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

Abstract

Solriamfetol (JZP‐110), a selective dopamine and norepinephrine reuptake inhibitor with wake‐promoting effects, is renally excreted ∼90% unchanged within 48 hours. Effects of renal impairment and hemodialysis on the pharmacokinetics and safety of 75‐mg single‐dose solriamfetol were evaluated in adults with normal renal function (n = 6); mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment; and end‐stage renal disease (ESRD) with and without hemodialysis (n = 7). Relative to normal renal function, geometric mean area under the plasma concentration–time curve from time zero to infinity increased 53%, 129%, and 339%, and mean half‐life was 1.2‐, 1.9‐, and 3.9‐fold higher with mild, moderate, and severe renal impairment, respectively. Renal excretion of unchanged solriamfetol over 48 hours was 85.8%, 80.0%, 66.4%, and 57.1% in normal, mild, moderate, and severe renal impairment groups, respectively; mean maximum concentration and time to maximum concentration did not vary substantially. Decreases in solriamfetol clearance were proportional to decreases in estimated glomerular filtration rate. Geometric mean area under the plasma concentration–time curve from time zero to time of last quantifiable concentration increased 357% and 518% vs normal in ESRD with and without hemodialysis, respectively, with half‐life >100 hours in both groups. Over the 4‐hour hemodialysis period, ∼21% of solriamfetol dose was removed. Adverse events included headache (n = 1) and nausea (n = 1). Six days after dosing, 1 participant had increased alanine and aspartate aminotransferase, leading to study discontinuation. While these adverse events were deemed study‐drug related, they were mild and resolved. Results from this study combined with population pharmacokinetic modeling/simulation suggest that solriamfetol dosage adjustments are necessary in patients with moderate or severe but not with mild renal impairment. Due to significant exposure increase/prolonged half‐life, dosing is not recommended in patients with ESRD.

Recently Approved and Upcoming Treatments for Narcolepsy

“…Solriamfetol C max and t max values are not substantially affected by mild to severe renal impairment [29]. However, there are incremental decreases in clearance with worsening renal function, and these correspond to increases in AUC ∞ (53%, 129%, 339%) and t ½ (1.2-, 1.9-, 3.9-fold) in mild, moderate and severe renal impairment, respectively, relative to no renal impairment.…”

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.…”

“…12,13 As previously noted, the 300-mg dose was the highest dose evaluated in phase 3 studies in participants with narcolepsy or OSA. [7][8][9] The 900-mg dose was selected for this study because it was likely to be the highest dose that could be studied without having an adverse impact on tolerability or study discontinuation and because it was predicted to result in exposures greater than what would be estimated in individuals who might have increased exposure to therapeutic doses of solriamfetol (eg, those with renal impairment 6 ).…”

“…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. [7][8][9][10] Solriamfetol has low potential for drug-drug interactions, including a lack of interaction with oral hormonal contraceptives (a concern with some wake-promoting agents), and relatively low abuse potential (similar to or lower than that of phentermine).…”

Single‐Dose Pharmacokinetics, Safety, and Tolerability of Avadomide (CC‐122) in Subjects With Mild, Moderate, or Severe Renal Impairment

“…Although elimination can occur through several routes, most small‐molecule drugs are cleared by elimination of unchanged parent drug via the kidney and/or by metabolism in the liver and/or gastrointestinal tract. If the elimination of a drug is predominantly through the renal excretory pathway, impaired renal function usually alters the drug's exposure to the extent that the dosage regimen needs to be changed for patients with various degrees of renal impairment from that used in patients with normal renal function, especially for drugs with a narrow therapeutic index . Therefore, assessing the effect of organ impairment (including renal impairment and hepatic impairment) on drug exposure is required for all investigational drugs.…”