A Phase I, Randomized, Crossover, Open-label Study of the Pharmacokinetics of Solriamfetol (JZP-110) in Healthy Adult Subjects With and Without Food

Abstract

Purpose: Solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, is currently being evaluated for the reduction of sleepiness and improvement of wakefulness in patients with narcolepsy and obstructive sleep apnea. The purpose of this study was to evaluate the effect of food on the pharmacokinetic (PK) parameters and bioavailability of solriamfetol at the highest intended therapeutic dose in healthy adults and to characterize its renal excretion under fasting conditions. Methods: In this open-label, randomized, crossover study, healthy adult subjects received a single 300-mg dose of solriamfetol in a fasted condition (10 h) and in a fed condition (30 min after the start of a standardized high-fat, high-calorie breakfast), with at least a 7-day washout period between doses. Blood samples for PK analyses were collected during both conditions at prespecified time points. Urine samples were collected up to 48 h postdose in the fasted condition. Samples were analyzed for solriamfetol (plasma and urine) and N-acetyl solriamfetol (urine) by using validated LC-MS/MS bioanalytical methods. The effect of food on solriamfetol relative bioavailability was examined by comparing the 90% confidence intervals (CIs) of the fed/fasted ratios of natural log-transformed PK parameters C max , AUC 0et , and AUC 0e∞ with the prespecified range of 80%e 125%. Safety and tolerability were also assessed. Findings: A total of 32 subjects were enrolled (50% female; 53.1% black, 46.9% white; mean age, 35.6 years), and 31 were included in the PK analyses. Solriamfetol was rapidly absorbed in both conditions. The 90% CIs for the fed/fasted geometric mean ratios were 89.2e98.8 for C max (ratio of 93.9%) and 93.8e101.5 for AUC 0e∞ (ratio of 97.6%), indicating the absence of a food effect. In the fasted condition, 89.8% of solriamfetol was recovered in urine as unchanged drug over 48 h; 1.1% was excreted as a minor metabolite, N-acetyl solriamfetol. A total of 55 adverse events (AEs), all mild, were reported by 18 subjects (56.3%). The frequency and type of AEs were similar in the 2 conditions; the most common AEs (insomnia, headache, hypervigilance, decreased appetite, and nausea) were all mild in severity and resolved without treatment. Implications: Solriamfetol relative bioavailability was bioequivalent in the fed and fasted conditions, showing that solriamfetol can be taken without regard to meals; furthermore, tolerability was similar in both conditions. Renal excretion of unchanged drug is the primary route of elimination. (Clin Ther.

Recently Approved and Upcoming Treatments for Narcolepsy

“…Solriamfetol exhibits linear PKs over a dose range of 42-1008 mg (Table 2) [26]. It is rapidly absorbed after oral administration (median t max , 2 h); administration with food delays absorption by ~ 1 h but does not affect overall exposure (minimal changes in C max and AUC ∞ ) [28]. It is not extensively protein bound (13-19%) and has a mean t ½ of ~ 7 h [26].…”

Single‐Dose Pharmacokinetics and Safety of Solriamfetol in Participants With Normal or Impaired Renal Function and With End‐Stage Renal Disease Requiring Hemodialysis

“…7 The major route of solriamfetol elimination is via urinary excretion, with approximately 90% of drug excreted unchanged within 48 hours, and ß1% of the dose excreted as the minor metabolite, N-acetyl solriamfetol. 7 Renal impairment, as well as hemodialysis in individuals with end-stage renal disease (ESRD) could affect the pharmacokinetics (PK) of solriamfetol. Therefore, in accordance with US Food and Drug Administration guidance for PK studies in patients with impaired renal function, 8 this study was designed to evaluate the PK of solriamfetol in participants with renal impairment and those with ESRD undergoing hemodialysis compared with healthy participants with normal renal function.…”

“…Solriamfetol has high solubility and high permeability and is considered a Biopharmaceutics Classification System class 1 compound. Solriamfetol is rapidly absorbed after oral administration, with median time to maximum plasma concentration (C max ) at 2 hours after dosing and an apparent elimination half‐life (t 1/2 ) of ∼6 hours . Consumption of a high‐fat, high‐calorie meal does not change the rate and extent of solriamfetol exposure but delays time to C max by 1 hour, which likely has minimal clinical significance .…”

A Randomized, Double‐Blind, Placebo‐ and Positive‐Controlled, 4‐Period Crossover Study of the Effects of Solriamfetol on QTcF Intervals in Healthy Participants

“…3 The PK profile of solriamfetol in this study is consistent with what has previously been reported in healthy adults. 5,6 Solriamfetol was rapidly absorbed, with a median t max of 2 and 3 hours following oral administration of 300-and 900-mg doses, respectively. An approximately 3-fold higher solriamfetol C max and 3.5-fold greater AUC 0-inf were observed following the 900-mg dose compared with the 300-mg dose, indicating dose-proportional PK.…”

“…1 Solriamfetol is rapidly absorbed following oral administration, has a terminal half-life of approximately 6 hours, and is mostly excreted in the urine unchanged (>90%). 5 Renal impairment increases overall exposure to solriamfetol, with greater increases in exposure as the level of renal function worsens. 6 The safety and efficacy of solriamfetol (maximum dose evaluated, 300 mg) in reducing EDS in patients with narcolepsy or OSA have been established in phase 3 clinical studies, including 6-and 12-week randomized, double-blind, placebo-controlled studies and a 1-year open-label extension study.…”