airway resistance as measured by forced expiratory volume in 1 second (FEV1) and forced expiratory flow (FEF) during expiration of 25 to 75% of the forced vital capacity (FEF25-75%). A slight trend of reduced FEV1 was detected at non-therapeutic single doses (>10 mg). Multiple doses of siponimod were associated with mild to moderate changes in FEV1 and FEF25-75% which were not dose- and daytime-dependent and were not associated with any clinical signs of increased airway resistance.
The time (Tmax) to reach maximum plasma concentrations (Cmax) after multiple oral administration of siponimod is about 4 hours (range: 2 to 12 hours). Siponimod absorption is extensive (≥70%, based on the amount of radioactivity excreted in urine and the amount of metabolites in faeces extrapolated to infinity). The absolute oral bioavailability of siponimod is approximately 84%. For 2 mg siponimod given once daily over 10 days, a mean Cmax of 30.4 ng/ml and mean AUCtau of 558 h*ng/ml were observed on day 10. Steady state was reached after approximately 6 days of multiple once-daily administration of siponimod.
Despite a delay in Tmax to 8 hours after a single dose, food intake had no effect on the systemic exposure of siponimod (Cmax and AUC), therefore siponimod may be taken without regard to meals.
Siponimod is distributed to body tissues with a moderate mean volume of distribution of 124 litres. The siponimod fraction found in plasma is 68% in humans. Siponimod readily crosses the blood-brain barrier. Protein binding of siponimod is >99.9% in healthy subjects and in patients with hepatic or renal impairment.
Siponimod is extensively metabolised, mainly by cytochrome P450 2C9 (CYP2C9) (79.3%), and to a lesser extent by cytochrome P450 3A4 (CYP3A4) (18.5%).
The pharmacological activity of the main metabolites M3 and M17 is not expected to contribute to the clinical effect and the safety of siponimod in humans.
In vitro investigations indicated that siponimod and its major systemic metabolites M3 and M17 do not show any clinically relevant drug-drug interaction potential at the therapeutic dose of 2 mg once daily for all investigated CYP enzymes and transporters, and do not necessitate clinical investigation.
CYP2C9 is polymorphic and the genotype influences the fractional contributions of the two oxidative metabolism pathways to overall elimination. PBPK modelling indicates a differential CYP2C9 genotype-dependent inhibition and induction of CYP3A4 pathways. With decreased CYP2C9 metabolic activity in the respective genotypes, a larger effect of the CYP3A4 perpetrators on siponimod exposure is anticipated.
An apparent systemic clearance (CL/F) of 3.11 l/h was estimated in MS patients. The apparent elimination half-life of siponimod is approximately 30 hours.
Siponimod is eliminated from the systemic circulation mainly due to metabolism and subsequent biliary/faecal excretion. Unchanged siponimod was not detected in urine.
Siponimod concentration increases in an apparent dose proportional manner after multiple once-daily doses of siponimod 0.3 mg to 20 mg.
Steady-state plasma concentrations are reached after approximately 6 days of once-daily dosing and steady-state levels are approximately 2- to 3-fold greater than after the initial dose. An up-titration regimen is used to reach the clinically therapeutic dose of 2 mg siponimod after 6 days and 4 additional days of dosing are required to reach the steady-state plasma concentrations.
The CYP2C9 genotype influences siponimod CL/F. Two population pharmacokinetic analyses indicated that CYP2C9*1*1 and *1*2 subjects behave as extensive metabolisers, *2*2 and *1*3 subjects as intermediate metabolisers and *2*3 and *3*3 subjects as poor metabolisers. Compared to CYP2C9*1*1 subjects, individuals with the CYP2C9*2*2, *1*3, *2*3 and *3*3 genotypes have 20%, 35-38%, 45-48% and 74% smaller CL/F values, respectively. Siponimod exposure is therefore approximately 25%, 61%, 91% and 284% higher in CYP2C9*2*2, *1*3, *2*3 and *3*3 subjects, respectively, as compared to *1*1 subjects (see table).
There are other less frequent occurring polymorphisms for CYP2C9. The pharmacokinetics of siponimod have not been evaluated in such subjects. Some polymorphisms such as *5, *6, *8 and *11 are associated with decreased or loss of enzyme function. It is estimated that CYP2C9 *5, *6, *8 and *11 alleles have a combined frequency of approximately 10% in populations with African ancestry, 2% in Latinos/Hispanics and <0.4% in Caucasians and Asians.
CYP2C9 genotype effect on siponimod CL/F and systemic exposure:
| CYP2C9 genotype | Frequency in Caucasians | Estimated CL/F (L/h) | % CYP2C9*1*1 CL/F | % exposure increase versus CYP2C9*1*1 |
|---|---|---|---|---|
| Extensive metabolisers | ||||
| CYP2C9*1*1 | 62-65 | 3.1-3.3 | 100 | - |
| CYP2C9*1*2 | 20-24 | 3.1-3.3 | 99-100 | - |
| Intermediate metabolisers | ||||
| CYP2C9*2*2 | 1-2 | 2.5-2.6 | 80 | 25 |
| CYP2C9*1*3 | 9-12 | 1.9-2.1 | 62-65 | 61 |
| Poor metabolisers | ||||
| CYP2C9*2*3 | 1.4-1.7 | 1.6-1.8 | 52-55 | 91 |
| CYP2C9*3*3 | 0.3-0.4 | 0.9 | 26 | 284 |
Results from population pharmacokinetics suggest that dose adjustment is not necessary in elderly patients (age 65 years and above). No patients over 61 years of age were enrolled in clinical studies. Siponimod should be used with caution in the elderly.
Results from population pharmacokinetics suggest that gender-based dose adjustment is not necessary.
The single-dose pharmacokinetic parameters were not different between Japanese and Caucasian healthy subjects, indicating absence of ethnic sensitivity on the pharmacokinetics of siponimod.
No siponimod dose adjustments are needed in patients with mild, moderate or severe renal impairment. Mean siponimod half-life and Cmax (total and unbound) were comparable between subjects with severe renal impairment and healthy subjects. Total and unbound AUCs were only slightly increased (by 23 to 33%) compared to healthy subjects. The effects of end-stage renal disease or haemodialysis on the pharmacokinetics of siponimod have not been studied. Due to the high plasma protein binding (>99.9%) of siponimod, haemodialysis is not expected to alter the total and unbound siponimod concentration and no dose adjustments are anticipated based on these considerations.
Siponimod must not be used in patients with severe hepatic impairment. No dose adjustments for siponimod are needed in patients with mild or moderate hepatic impairment. The unbound siponimod pharmacokinetics AUC is 15% and 50% higher in subjects with moderate and severe hepatic impairment, respectively, in comparison with healthy subjects for the 0.25 mg single dose studied. The mean half-life of siponimod was unchanged in hepatic impairment.
In repeat-dose toxicity studies in mice, rats and monkeys, siponimod markedly affected the lymphoid system (lymphopenia, lymphoid atrophy and reduced antibody response), which is consistent with its primary pharmacological activity at S1P1 receptors.
Dose-limiting toxicities in animal species were nephrotoxicity in mice, body weight development in rats and adverse CNS and gastrointestinal effects in monkeys. The main target organs of toxicity in rodents included the lung, liver, thyroid, kidney and uterus/vagina. In monkeys, effects on muscle and skin were additionally observed. These toxicities developed at more than 30-fold higher systemic siponimod levels than the AUC-based human exposure at the maintenance dose of 2 mg/day.
Siponimod did not exert any phototoxic or dependence potential and was not genotoxic in vitro and in vivo.
In carcinogenicity investigations, siponimod induced lymphoma, haemangioma and haemangiosarcoma in mice, whereas follicular adenoma and carcinoma of the thyroid gland were identified in male rats. These tumour findings were either regarded as mouse-specific or attributable to metabolic liver adaptations in the particularly sensitive rat species and are of questionable human relevance.
Siponimod did not affect male and female fertility in rats up to the highest dose tested, representing an approximate 19-fold safety margin based on human systemic exposure (AUC) at a daily dose of 2 mg.
The receptor affected by siponimod (sphinosine-1-phosphate receptor) is known to be involved in vascular formation during embryogenesis.
In embryofoetal development studies conducted in rats and rabbits, siponimod induced embryotoxic effects in the absence of maternal toxicity. In both species, prenatal mortality was increased. While in rats a higher number of foetuses with external, skeletal and visceral malformations (e.g. cleft palate and misshapen clavicles, cardiomegaly and oedema) were noted, in rabbit foetuses skeletal and visceral variations were predominantly observed.
In the prenatal and postnatal development study performed in rats, there was in increased number of dead (stillborn or found dead before postnatal day 4) and malformed pups (male pups with urogenital malformations and/or decreased anogenital distance; pups of both sexes with oedema, swollen soft cranium, or flexed hindlimbs).
The exposure levels (AUC) at the respective NOAELs for embryofoetal (rats and rabbits) and pre/postnatal (rats) development were below the human systemic exposure (AUC) at a daily dose of 2 mg and consequently no safety margin exists.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
