. Solriamfetol has no appreciable binding affinity todopamine, serotonin, norepinephrine, GABA, adenosine, histamine, orexin, benzodiazepine,muscarinic acetylcholine, or nicotinic acetylcholine receptors.
Cardiac Electrophysiology
The effect of solriamfetol 300 mg and 900 mg (twice and six times the maximum recommendeddose, respectively) on the QTc interval was eva luated in a randomized, double-blind, placebo-,and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy subjects.
A large increase in heart rate was observed in both solriamfetol treatment groups (mean changefrom baseline in HR of 21 and 27 bpm in the 300 and 900 mg groups, respectively, comparedwith 8 bpm in the placebo group). These heart rate effects impact the interpretability of the QTceffects, particularly in the 900 mg group. In this study, solriamfetol 300 mg did not prolong theQTcF interval to a clinically relevant extent.
12.3 Pharmacokinetics
Solriamfetol exhibits linear kinetics over the dose range of 42 to 1008 mg (approximately 0.28 to6.7 times the maximum recommended dosage). Steady state is reached in 3 days, and once-dailyadministration is expected to result in minimal accumulation (1.06 times single-dose exposure).
Absorption
The oral bioavailability of solriamfetol is approximately 95%. Peak plasma concentration ofsolriamfetol occurs at a median Tmax of 2 hours (range 1.25 to 3.0 hours) post-dose under fastedconditions.
Effect of Food
Ingestion of solriamfetol with a high-fat meal resulted in minimal change in Cmax and AUCinf;
however, a delay of approximately 1 hour in Tmax was observed.
Distribution
The apparent volume of distribution of solriamfetol is approximately 199 L. Plasma protein
binding ranged from 13.3% to 19.4% over solriamfetol concentration range of
0.059 to 10.1 mcg/mL in human plasma. The mean blood-to-plasma concentration ratio ranged
from 1.16 to 1.29.
Elimination
Solriamfetol exhibits first-order elimination after oral administration. The apparent meanelimination half-life is about 7.1 hours.
Metabolism
Solriamfetol is minimally metabolized in humans.
Excretion
Approximately 95% of the dose was recovered in urine as unchanged solriamfetol, and 1% orless of the dose was recovered as the minor inactive metabolite N-acetyl solriamfetol in a massbalance study. Renal clearance (18.2 L/h) represented the majority of apparent total clearance(19.5 L/h). Active tubular secretion is likely involved in the renal elimination of the parent drug.
Specific Populations
Population PK analysis indicated that age, gender, and race do not have clinically relevant effectson the pharmacokinetics of solriamfetol. No dose adjustments were made in clinical studies thatenrolled patients ages 65 and above.
Patients with Renal Impairment
Exposures to solriamfetol in patients with renal impairment compared to subjects with normalrenal function (eGFR ≥ 90 mL/min/1.73 m2) are summarized in Figure 1. The half-life ofsolriamfetol was 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. Exposure (AUC) and half-life ofsolriamfetol was significantly increased in patients with ESRD (eGFR <15 mL/min/1.73 m2)[see Use in Specific Populations (8.6)]. An average of 21% of solriamfetol |
