Chemical formula: C₁₀H₁₄N₂O₂ Molecular mass: 194.234 g/mol
The mechanism(s) of solriamfetol to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea has not been fully characterised. However, its efficacy could be mediated through its activity as a dopamine and norepinephrine reuptake inhibitor (DNRI).
In radioligand-binding experiments with cells expressing cloned human receptors/transporters, solriamfetol showed affinity for the dopamine (replicate Ki = 6.3 and 14.2 μM) and norepinephrine transporter (replicate Ki = 3.7 and >10 μM) but no appreciable affinity to the serotonin transporter. Solriamfetol inhibited the reuptake of dopamine (replicate IC50 = 2.9 and 6.4 μM) and norepinephrine (IC50 = 4.4 μM) but not of serotonin by these cells.
In parenteral doses resulting in clear wake-promoting effects in rats, solriamfetol increased individual dopamine levels in the striatum and norepinephrine levels in the prefrontal cortex, and did not show appreciable binding to the rat dopamine and norepinephrine transporter in an autoradiography experiment.
The oral bioavailability of solriamfetol is approximately 95% with peak plasma concentrations occurring at a median Tmax of 2 hours (range 1.25 to 3 hours) under fasted conditions.
Ingestion of solriamfetol with a high-fat meal resulted in minimal changes in Cmax and AUC; however, a delay of approximately 1 hour was observed in Tmax. The results show that solriamfetol can be taken without regard to food.
The apparent volume of distribution of solriamfetol is approximately 198.7 L, indicating extensive tissue distribution beyond the vascular compartment. Plasma protein binding ranged from 13.3% to 19.4% over the solriamfetol concentration range of 0.059 to 10.1 μg/mL in human plasma. The mean blood-to-plasma concentration ratio ranged from 1.16 to 1.29, suggesting a small extent of binding of solriamfetol to blood cells.
Solriamfetol is minimally metabolised in humans.
With the exception of weak inhibition of CYP2D6 (IC50 of 360 μM), solriamfetol is not a substrate or inhibitor of any of the major CYP enzymes and does not induce CYP1A2, 2B6, 3A4 or UGT1A1 enzymes at clinically relevant concentrations. Solriamfetol does not appear to be a substrate or inhibitor of membrane transporters P-gp, BCRP, OATP1B1, OATP1B3, OAT1 or OAT3. Solriamfetol is primarily excreted unchanged in the urine and is a low-affinity substrate of multiple renal cationic active substance transporters, without strong affinity for any individual transporter tested (OCT2, MATE1, OCTN1 and OCTN2). Solriamfetol is not an inhibitor of renal transporters OCT1, MATE2K, OCTN1 or OCTN2 but is a weak inhibitor of OCT2 (IC50 of 146 μM) and MATE1 (IC50 of 211 μM). Taken together, these results show that clinically relevant PK drug interactions are unlikely to occur in patients taking solriamfetol.
The apparent mean elimination half-life of solriamfetol is 7.1 hours, and the apparent total clearance is approximately 19.5 L/h. Renal clearance for solriamfetol is approximately 18.2 L/h.
In a human mass-balance study, approximately 95% of the dose was recovered in urine as unchanged solriamfetol and 1% or less of the dose was recovered as the minor inactive metabolite N-acetyl solriamfetol. Renal clearance represented the majority of apparent total clearance and exceeded creatinine clearance by approximately 3-fold, indicating that active tubular secretion of the parent drug is likely the major elimination pathway.
Solriamfetol exhibits linear pharmacokinetics over the clinical dose range. Steady state is reached in 3 days, and once-daily administration of 150 mg is expected to result in minimal solriamfetol accumulation (1.06 times single-dose exposure).
Compared to subjects with normal renal function (eGFR≥90 mL/min/1.73 m²), AUC of solriamfetol was higher by approximately 1.5-, 2.3-, and 4.4-fold, and t½ increased approximately 1.2-, 1.9-, and 3.9- fold in patients with mild (eGFR 60-89 mL/min/1.73 m²), moderate (eGFR 30-59 mL/min/1.73 m²), or severe (eGFR<30 mL/min/1.73 m²) renal impairment, respectively. In general, mean Cmax and median Tmax values were not affected by renal impairment.
Compared to subjects with normal renal function (eGFR≥90 mL/min/1.73 m²), AUC of solriamfetol was higher by approximately 6.2- and 4.6-fold, respectively, in patients with ESRD without hemodialysis and in patients with ESRD undergoing hemodialysis, and t½ increased at least 13-fold. Solriamfetol is not recommended for use in patients with ESRD. In patients with ESRD, an average of 21% of solriamfetol was removed by hemodialysis.
Population PK analysis indicated that the intrinsic covariates of age, gender, and race do not have clinically relevant effects on the pharmacokinetics of solriamfetol
Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity, and male and female fertility.
Repeated dose toxicity studies with daily oral application were conducted in mice (duration 3 months, NOAEL 17 mg/kg/day), rats (duration 6 months with a 3-month recovery period, NOAEL not established, LOAEL 29 mg/kg/day) and dogs (duration 12 months with a 3-month recovery period, NOAEL not established, LOAEL 8 mg/kg/day). AUC-based safety factors for solriamfetol derived from these studies (based on comparison with clinical AUC at the maximum recommended human dose of 150 mg/day) were <1 for mice (based on NOAEL) and <2 for rats and dogs (based on LOAEL), mainly due to exaggerated pharmacological effects of solriamfetol on CNS activity.
Long-term carcinogenicity studies have been performed in mice, treated with oral solriamfetol doses of 20, 65 and 200 mg/kg/day for up to 104 weeks, and in rats, treated with oral solriamfetol doses of 35, 80 and 200 mg/kg/day for up to 101 weeks. Solriamfetol did not increase the incidence of neoplastic findings in these lifetime carcinogenicity assays. AUC-based safety margins at the high dose to the maximal recommended human dose (MRHD, 150 mg/day) were about 7.8 in mice and about 20.7 in rats. In the light of negative genotoxicity and no increase of tumour incidence in both carcinogenicity studies, it can be concluded that solriamfetol does not pose a carcinogenic risk to humans. Compared to controls, survival rate was decreased in solriamfetol-treated (male) mice, maximal at a dose of 65 mg/kg/day (AUC-based safety margin to MRHD about 2.9), but not in solriamfetol-treated rats.
Possible effects on embryofoetal development were investigated in pregnant rats and rabbits. Embryofoetal toxicity (increased postimplantation loss in rats, increased incidence of skeletal alterations that included sternebrae malalignment in rats and rabbits, hindlimb rotation and bent bones in rats, and decreased foetal weights in both species) and situs inversus in rats was only evident in the presence of maternal toxicity (decreased body weights). Whether embryotoxicity was a consequence of maternal toxicity or a direct effect of solriamfetol cannot be determined. In a distribution study in pregnant rats 14C-solriamfetol was detected in foetal membrane (around twice as high as in blood), placenta and whole foetus (nearly similar to blood concentration) and thus a direct toxic effect on the foetus cannot be excluded. In rats the exposure margins at the maternal and developmental NOAEL are below the human exposure (0.6-0.7 based on AUC) at the MRHD, while in rabbits the exposure margins at the maternal and developmental NOAEL is <6 (based on mg/m² body surface area).
In rats exposure levels (AUC) above 0.6-0.7 times the human exposure (AUC) at the MRHD during pregnancy and lactation resulted in maternal toxicity and adverse effects on growth and development in the offspring. At exposure levels (AUC) 8 to 12 times the human exposure (AUC) at the MRHD no long-term effects on learning and memory were observed, but mating and pregnancy indices of the offspring were decreased.
© 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.