Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: psychoanaleptics, centrally acting sympathomimetics, ATC code: N06BA14

Mechanism of action

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).

Pharmacodynamic effects

In vitro data
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 vivo animal data
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.

Clinical efficacy and safety

Narcolepsy
Study 1, a 12-week, randomised, double-blind, placebo-controlled, parallel-group study, evaluated the efficacy of solriamfetol in adult patients with narcolepsy (with or without cataplexy).

For entry into this study patients had to have excessive daytime sleepiness (an Epworth Sleepiness Scale [ESS] score greater than or equal to 10), and trouble maintaining wakefulness (mean sleep latency less than 25 minutes) as documented by the mean of the first 4 trials of the 40-minute Maintenance of Wakefulness Test (MWT) at baseline.

The measures of efficacy were change from baseline to Week 12 on: ability to stay awake as measured by mean sleep latency on the MWT, excessive daytime sleepiness as measured by the ESS, and improvement in overall clinical condition as assessed by the Patient Global Impression of Change (PGIc) scale. The ESS is an 8- item patient-reported measure of likelihood of falling asleep in usual daily life activities. The PGIc is a 7-point scale ranging from “very much improved” to “very much worse” which assesses the patient’s report of change in their clinical condition.

Patients with narcolepsy were characterised by impaired wakefulness and excessive daytime sleepiness, as indicated by baseline MWT mean sleep latency and ESS scores, respectively (Table 1). Most patients had prior use of psychostimulants.
Cataplexy was present in approximately half of patients overall; demographic and baseline characteristics were similar between patients with cataplexy and those without cataplexy.

In this study, patients with narcolepsy were randomised to receive solriamfetol 75 mg, 150 mg, or 300 mg (two times the maximum recommended daily dose), or placebo once daily. At Week 12, patients randomised to the 150 mg dose showed statistically significant improvements on the MWT and ESS (co-primary endpoints), as well as on the PGIc (key secondary endpoint), compared with placebo. Patients randomised to receive 75 mg showed statistically significant improvement on the ESS, but not on the MWT or PGIc (Table 1). These effects were dose-dependent, observed at Week 1 and maintained over the study duration (Figure 1). In general, at the same doses, a smaller magnitude of effect was observed in patients with more severe baseline levels of sleepiness relative to those who were less severe. At Week 12, patients who were randomised to receive 150 mg of solriamfetol demonstrated sustained improvements in wakefulness throughout the day that were statistically significant compared to placebo for each of the 5 MWT trials, spanning approximately 9 hours after dosing. Dose-dependent improvements in the ability to conduct daily activities were observed, as measured by the Functional Outcomes of Sleep Questionnaire Short Version (FOSQ-10). Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.

Night-time sleep as measured with polysomnography was not affected by the use of solriamfetol.
Table 1. Overview of Efficacy Results at Week 12 in Patients with Narcolepsy in Study 1
Mean        Difference from
Treatment       Mean Baseline
Change from Placebo (95%          P - Value
Groups (N)         Score (SD)
Baseline             CI)
Study 1                                   LS Mean
Placebo (58)                                (SE)
MWT                            6.15 (5.68)                         2.62 (-1.04, Sunosi 75 mg                             2.12 (1.29)
(min)                          7.50 (5.39)                            6.28)              0.1595 (59) Sunosi 150                          4.74 (1.34)
7.85 (5.74)                         7.65 (3.99,          <0.0001 mg (55)                                  9.77 (1.33)
11.31)
Study 1                                    LS Mean
Placebo (58)                                 (SE)
17.3 (2.86)
Sunosi 75 mg                              -1.6 (0.65)
17.3 (3.53)                       -2.2 (-4.0, -0.3)       0.0211
(59) Sunosi 150                           -3.8 (0.67)
17.0 (3.55)                       -3.8 (-5.6, -2.0)      <0.0001 mg (55)                                   -5.4 (0.66)
Percentage
Percentage of Patients                   Difference from
P - Value
Improved*                            Placebo (95%
CI)
PGIc      Study 1
Placebo (58)
39.7%
Sunosi 75 mg
67.8%                        28.1 (10.8, 45.5)             0.0023†
(59) Sunosi 150
78.2%                        38.5 (21.9, 55.2)             <0.0001 mg (55)
SD = Standard Deviation; SE = Standard Error; LS Mean = Least Square Mean; Difference From Placebo = LS Mean Difference between change from baseline between active drug and placebo. MWT results are derived from the first 4 trials of the MWT and a positive change from baseline represents improvement in the sleep latency time. On the ESS, a negative change from baseline represents improvement in excessive daytime sleepiness. *The percentage of patients improved on the PGIc includes those who reported very much, much and minimal improvements; †Nominal p-value.


Figure 1: Co-Primary Efficacy Endpoints in Patients with Narcolepsy in Study 1 


OSA
Study 2, a 12-week, randomised, double blind, placebo-controlled parallel-group study, evaluated the efficacy of solriamfetol in adult patients with OSA. The co- primary and key secondary endpoints in this study were identical to Study 1. Study 3 was a 6-week, randomised-withdrawal, double-blind, placebo-controlled study of the efficacy of solriamfetol in adult patients with OSA. The measures of efficacy in the randomised withdrawal period were change from the beginning to the end of the randomised-withdrawal period on the MWT, the ESS, and worsening in overall clinical condition as assessed by the PGIc.

For entry into both studies, patients had to have excessive daytime sleepiness (ESS score ≥10) and trouble maintaining wakefulness (mean sleep latency <30 minutes as documented by the mean of the first 4 trials of the MWT) at baseline. Patients were eligible if they: 1) were currently using a primary OSA therapy (at any level of adherence); 2) had previously used a primary therapy for at least one month with at least one documented adjustment to the therapy; or 3) had undergone a surgical intervention in an attempt to treat the underlying obstruction. Patients were encouraged to stay on their current primary OSA therapy at the same level of use throughout the study. Patients were excluded only on the basis of their primary therapy use if they had refused to try a primary therapy such as CPAP, an oral appliance, or a surgical intervention to treat their underlying obstruction.

In Study 2, patients with OSA were characterised by impaired wakefulness and excessive daytime sleepiness (EDS), as indicated by baseline MWT mean sleep latency and ESS scores, respectively (Table 2). Approximately 71% of patients were adherent (e.g. ≥4 hours per night on ≥70% of nights); demographic and baseline characteristics were similar between patients regardless of adherence to primary OSA therapy. At baseline, primary OSA therapy was used by approximately 73% of patients; of these patients, 92% of patients were using positive airway pressure (PAP).

Patients were randomised to receive solriamfetol 37.5 mg, 75 mg, 150 mg, 300 mg (two times the maximum recommended daily dose), or placebo once daily. At Week 12, patients randomised to the 75 mg and150 mg dose arms showed statistically significant improvements on the MWT and ESS (coprimary endpoints), as well as on the PGIc (key secondary endpoint), compared with placebo (Table 2). Patients randomised to 37.5 mg solriamfetol showed statistically significant improvements based on the MWT and ESS. These effects were observed at Week 1, maintained over the study duration and were dose-dependent (Figure 2). At Week 12, patients who were randomised to receive 75 mg and 150 mg of Sunosi demonstrated sustained improvements in wakefulness throughout the day that were statistically significant compared to placebo for each of the 5 MWT trials, spanning approximately 9 hours after dosing. Dose- dependent improvements in the ability to conduct daily activities were observed, as measured by the FOSQ-10. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.

Night-time sleep as measured with polysomnography was not affected by the use of solriamfetol in Study 2. No clinically meaningful changes in patient use of primary OSA therapy were observed across the 12-week study period in any treatment group. Adherence/non-adherence to primary OSA therapy did not suggest evidence of differential efficacy.

In Study 3, baseline demographics and disease characteristics were similar to the study population in Study 2. The dose was initiated at 75 mg once daily and could be titrated up one dose level in intervals no shorter than every 3 days, according to efficacy and tolerability, to 150 mg or 300 mg. Patients could also titrate down to 75 mg or 150 mg. Patients treated with solriamfetol remained improved, whereas placebo-treated patients worsened (LS mean difference of 11.2 minutes on MWT and -4.6 on ESS; both p<0.0001) during the randomised-withdrawal period after 4 weeks of open-label treatment. Fewer patients treated with solriamfetol reported worsening on the PGIc (percentage difference of 30%; p=0.0005).
Table 2. Overview of Efficacy Results at Week 12 in Patients with OSA in Study 2
Mean                         Difference from
Treatment Group                   Mean Change
Baseline                       Placebo (95%    P -Value
(N)                        from Baseline
Score (SD)                            CI)
LS Mean (SE)
MWT                                                                      - Placebo (114)         12.58 (7.14)      0.21 (1.0)                                 - (min)                                                            4.53 (1.16, 7.90) Sunosi 37.5 mg        13.6 (8.15)       4.74 (1.42)                             0.0086 8.87 (5.59, 12.14)
(56)                  12.44 (6.91)      9.08 (1.36)                            <0.0001 10.74 (8.05,
Sunosi 75 mg (58)     12.54 (7.18)     10.96 (0.97)                            <0.0001 13.44)
Sunosi 150 mg
(116)

Placebo (114)                                      LS Mean (SE)
ESS        Sunosi 37.5 mg                15.6 (3.32)           -3.3 (0.45)                     -                       - (56)                          15.1 (3.53)           -5.1 (0.64)             -1.9 (-3.4, -0.3)            0.0161 Sunosi 75 mg (58)             15.0 (3.51)           -5.0 (0.62)             -1.7 (-3.2, -0.2)            0.0233 Sunosi 150 mg                 15.1 (3.37)           -7.7 (0.44)             -4.5 (-5.7, -3.2)           <0.0001 (116)
Percentage
Percentage of Patients                    Difference from
P -Value
Improved*                             Placebo (95%
CI)
Placebo (114)
-
PGIc        Sunosi 37.5 mg                               49.1%                                                         - 6.2 (-9.69, 22.16)
(56)                                         55.4%                                                      0.4447 23.3 (8.58, 38.01)
Sunosi 75 mg (58)                            72.4%                                                      0.0035 40.5 (29.81,
Sunosi 150 mg                                89.7%                                                      <0.0001 51.25)
(116)
SD = Standard Deviation; SE = Standard Error; LS Mean = Least Square Mean; Difference From Placebo = LS Mean Difference on change from baseline between active drug and placebo. MWT results are derived from the first 4 trials of the MWT and a positive change from baseline represents improvement in the sleep latency time. On the ESS, a negative change from baseline represents improvement in excessive daytime sleepiness. *The percentage of patients improved on the PGIc includes those who reported very much, much and minimal improvements.


Figure 2: Co-Primary Efficacy Endpoints in Patients with OSA in Study 2 


Long-term efficacy in narcolepsy and OSA
Study 4 was a long-term safety and maintenance of efficacy study for up to a year of treatment with solriamfetol, including a 2-week randomised-withdrawal, placebo- controlled period after at least 6 months of treatment with solriamfetol, in adult patients with narcolepsy or OSA who had completed a prior trial.

The measures of efficacy in the randomised withdrawal period were change from the beginning to the end of the randomised-withdrawal period on the ESS and worsening in overall clinical condition as assessed by the PGIc. Dose initiation and titration was identical to Study 3.
Patients treated with solriamfetol remained improved, whereas placebo-treated patients worsened (LS mean difference of -3.7 on ESS; p<0.0001) during the randomised-withdrawal period after at least 6 months of open-label treatment. Fewer patients treated with solriamfetol reported worsening on the PGIc (percentage difference of -36.2%; p<0.0001). These results demonstrate long-term maintenance of efficacy with continued solriamfetol treatment, and a reversal of treatment benefit upon discontinuation of that treatment.

For patients who were using a primary OSA therapy at the beginning of the study, primary OSA therapy use did not change over the course of the long-term study.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption

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.

Distribution

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.

Biotransformation

Solriamfetol is minimally metabolised in humans.
Interactions
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.

Elimination
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.

Linearity/non-linearity

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).

Special populations

Renal impairment
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 t1/2 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 t1/2 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.

Age, gender, race
Population PK analysis indicated that the intrinsic covariates of age, gender, and race do not have clinically relevant effects on the pharmacokinetics of solriamfetol.