Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses.

Background & Aims: The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs).

Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171).

Safety, pharmacokinetics and antiviral activity of ABI-H2158, a hepatitis B virus core inhibitor: A randomized, placebo-controlled phase 1 study.

Treatment for chronic hepatitis B virus infection (cHBV) is mostly indefinite, with new finite-duration therapies needed. We report safety, pharmacokinetics and antiviral activity of the investigational HBV core inhibitor ABI-H2158. This Phase 1a/b study (NCT03714152) had three parts: Part A, participants received a single ascending oral dose of ABI-H2158 (5-500 mg) or placebo; Part B, participants received multiple doses of ABI-H2158 300 mg once (QD) or twice (BID) daily or placebo, for 10 days; Part C, cHBV patients received ABI-H2158 (100, 300, or 500 mg QD or 300 mg BID) or placebo, for 14 days.

Development of a lower-sodium oxybate formulation for the treatment of patients with narcolepsy and idiopathic hypersomnia.

Introduction: Sodium oxybate (SXB) is a standard of care for cataplexy, excessive daytime sleepiness, and disrupted nighttime sleep in narcolepsy. At recommended dosages in adults (6-9 g/night), SXB increases daily dietary intake of sodium by 1100-1640 mg. Because excess sodium intake is associated with increased blood pressure and cardiovascular risk, an oxybate formulation containing 92% less sodium than SXB (lower-sodium oxybate; LXB) was developed to provide an alternative oxybate treatment option.

Population Pharmacokinetic Model Development and Simulation for Recombinant Erwinia Asparaginase Produced in Pseudomonas fluorescens (JZP-458).

JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme expected to lack immunologic cross-reactivity to Escherichia coli-derived asparaginases. It is being developed as part of a multiagent chemotherapeutic regimen to treat acute lymphoblastic leukemia or lymphoblastic lymphoma patients who develop E coli-derived asparaginase hypersensitivity. A population pharmacokinetic (PopPK) model was developed for JZP-458 using serum asparaginase activity (SAA) data from a phase 1, single-dose study (JZP458-101) in healthy adults.

Solriamfetol for Excessive Daytime Sleepiness in Parkinson's Disease: Phase 2 Proof-of-Concept Trial.

Background: Solriamfetol is approved (US and EU) for excessive daytime sleepiness (EDS) in narcolepsy and obstructive sleep apnea.

Objectives: Evaluate solriamfetol safety/efficacy for EDS in Parkinson's disease (PD).

Methods: Phase 2, double-blind, 4-week, crossover trial: adults with PD and EDS were randomized to sequence A (placebo, solriamfetol 75, 150, 300 mg/d), B (solriamfetol 75, 150, 300 mg/d, placebo), or C (placebo).

Pharmacokinetics, bioavailability, and bioequivalence of lower-sodium oxybate in healthy participants in two open-label, randomized, crossover studies.

American Academy of Sleep Medicine practice parameters designate sodium oxybate (SXB) as a standard of care for cataplexy, excessive daytime sleepiness (EDS), and disrupted night-time sleep in narcolepsy. Recently, a lower-sodium oxybate (LXB) with 92% less sodium than SXB was approved in the United States for the treatment of cataplexy or EDS in patients 7 years of age and older with narcolepsy. Two phase I, open-label, randomized, single-dose crossover pharmacokinetic studies in healthy adults were conducted.

A Randomized, Double-Blind, Placebo- and Positive-Controlled, 4-Period Crossover Study of the Effects of Solriamfetol on QTcF Intervals in Healthy Participants.

Solriamfetol, a dopamine and norepinephrine reuptake inhibitor, is approved (United States and European Union; Sunosi) to treat excessive daytime sleepiness associated with narcolepsy (75-150 mg/day) or obstructive sleep apnea (37.5-150 mg/day). A thorough QT/QTc study assessed solriamfetol effects on QT interval (Fridericia correction for heart rate; QTcF).

Population and Noncompartmental Pharmacokinetics of Sodium Oxybate Support Weight-Based Dosing in Children and Adolescents With Narcolepsy With Cataplexy.

The pharmacokinetics (PKs) of sodium oxybate (SXB) was evaluated in a subset of participants from a study of SXB treatment in children (aged 7-11 years; n = 11) and adolescents (aged 12-17 years; n = 18) with narcolepsy with cataplexy. PK evaluation was conducted over 2 nights during the period when participants received a stable nightly SXB dose. The SXB dose on night 1 was half of night 2 and was administered in two equally divided doses: dose 1 was administered > 2 hours after the evening meal, and dose 2 was administered ≥ 4 hours after dose 1.

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

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.

A Phase I, Randomized, Crossover, Open-label Study of the Pharmacokinetics of Solriamfetol (JZP-110) in Healthy Adult Subjects With and Without Food.

Purpose: Solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, is currently being evaluated for the reduction of sleepiness and improvement of wakefulness in patients with narcolepsy and obstructive sleep apnea. The purpose of this study was to evaluate the effect of food on the pharmacokinetic (PK) parameters and bioavailability of solriamfetol at the highest intended therapeutic dose in healthy adults and to characterize its renal excretion under fasting conditions.

Methods: In this open-label, randomized, crossover study, healthy adult subjects received a single 300-mg dose of solriamfetol in a fasted condition (10 h) and in a fed condition (30 min after the start of a standardized high-fat, high-calorie breakfast), with at least a 7-day washout period between doses.

Pharmacokinetic profile of defibrotide in patients with renal impairment.

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction.

Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson's disease.

The objective of this study was to assess the efficacy, safety, and pharmacokinetics of XP21279-carbidopa in patients with Parkinson's disease who experience motor fluctuations compared with immediate-release carbidopa-levodopa tablets. XP21279 is a levodopa prodrug that is actively absorbed by high-capacity nutrient transporters expressed throughout the gastrointestinal tract and then rapidly converted to levodopa by carboxylesterases. XP21279-carbidopa sustained-release bilayer tablets were developed to overcome pharmacokinetic limitations of levodopa by providing more continuous exposure.

A randomized, double-blind, placebo-controlled, dose-response study to assess the pharmacokinetics, efficacy, and safety of gabapentin enacarbil in subjects with restless legs syndrome.

Objective: The objective of this study was to determine steady-state gabapentin exposures and corresponding relief of symptoms and safety profile produced by 4 dose levels of gabapentin enacarbil (GEn) in subjects with restless legs syndrome (RLS).

Methods: Subjects with RLS (n = 217) were randomized to receive once-daily, orally administered GEn 600 (n = 48), 1200 (n = 45), 1800 (n = 38), or 2400 mg (n = 45) or placebo (n = 41) in this 12-week, double-blind, multicenter study (NCT01332305). Clinic visits were at screening, baseline, and weeks 1, 2, 3, 4, 6, 8, 10, and 12; plasma gabapentin concentrations were measured by a validated liquid chromatography-mass spectrometry/mass spectrometry method at weeks 4 and 12.

Actively transported levodopa prodrug XP21279: a study in patients with Parkinson disease who experience motor fluctuations.

Objective: The objectives of this study were to assess the pharmacokinetic profile, efficacy, and safety of XP21279 administered with carbidopa (CD) in subjects with Parkinson disease (PD) experiencing motor fluctuations and explore dose correspondence between CD-levodopa (LD) and XP21279 administered with CD.

Methods: Subjects received CD-LD 3 or 4 times daily for 2 weeks, followed by XP21279 plus CD 3 times daily for 2 weeks at fixed dosing times, allowing dose adjustment to optimize clinical response, in this multiple-dose, multicenter, open-label, 2-period, sequential-treatment study. Pharmacokinetic parameters, including LD exposure, were assessed over 16 hours on the last day of each treatment period.

Evaluation of gabapentin enacarbil on cardiac repolarization: a randomized, double-blind, placebo- and active-controlled, crossover thorough QT/QTc study in healthy adults.

Background: Gabapentin enacarbil, a transported prodrug of gabapentin, was recently approved by the US Food and Drug Administration for the treatment of moderate to severe restless legs syndrome.

Objective: As part of the overall safety evaluation of gabapentin enacarbil, the present definitive QT/QTc study was conducted to assess the effects of gabapentin enacarbil on cardiac repolarization in accordance with the International Conference on Harmonization E14 guidance.

Methods: This randomized, double-blind, placebo- and active-controlled, crossover study enrolled 54 healthy adults.

The effect of dosing frequency on the pharmacokinetics of a fentanyl HCl patient-controlled transdermal system (PCTS).

Introduction: The fentanyl HCl patient-controlled transdermal system (PCTS) is a noninvasive, needle-free, credit card-sized drug delivery system designed for the on-demand management of acute pain in a medically supervised setting. The objective of these studies was to determine the effect of dosing frequency on the pharmacokinetics of fentanyl delivered by the PCTS.

Methods: All three studies were single-centre, open-label, randomised, crossover studies.

Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: a pediatric oncology group study.

Purpose: To determine the maximum tolerated dose and pharmacokinetics of Doxil in children with recurrent or refractory solid tumors. Doxil is pegylated doxorubicin.

Experimental Design: Eligible patients were children with refractory tumors who had received cumulative anthracycline doses <300 mg/m(2).

Propofol dosing regimens for ICU sedation based upon an integrated pharmacokinetic-pharmacodynamic model.

Background: The pharmacology of propofol infusions administered for long-term sedation of intensive care unit (ICU) patients has not been fully characterized. The aim of the study was to develop propofol dosing guidelines for ICU sedation based on an integrated pharmacokinetic-pharmacodynamic model of propofol infusions in ICU patients.

Methods: With Institutional Review Board approval, 30 adult male medical and surgical ICU patients were given target-controlled infusions of propofol for sedation, adjusted to maintain a Ramsay sedation scale score of 2-5.

A double-blind, randomized comparison of i.v. lorazepam versus midazolam for sedation of ICU patients via a pharmacologic model.

Background: Benzodiazepines, such as lorazepam and midazolam, are frequently administered to surgical intensive care unit (ICU) patients for postoperative sedation. To date, the pharmacology of lorazepam in critically ill patients has not been described. The aim of the current study was to characterize and compare the pharmacokinetics and pharmacodynamics of lorazepam and midazolam administered as continuous intravenous infusions for postoperative sedation of surgical ICU patients.

Population pharmacodynamics of midazolam administered by target controlled infusion in SICU patients after CABG surgery.

Background: Midazolam is used commonly for sedation in the surgical intensive care unit. A suboptimal dosing regimen may lead to relative overdosing, which could result in delayed extubation and increased cost. This multicenter trial characterized midazolam pharmacodynamics in patients recovering from coronary artery bypass grafting.

Population pharmacokinetics of midazolam administered by target controlled infusion for sedation following coronary artery bypass grafting.

Background: Midazolam is commonly used for short-term postoperative sedation of patients undergoing cardiac surgery. The purpose of this multicenter study was to characterize the pharmacokinetics and intersubject variability of midazolam in patients undergoing coronary artery bypass grafting.

Methods: With institutional review board approval, 90 consenting patients undergoing coronary artery bypass grafting were enrolled at three study centers.

Scaling factors to relate drug metabolic clearance in hepatic microsomes, isolated hepatocytes, and the intact liver: studies with induced livers involving diazepam.

Microsomal protein recovery and hepatocellularity have been determined and investigated as scaling factors for interrelating clearance by hepatic microsomes, freshly isolated hepatocytes and whole liver from untreated (UT) rats and rats treated with either the cytochrome P450 inducer phenobarbital (PB) or dexamethasone (DEX). Hepatocellularity in UT rats (1.1 x 10(8) hepatocytes/g liver) was not significantly different after either PB or DEX induction (1.

Selectivity of omeprazole inhibition towards rat liver cytochromes P450.

1. The potency and selectivity of omeprazole as an inhibitor of cytochrome P450-mediated drug oxidations has been assessed in hepatic microsomes from the untreated, phenobarbitone-treated, beta-naphthoflavone-treated and dexamethasone-treated rat. Using the marker substrates diazepam, ethoxycoumarin, ethoxyresofurin and ethylmorphine in the above microsomal preparations, inhibitory activity against CYP1A, 2B, 2C and 3A members of the cytochrome P450 superfamily were determined.

Diazepam-omeprazole inhibition interaction: an in vitro investigation using human liver microsomes.

1. The metabolism of diazepam to its primary metabolites 3-hydroxydiazepam (3HDZ) and nordiazepam (NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a Vmax/Km ratio of 0.

Effect of omeprazole on diazepam disposition in the rat: in vitro and in vivo studies.

Purpose: The inhibitory effects of omeprazole on diazepam metabolism in vitro and in vivo are compared in the rat.

Methods: 3-hydroxylation and N-demethylation of diazepam was investigated in the presence of a range of omeprazole concentrations (2-500 microM) in hepatic microsomes and hepatocytes. Zero order infusions together with matched bolus doses of omeprazole were used to achieve a range of steady state plasma concentrations (10-50mg/L) and to study the diazepam-omeprazole interaction in vivo.