Molecular mass: 460.97 g/mol PubChem compound: 11363176
Ponesimod is a sphingosine 1-phosphate (S1P) receptor 1 modulator. Ponesimod binds with high affinity to S1P receptor 1 located on lymphocytes.
Ponesimod blocks the capacity of lymphocytes to egress from lymph nodes reducing the number of lymphocytes in peripheral blood. The mechanism by which ponesimod exerts therapeutic effects in multiple sclerosis may involve reduction of lymphocyte migration into the central nervous system.
In healthy volunteers, ponesimod induces a dose-dependent reduction of the peripheral blood lymphocyte count from a single dose of 5 mg onwards, with the greatest reduction observed 6 hours post-dose, caused by reversible sequestration of lymphocytes in lymphoid tissues. After 7 daily doses of 20 mg, the greatest decrease in absolute mean lymphocyte count was to 26% of baseline (650 cells/µL), observed 6 hours after administration. Peripheral blood B cells [CD19+] and T cells [CD3+], T-helper [CD3+CD4+], and T-cytotoxic [CD3+CD8+] cell subsets are all affected, while NK cells are not. T-helper cells were more sensitive to the effects of ponesimod than T-cytotoxic cells.
Pharmacokinetic/Pharmacodynamic modelling indicates lymphocyte counts returned to the normal range in >90% of healthy subjects within 1 week of stopping therapy. In the development program, peripheral lymphocyte counts returned to the normal range within 1 week after discontinuation of ponesimod.
In the OPTIMUM study, lymphocyte counts returned to the normal range in 94% of patients and to above 0.8 × 109cells/L in 99% of patients at the first scheduled follow-up visit (day 15) upon discontinuation of ponesimod treatment.
Ponesimod causes a transient dose dependent reduction in HR and AV conduction delays upon treatment initiation. The HR decreases plateaued at doses greater than or equal to 40 mg, and bradyarrhythmic events (AV blocks) were detected at a higher incidence under ponesimod treatment, compared to placebo. This effect starts within the first hour of dosing and is maximal at 2-4 hours post-dose and HR generally returns to pre-dose values by 4-5 hours post-dose on day 1 and the effect diminishes with repeated administration, indicating tolerance.
With the gradual up-titration of ponesimod, the HR reduction is less pronounced and no second-degree AV blocks of Mobitz type II or higher degree were observed.
The decrease in HR induced by ponesimod can be reversed by atropine.
In a thorough QT study of supra-therapeutic doses of 40 mg and 100 mg (2- and 5-fold respectively, the recommended maintenance dose) ponesimod at steady-state, ponesimod treatment resulted in mild prolongation of individually corrected QT (QTcI) interval, with the upper bound of 90% two-sided confidence interval (CI) at 11.3 ms (40 mg) and 14.0 ms (100 mg). There was no consistent signal of increased incidence of QTcI outliers associated with ponesimod treatment, either as absolute values or change from baseline. Based on the concentration-effect relationship, no clinically relevant effect on QTc interval is expected for the therapeutic dose of 20 mg.
Dose-dependent reductions in absolute forced expiratory volume over 1 second were observed in ponesimod-treated subjects and were greater than in subjects taking placebo.
The pharmacokinetics of ponesimod is similar in healthy subjects and subjects with multiple sclerosis. The pharmacokinetic profile of ponesimod showed “low to moderate” inter-subject variability, approximately 6%–33%, and “low” intra-subject variability, approximately 12%-20%.
The time to reach maximum plasma concentration of ponesimod is 2-4 hours post-dose. The absolute oral bioavailability of a 10 mg dose is 83.8%.
Food does not have a clinically relevant effect on ponesimod pharmacokinetics, therefore ponesimod may be taken with or without food.
Following intravenous administration in healthy subjects, the steady-state volume of distribution of ponesimod is 160 L.
Ponesimod is highly bound to plasma proteins, (>99%) and is mainly (78.5%) distributed in the plasma fraction of whole blood. Animal studies show that ponesimod readily crosses the blood-brain-barrier.
Ponesimod is extensively metabolised prior to excretion in humans, though unchanged ponesimod was the main circulating component in plasma. Two inactive circulating metabolites, M12 and M13, have also been identified in human plasma. M13 is approximately 20% and M12 is 6% of total drug-related exposure. Both metabolites are inactive at S1P receptors at concentrations achieved with therapeutic doses of ponesimod.
In vitro studies with human liver preparations indicate that metabolism of ponesimod occurs through multiple, distinct enzyme systems, including multiple CYP450 (CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12), UGT (mainly UGT1A1 and UGT2B7) and non CYP450 oxidative enzymes, without major contribution by any single enzyme.
In vitro investigations indicate that at the therapeutic dose of 20 mg once-daily, ponesimod and its metabolite M13 do not show any clinically relevant drug-drug interaction potential for CYP or UGT enzymes, or transporters.
After a single intravenous administration, the total clearance of ponesimod is 3.8 L/hour. The elimination half-life after oral administration is approximately 33 hours.
Following a single oral administration of 14C-ponesimod, 57% to 80% of the dose was recovered in faeces (16% as unchanged ponesimod), and 10% to18% in urine (no unchanged ponesimod).
Following ponesimod oral dosing, Cmax and AUC increased approximately dose proportionally in the dose range studied (1-75 mg). Steady-state levels are approximately 2.0 to 2.6-fold greater than with a single dose and are achieved following 4 days of administration of the maintenance dose of ponesimod.
No dose adjustment is necessary in patients with renal impairment. In adult subjects with moderate or severe renal impairment (estimated creatinine clearance (CrCl) as determined by the Cockroft-Gault between 30-59 mL/min for moderate and <30 mL/min for severe), there were no significant changes in ponesimod Cmax and AUC compared to subjects with normal renal function (CrCl>90 mL/min). The effect of dialysis on the pharmacokinetics of ponesimod has not been studied. Due to the high plasma protein binding (greater than 99%) of ponesimod, dialysis is not expected to alter the total and unbound ponesimod concentration and no dose adjustments are anticipated based on these considerations.
In adult subjects without MS with mild, moderate or severe hepatic impairment (Child-Pugh class A, B and C, respectively, N=8 for each category), ponesimod AUC0-∞ was increased by 1.3-, 2.0- and 3.1-fold respectively compared to healthy subjects. Based on the population pharmacokinetic assessment in a larger group of subjects (N=1245), including 55 subjects with MS with mild hepatic impairment (classified based on the National Cancer Institute – Organ Dysfunction Working Group criteria), a 1.1-fold increase of ponesimod AUC0-∞ was estimated, compared to subjects with normal hepatic function.
Ponesimod is contraindicated in patients with moderate and severe hepatic impairment, as the risk of adverse reactions may be greater.
No dose adjustment is needed in patients with mild hepatic impairment (Child-Pugh class A).
The results from a population pharmacokinetics analysis indicated that age (range: 17 to 65 years) does not significantly influence the pharmacokinetics of ponesimod. Ponesimod has not been investigated in the elderly population (>65 years).
Gender has no clinically significant influence on ponesimod pharmacokinetics.
No clinically relevant pharmacokinetic differences were observed between Japanese and Caucasian or Black and White subjects.
In the lung, transient adaptive pulmonary histiocytosis and lung weight increase were observed in mice, rats, and dogs after 4 weeks of administration of ponesimod but were no longer present or were less pronounced after 13 to 52 weeks of administration. The no-observed-adverse-effect levels (NOAELs) for lung findings were identified in rat and dog 4-week toxicity studies and were associated with Cmax and AUC0-24 values similar or inferior to human systemic exposures following recommended human dose (RHD) of 20 mg/day.
In the dog, arterial lesions observed in the heart were secondary to haemodynamic changes. The dog is known to be particularly sensitive to hemodynamic changes in the heart and the associated toxicity may be species specific and not predictive of a risk in humans. When compared with human systemic exposures at RHD of 20 mg/day the NOAEL in the dog was 4.3 and 6.2 times the human systemic exposures based on AUC0–24 and Cmax, respectively.
Ponesimod did not reveal a genotoxic potential in vitro and in vivo.
Oral carcinogenicity studies of ponesimod were conducted in mice and rats for up to 2 years. In rats, no neoplastic lesions were observed up to the highest dose tested, corresponding with a plasma ponesimod exposure (AUC) which is 18.7 times that in humans at the RHD of 20 mg. In mice, ponesimod increased the combined total incidence of hemangiosarcoma and hemangioma in all treated males and high dose females. The lowest dose tested in females is the no-observed-effect-level (NOEL) for carcinogenesis, and the AUC0-24 is 2.4 times the human systemic exposures at RHD of 20 mg.
Ponesimod had no effect on male and female fertility in rats at plasma exposures (AUC) up to approximately 18 and 31 times (for males and females, respectively) that in humans at the RHD of 20 mg/day.
When ponesimod was orally administered to pregnant rats during the period of organogenesis, embryo-foetal survival, growth, and morphological development were severely compromised. Teratogenic effects with major skeletal and visceral abnormalities were also observed. When ponesimod was orally administered to pregnant rabbits during the period of organogenesis, a slight increase in post-implantation losses and foetal findings (visceral and skeletal) were noted. Plasma exposure (AUC) in rats and rabbits at the NOAEL (1 mg/kg/day in both species) is less than that in humans at the RHD of 20 mg/day.
When ponesimod was orally administered to female rats throughout pregnancy and lactation, decreased pup survival and body weight gain, and delayed sexual maturation were observed in the offspring at the highest dose tested. Fertility of the F1 females was reduced. The AUC0-24 at the NOAEL of 10 mg/kg/day is 1.2 to 1.5 times that in humans at the RHD of 20 mg/day. Ponesimod was present in the plasma of F1 pups, indicating exposure from the milk of the lactating dam.
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