was removed byhemodialysis. In general, median Tmax values were not affected by renal impairment.
Figure 1. Effect of Renal Impairment on Solriamfetol PharmacokineticsDrug Interaction Studies
In Vitro Studies
CYP and UGT Enzymes: Solriamfetol was minimally metabolized in vitro. Solriamfetol is not aninhibitor of CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. It does not induceCYP1A2, 2B6, 3A4, or UGT1A1 enzymes at clinically relevant concentrations.
Transporter Systems: Solriamfetol is a low-avidity substrate of OCT2, MATE1, OCTN1, andOCTN2. Solriamfetol is a weak inhibitor of OCT2 (IC50 of 146 μM) and MATE1 (IC50 of211 μM), and is not an inhibitor of OCT1, MATE2-K, OCTN1, or OCTN2. Solriamfetol doesnot appear to be a substrate or inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, or OAT3.
Based on in vitro data, clinically significant PK drug interactions with major CYPs andtransporters are not expected in patients taking SUNOSI.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Solriamfetol did not increase the incidence of tumors in rats or mice treated orally for up to 101and 104 weeks at 35, 80, and 200 mg/kg/day (rat), and 20, 65, and 200 mg/kg/day (mouse),respectively. These doses are approximately 2, 6, and 18 times (rat), and 0.4, 2.6, and 7 times(mouse) the MRHD based on AUC.
Mutagenesis
Solriamfetol was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay orclastogenic in the in vitro mammalian chromosomal aberration assay or in the in vivo mousebone marrow micronucleus assay.
Impairment of Fertility
Solriamfetol did not affect fertility or sperm parameters when administered orally to male rats for8 weeks at doses of 35 and 110 mg/kg/day, which are approximately 2 and 7 times the MRHD,based on mg/m2 body surface area. At 350 mg/kg/day, which is approximately 22 times theMRHD based on mg/m2 body surface area, solriamfetol decreased sperm count and spermconcentration without affecting fertility.
Solriamfetol did not affect fertility when administered orally to female rats for 2 weekspremating, during mating, and through gestation day 7 at 15, 67, and 295 mg/kg/day, which areapproximately 1, 4, and 19 times the MRHD, based on mg/m2 body surface area.
14 CLINICAL STUDIES
14.1 Narcolepsy
The efficacy of SUNOSI in improving wakefulness and reducing excessive daytime sleepinesswas demonstrated in a 12-week, multi-center, randomized, double-blind, placebo-controlled,parallel-group study (Study 1; NCT02348593) in adult patients with a diagnosis of narcolepsyaccording to the ICSD-3 or DSM-5 criteria.
Wakefulness and sleepiness were assessed using the Maintenance of Wakefulness Test (MWT)and the Epworth Sleepiness Scale (ESS). The MWT measures an individual’s ability to remainawake during the daytime in a darkened, quiet environment. Patients were instructed to remainawake for as long as possible during 40-minute test sessions, and sleep latency was determinedas the mean number of minutes patients could remain awake in the first four test sessions. TheESS is an 8-item questionnaire by which patients rate their perceived likelihood of falling asleepduring usual daily life activities. Change in overall symptom severity was assessed using the
Patient Global Impression of Change (PGIc) scale. The PGIc is a 7-point patient-reported scaleby which patients rate their symptom change since the beginning of the study. R |
