Safety and pharmacokinetics (PK) were assessed in subjects with liver impairment (Child-Pugh Classification [CPC]: mild 5–6 and moderate 7–9) following administration of escalating doses of nalbuphine (NAL) extended-release (ER) (27, 54, 108, and 162 mg) and compared with healthy controls receiving NAL ER 162 mg. Subjects with severe liver impairment (CPC: 10-15) were administered fixed-dose NAL ER 27 mg. Men and women aged ≥18 to ≤80 years with stable hepatic impairment and a BMI ≥18.0 to ≤40 kg/m2 were eligible. PK parameters (Cmax, AUC, T½el, and Tmax) were calculated using noncompartmental methods. The study population (n=28) was 49–69 years old, 64.3% male, and 67.9% white and had a mean BMI of 30.1 kg/m2. NAL Cmax and AUC increased in a nearly dose-proportional manner in subjects with mild or moderate hepatic impairment. Mean NAL T½el and Tmax were unchanged by level of hepatic impairment. NAL Cmax and AUC in moderate and severe hepatic impairment increased by ~3- to 4-fold and ~6- to 8-fold versus those with no hepatic impairment. All metabolite exposure appeared to increase in an approximately dose-proportional manner. As expected, with increased severity of hepatic impairment, metabolite exposures remained lower or similar. All NAL ER doses were determined safe. Most treatment-emergent adverse events (TEAEs) were mild or moderate and transient. The most frequently reported TEAEs were nervous system disorders (19 events [46.4%; 13/28]). Somnolence (15 events [39.3%; 11/28) was reported with all NAL ER doses except 27 mg. No serious TEAEs occurred. Thus, no dosing adjustment may be needed for patients with mild hepatic impairment. Subjects with moderate hepatic impairment and those with severe hepatic impairment may be administered a lower daily NAL ER dose of ~4 mg to ~120 mg and ~2 mg to ~45 mg, respectively. Thus, the population of patients accessible for the safe dosing of NAL ER could potentially be expanded to those with various degrees of hepatic impairment in medical conditions in which NAL ER is indicated for use.

ESDRLB025 - Safety and Pharmacokinetics of Nalbuphine Following Administration of Nalbuphine ER Tablets in Subjects with Impaired Hepatic Function

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