Pharmacokinetics of long-acting naltrexone in subjects with mild to moderate hepatic impairment.

Long-acting naltrexone is an extended-release formulation developed with the goal of continuous naltrexone exposure for 1 month for the treatment of alcohol dependence. The influence of mild and moderate hepatic impairment on naltrexone pharmacokinetics following long-acting naltrexone 190-mg administration was assessed. Subjects with mild (Child-Pugh grade A) and moderate (Child-Pugh grade B) hepatic impairment (n = 6 per group) and matched control subjects (n = 13) were enrolled. Naltrexone and 6beta-naltrexol concentrations were determined over a period of 63 days following a single intramuscular dose. Naltrexone and 6beta-naltrexol concentrations were detected in all subjects through 28 days. Total exposure (AUC(0-infinity)) of naltrexone and 6beta-naltrexol was similar across all groups. The long apparent half-lives of naltrexone and 6beta-naltrexol (5-8 days) were attributed to the slow release of naltrexone (long-acting naltrexone exhibits absorption rate-limited elimination or "flip-flop" kinetics); elimination was not altered in subjects with hepatic impairment. Based on pharmacokinetic considerations, the dose of long-acting naltrexone does not need to be adjusted in patients with mild or moderate hepatic impairment.

PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models.

Phosphoinositide-3 kinase (PI3K)-δ and PI3K-γ are preferentially expressed in immune cells, and inhibitors targeting these isoforms are hypothesized to have anti-inflammatory activity by affecting the adaptive and innate immune response. We report on a potent oral PI3K-δ and PI3K-γ inhibitor (IPI-145) and characterize this compound in biochemical, cellular, and in vivo assays. These studies demonstrate that IPI-145 exerts profound effects on adaptive and innate immunity by inhibiting B and T cell proliferation, blocking neutrophil migration, and inhibiting basophil activation. We explored the therapeutic value of combined PI3K-δ and PI3K-γ blockade, and IPI-145 showed potent activity in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models. These findings support the hypothesis that inhibition of immune function can be achieved through PI3K-δ and PI3K-γ blockade, potentially leading to significant therapeutic effects in multiple inflammatory, autoimmune, and hematologic diseases.

Population pharmacokinetics of extended-release injectable naltrexone (XR-NTX) in patients with alcohol dependence.

OBJECTIVE: Injectable extended-release naltrexone (XR-NTX; Vivitrol) has recently been approved for the treatment of alcohol dependence. A population pharmacokinetic (PPK) analysis examined the possibility of altered pharmacokinetics for naltrexone and its primary metabolite, 6beta-naltrexol, in subpopulations with a potential for alcohol-dependence treatment. METHOD: Data from four clinical studies of XR-NTX were pooled. Absorption was modeled as a sequential release in three phases. The pharmacokinetics of naltrexone and 6beta-naltrexol were modeled as one-compartment disposition submodels, parameterized in terms of clearance (CL) and volume of distribution (V). The impact of age, weight, gender, race, hepatic function, renal function, smoking, and alcohol/opioid dependence on PPK parameter estimates was analyzed. RESULTS: Plasma concentrations were available from 453 subjects. More than half of the subjects (59%) were alcohol dependent, and 27% were dependent on both alcohol and opioids. Naltrexone CL (140 L/h) and V (38,300 L) were dependent on weight (changes of 0.548 L/h/kg and 0.655 L/kg, respectively) and were 23% and 35% higher, respectively, in subjects with alcohol and/or opioid dependence than in healthy subjects. Naltrexone CL also was dependent on age (-0.108 L/h/year); 6beta-naltrexol CL (65.1 L/h) was dependent on creatinine CL (0.229 L/h/ml/minute) and alkaline phosphatase (-0.130 L/h/IU/L), and was increased by 18% in smokers and in alcohol- and/or opioid-dependent subjects. CONCLUSIONS: Although statistically significant covariate-parameter relationships were identified, they were not considered clinically meaningful, suggesting that dosing adjustments of XR-NTX based on weight, age, gender, health status, smoking status, creatinine CL, and hepatic function differences should not be necessary.

Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone.

BACKGROUND: Oral naltrexone is effective in the treatment of alcohol dependence; however, a major limitation of its clinical utility is poor patient adherence to the daily dosing schedule. A biodegradable, long-acting naltrexone microsphere formulation was developed to achieve continuous naltrexone exposure for 1 month in the treatment of alcohol dependence. METHODS: The single- and multiple-dose safety and pharmacokinetics of a long-acting naltrexone microsphere preparation were evaluated in healthy subjects. One group of subjects (n = 28) received a single dose of oral naltrexone 50 mg followed by a single gluteal intramuscular (IM) injection of long-acting naltrexone 190 or 380 mg or placebo. A different group of subjects (n = 14) received oral naltrexone 50 mg daily for 5 days, followed by IM long-acting naltrexone 380 mg or placebo every 28 days for a total of 4 doses. A 7-day washout period separated oral and IM administrations. Blood samples were collected to determine plasma concentrations of naltrexone and the primary metabolite, 6beta-naltrexol. RESULTS: After a single IM injection of long-acting naltrexone 380 mg, naltrexone plasma concentrations were measurable in all subjects for at least 31 days postdose. The pharmacokinetics were proportional to the dose and multiple dose observations were consistent with single dose observations. Mean apparent elimination half-lives for naltrexone and 6beta-naltrexol ranged from 5 to 7 days. Exposure to 6beta-naltrexol was reduced with IM injection compared with that oral administration. No serious adverse events occurred. CONCLUSIONS: This study demonstrated that the long-acting naltrexone formulation was well tolerated, displayed predictable pharmacokinetics, and resulted in no meaningful drug accumulation upon multiple dosing. Intramuscular administration avoids first-pass metabolism and changes the exposure ratio of 6beta-naltrexol to naltrexone compared with oral administration. By providing continuous exposure to naltrexone for several weeks following IM injection, this long-acting naltrexone formulation may offer therapeutic benefit to those patients who experience difficulty adhering to the daily administration schedule necessitated by oral naltrexone therapy.