Effects of CYP3A Modulators on the Pharmacokinetics of Naloxegol.

Naloxegol, a peripherally acting μ-opioid receptor antagonist, was recently approved in the United States for the treatment of opioid-induced constipation. This study evaluated the effects of CYP3A inhibition and induction on the pharmacokinetics, safety, and tolerability of naloxegol. Separate open-label, nonrandomized, fixed-sequence, 3-period, 3-treatment, crossover studies of naloxegol (25 mg by mouth [PO]) in the absence or presence of the inhibitors ketoconazole (400 mg PO) and diltiazem extended release (240 mg PO), or the inducer rifampin (600 mg PO) were conducted in healthy volunteers.

Absorption, distribution, metabolism, and excretion of [14C]-labeled naloxegol in healthy subjects.

Objective: To characterize the absorption, distribution, metabolism, and excretion of naloxegol, a PEGylated derivative of the µ-opioid antagonist naloxone, in healthy male subjects.

Materials And Methods: [14C]-Labeled naloxegol (27 mg, 3.43 MBq) was administered as an oral solution to 6 fasted subjects.

The effect of quinidine, a strong P-glycoprotein inhibitor, on the pharmacokinetics and central nervous system distribution of naloxegol.

Naloxegol is a PEGylated, oral, peripherally acting μ-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO).

The effects of renal impairment on the pharmacokinetics, safety, and tolerability of naloxegol.

The impact of renal impairment on the pharmacokinetics of a 25-mg oral dose of naloxegol was examined in patients with renal impairment classified as moderate, severe, or end-stage renal disease (ESRD) and compared with healthy subjects (n = 8/group). Geometric mean area under the plasma concentration-time curve (AUC) was increased in patients with moderate (1.7-fold) or severe (2.

The effects of mild or moderate hepatic impairment on the pharmacokinetics, safety, and tolerability of naloxegol.

Naloxegol is a peripherally acting µ-opioid receptor antagonist (PAMORA) in development for the treatment of opioid-induced constipation (OIC). The pharmacokinetics of a single oral 25-mg dose of naloxegol in plasma was assessed in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment and compared with healthy volunteers. Participants were matched for sex, age, and body mass index.

Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in patients with generalized anxiety disorder and a history of inadequate treatment response: a randomized, double-blind study.

Background: For many patients with generalized anxiety disorder (GAD), first-line treatment does not lead to remission. This study investigated the efficacy and tolerability of adjunctive extended-release quetiapine fumarate (quetiapine XR) in patients with GAD and an inadequate response to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

Methods: Patients were randomized to quetiapine XR or placebo adjunctive to SSRI/SNRIs in an 11-week study.

Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in patients with generalized anxiety disorder and a history of inadequate treatment response: a randomized, double-blind study.

Background: For many patients with generalized anxiety disorder (GAD), first-line treatment does not lead to remission. This study investigated the efficacy and tolerability of adjunctive extended-release quetiapine fumarate (quetiapine XR) in patients with GAD and an inadequate response to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

Methods: Patients were randomized to quetiapine XR or placebo adjunctive to SSRI/SNRIs in an 11-week study.

Double-blind, randomized study of extended release quetiapine fumarate (quetiapine XR) monotherapy in older patients with generalized anxiety disorder.

Objective: The objective of the study was to evaluate once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in older patients with generalized anxiety disorder (GAD).

Methods: An 11-week (9-week treatment; 2-week posttreatment), randomized, double-blind, placebo-controlled study (D1448C00015) of flexibly-dosed quetiapine XR (50-300 mg/day) or placebo conducted at 47 sites (Estonia, Poland, Russia, Ukraine, and USA) between September 2006 and April 2008. Patients (≥66 years) with DSM-IV diagnosis of GAD, Hamilton Anxiety Rating Scale (HAM-A) total score of ≥20 with item 1 (anxious mood) and 2 (tension) scores of ≥2, Clinical Global Impressions-Severity of Illness (CGI-S) score of ≥4, and Montgomery Åsberg Depression Rating Scale (MADRS) total score of ≤16 were eligible for inclusion.

Efficacy and tolerability of extended release quetiapine fumarate monotherapy in the acute treatment of generalized anxiety disorder: a randomized, placebo controlled and active-controlled study.

The main objective of this study was to evaluate efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in generalized anxiety disorder (GAD). This was a 8 week randomized, 2-week follow-up, double-blind, placebo-controlled, and active-controlled study. Patients were randomized to quetiapine XR 150 (n=219) or 300 mg/day (n=207); escitalopram, 10 mg/day (n=213); or placebo (n=215).

Extended Release Quetiapine Fumarate (Quetiapine XR) as Adjunct Therapy in Patients with Generalized Anxiety Disorder and a History of Inadequate Treatment Response: A Randomized, Double-Blind Study.

Objective: To evaluate the efficacy and tolerability of adjunct extended release quetiapine fumarate (quetiapine XR) in patients with generalized anxiety disorder (GAD) and inadequate response to selective serotonin reuptake inhibitors/ serotonin norepinephrine reuptake inhibitors (SSRI/SNRIs).

Methods: 11-week (1-week single-blind placebo run-in; 8-week randomized treatment; 2-week post-treatment period), double-blind, placebo-controlled study. Patients were randomized to quetiapine XR or placebo adjunct to SSRI/SNRI.