Table 2.
Pharmacokinetics and pharmacodynamic of selected S1P modulators [4, 39, 58, 72, 74, 82, 101, 111, 112, 133, 136–142]
| Fingolimod | Siponimod | Amiselimod | Ozanimod | Etrasimod | Ponesimod | Cenerimod | |
|---|---|---|---|---|---|---|---|
| Doses (oral) | 0.5 mg once daily | CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2 requires 5-day titration (0.25 mg once daily progressing until 1 mg daily). Maintenance dose: 2 mg once daily starting on day 6. Genotypes *1/*3 or *2/*3 initiate with a 4-day titration (0.25 mg once daily until 0.75 mg daily); Day 5 starts with 1 mg once daily | It still is unapproved by FDA. A Phase 1 study in healthy used upwardly titrated in doses ranging from 0.4 to 1.6 mg to achieve 0.4 mg and 0.8 mg steady-state exposure | Starts ozanimod 0.23 mg once daily on days 1 through 4; then 0.46 mg daily on days 5 through 7; maintenance dose: 0.92 mg once daily starting on day 8 | It still is unapproved by FDA. Currently, 2 mg once daily dose is used in IBD Phase 3 trials. | 14-day dose titration (2 mg once daily progressing until 15 mg daily); on day 15, the maintenance dosage is 20 mg daily. | It still is unapproved by FDA.4 mg once daily in a double-blind, randomized, placebo-controlled, proof-of-concept study in SLE had an improve of the disease score activity and antibody production |
| S1P receptor selectivity | 1, 2, 3, 4, 5 | 1, 5 | 1, 5, 4 and minimal 2, 3 | 1, 5 | 1, 4, 5 | 1 | 1 |
| Pro-drug (requires phosphorylation) | Yes | No | Yes | No | No | No | No |
| Metabolites actives | Yes | No | Yes | Yes | No | No | Cytochrome P450 (CYP) enzyme‐independent metabolism and no major metabolites in plasma. |
| Half life | 6–9 days | 30 h | 380–420 h | 19–22 h | 26.2–33.3 h | 21.7–33.5h | Single dose 170–199 h. Multiple doses 283–539 h |
| Disease evaluated | MS | MS | CD, MS, SLE | IBD, MS | IBD, AD, RA | MS, Psoriasis | SLE |
| Development stage | Approved for MS | Approved for MS | Clinical Trials | Approved for MS | Clinical Trials | Approved for MS | Clinical Trials |
| Time to steady state | 8 weeks | 6 days | 10 weeks | 7 weeks | 7 days | 5 days | 4 weeks |
| Time to lymphocyte count reduction (h) | 4–6 | 4–6 | No data | 6–12 | 1–3 | 1–6 | Dose dependent |
| Lymphocyte decrease from baseline (%) | 70 | 33–76 | 60–66 | 34–68 | 39–53 | 50–70 | 70 |
| Tmax (h) | 12–16 | 3–4.5 | 12–16 | 10 | 8 | 2–5 | 4–6 |
| Drugs-drugs interaction | Potent Inhibitor CYP3A (ketoconazole) |
Drug-drug interactions with agents that induce or inhibit CYP 2C9 and 3A4 are likely to occur Contraindicated in CYP2C9*2*3 and *3*3 genotypes |
BRCP inhibitors, CYP2C8 inhibitors, MAO inhibitors | No metabolic pathways have been identified that contribute to extent to the overall elimination | |||
| Excretion | Fecal major route whereas urinary is minor | Biliary excretion | Urine (minor) and feces | Urine (minor)and feces | Feces | Feces and urine (minor) | Feces |
Tmax time to maximum plasma concentration, MS multiple sclerosis, CD Crohn’s disease, SLE systemic lupus erythematous, IBD inflammatory bowel disease, AD atopic dermatitis, RA rheumatoid arthritis, BRCP breast cancer resistance protein.