A phase I thorough QT/QTc study evaluating therapeutic and supratherapeutic doses of avacopan in healthy participants.

This phase I thorough QTc, double-blind, randomized, placebo- and positive-controlled, parallel group, multiple-dose study evaluated avacopan's effect on cardiac repolarization using concentration-QTc (C-QTc) as the primary analysis. Avacopan 30 mg b.i.

A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings.

Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R).

Efficacy and safety of apremilast in pediatric patients with moderate-to-severe plaque psoriasis: 16-week results from SPROUT, a randomized controlled trial.

Background: Approved systemic treatment options are limited for pediatric patients with moderate to severe plaque psoriasis.

Objective: To assess the efficacy and safety of apremilast over 16 weeks in pediatric patients with plaque psoriasis.

Methods: SPROUT (NCT03701763) was a phase 3, multicenter, randomized, double-blind, placebo-controlled study of apremilast in patients aged 6-17 years with moderate-to-severe psoriasis (Psoriasis Area and Severity Index [PASI] ≥12, body surface area ≥10%, static Physician Global Assessment [sPGA] ≥3) inadequately controlled by/inappropriate for topical therapy.

Pharmacokinetics, Tolerability, and Safety of Glecaprevir/Pibrentasvir Co-formulated Bilayer Tablet Following Repeated Administration in Healthy Chinese Adults.

Glecaprevir (GLE)/pibrentasvir (PIB) is an all-oral, interferon- and ribavirin-free, pan-genotypic fixed-dose combination regimen approved for the treatment of all major genotypes of hepatitis C virus (HCV) infection in many countries worldwide. To support clinical development in China, an open-label, single-center phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of GLE/PIB in healthy Chinese adults in Mainland China. Eighteen participants received 3 tablets of coformulated GLE/PIB 100/40 mg once daily (QD) for 7 days.

Effect of Varying Degrees of Hepatic Impairment on the Pharmacokinetics of Omecamtiv Mecarbil.

Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under investigation for the treatment of heart failure with reduced ejection fraction. OM is primarily eliminated via metabolism mediated by multiple cytochrome P450 enzymes. This phase 1 single-dose, multicenter, open-label, nonrandomized study evaluated the pharmacokinetics (PK) of OM and major metabolites M3 and M4, safety, and tolerability following oral administration of a single dose of 25-mg MR tablet in subjects with mild (n = 6) or moderate (n = 6) hepatic impairment (according to Child-Pugh classification) versus subjects with normal hepatic function (n = 6).

Effect of Omecamtiv Mecarbil on the Pharmacokinetics of Metformin, a Probe Substrate for MATE1/MATE2-K, in Healthy Subjects.

Background And Objective: Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure with reduced ejection fraction. The objective of this study was to evaluate the potential for OM to affect the pharmacokinetics of metformin.

Methods: This was an open-label, fixed-sequence study in 14 healthy subjects.

Switchability and minimal effect of food on pharmacokinetics of modified release tablet strengths of omecamtiv mecarbil, a cardiac myosin activator.

Omecamtiv mecarbil (OM) is a cardiac myosin activator in clinical development for the treatment of heart failure. The effect of food on the pharmacokinetics (PK) of 25, 37.5, and 50 mg strength modified release (MR) tablets and the bioequivalence of two 25 mg tablets versus one 50 mg MR tablet were evaluated in two open-label, randomized, cross-over studies in healthy subjects.

Effect of Varying Degrees of Renal Impairment on the Pharmacokinetics of Omecamtiv Mecarbil.

Background And Objective: Omecamtiv mecarbil is a novel selective cardiac myosin activator (myotrope) under investigation for the treatment of heart failure with reduced ejection fraction. The objective of this clinical study was to estimate the effect of varying degrees of renal impairment on the pharmacokinetics of omecamtiv mecarbil single dose (50 mg) under fasted conditions.

Methods: This phase I, open-label, non-randomized, parallel-group study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of omecamtiv mecarbil 50 mg in individuals with normal renal function or mild, moderate, and severe renal impairment, including end-stage renal disease requiring dialysis.

A Thorough QT Study of the Combination Glecaprevir + Pibrentasvir on Cardiac Repolarization in Healthy Subjects.

Purpose: Fixed-dose combination glecaprevir (GLE) 300 mg + pibrentasvir (PIB) 120 mg is an orally administered once daily antiviral regimen approved for the treatment of hepatitis C virus (HCV) infection. The objective of this study was to evaluate the potential for cardiac repolarization following GLE + PIB administration in healthy adults.

Methods: This placebo- and active-controlled, randomized, single-dose, 4-period, 4-sequence crossover study enrolled 48 healthy subjects.

Exposure-Response Relationships for the Efficacy and Safety of Risankizumab in Japanese Subjects with Psoriasis.

Background And Objective: Risankizumab, a humanized monoclonal interleukin-23 antagonist antibody, has efficacy for treatment of plaque psoriasis, generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP). These analyses characterized the relationships between risankizumab exposures and key efficacy and safety variables in Japanese patients with moderate-to-severe plaque psoriasis, GPP, or EP following treatment with 75 or 150 mg subcutaneous doses at weeks 0, 4, and every 12 weeks thereafter.

Methods: Risankizumab average plasma concentrations (Cavg) were correlated with probabilities of achieving efficacy end points (PASI 75, PASI 90, PASI 100, and sPGA 0/1) using data from Japanese patients (N = 225) and non-Japanese patients (N = 1678) with moderate-to-severe plaque psoriasis enrolled in global trials, or a Japan Phase 2/3 trial.

Population Pharmacokinetics of Glecaprevir/Pibrentasvir in HCV-infected Japanese Subjects in Phase 3 CERTAIN-1 and CERTAIN-2 Trials.

Glecaprevir (GLE)/pibrentasvir (PIB) 300 mg/120 mg once daily (Mavyret/Maviret) is an all-oral, pangenotypic, interferon- and ribavirin-free combination regimen approved for the treatment of chronic hepatitis C virus (HCV) infection. The objective of the current analyses was to characterize the pharmacokinetics (PK) of GLE/PIB in HCV-infected Japanese patients. Data from 332 subjects enrolled in 2 Japan phase 3 trials, CERTAIN-1 and CERTAIN-2, were used in the analyses.

A Phase 1 Study to Evaluate the Effect of Crushing, Cutting Into Half, or Grinding of Glecaprevir/Pibrentasvir Tablets on Exposures in Healthy Subjects.

Glecaprevir (GLE) and pibrentasvir (PIB) are direct-acting antivirals coformulated as a combination tablet for once-daily treatment of chronic hepatitis C virus infection. The objective of this study was to evaluate the effect of different methods of tablet manipulations-cutting in half, grinding into powder, or crushing-on the bioavailability of GLE and PIB relative to whole film-coated bilayer tablets. This was a phase 1, single-dose, open-label, randomized, 5-period, nonfasting crossover study in 25 healthy adult male and female subjects.

Correction to: Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection.

Unfortunately, in the original publication of this article, the copyright line was incorrectly published in PDF as "© The Author(s) 2017" instead of "©The Author(s) 2017 This article is an open access publication" and also the CC-BY description was not included. The description should be as follows.

Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection.

Background: Once-daily, orally administered, co-formulated glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor) (G/P) demonstrated pangenotypic activity and high sustained virologic response (SVR) rates in studies outside Japan. Here we report safety and efficacy in a subset of Japanese patients with chronic HCV infection who received G/P 300/120 mg in a phase 3, open-label, multicenter study (CERTAIN-1).

Methods: This analysis focuses on three difficult-to-treat subgroups: HCV GT1/2-infected patients who failed to achieve SVR after treatment with a direct acting antiviral (DAA)-containing regimen; GT1/2-infected patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.

Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 1 hepatitis C virus infection with and without cirrhosis.

Background: The once-daily, all oral, RBV-free, pangenotypic direct-acting anti-viral regimen consisting of co-formulated NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (G/P), demonstrated high rates of sustained virologic response (SVR) in phase 2 and 3 studies outside Japan.

Methods: CERTAIN-1 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in Japanese patients with chronic HCV GT1 infection. Patients without cirrhosis received 8 weeks of G/P or 12 weeks of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r, 25/150/100 mg); patients with cirrhosis received G/P for 12 weeks.

Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection.

Glecaprevir (nonstructural protein 3/4A protease inhibitor) and pibrentasvir (nonstructural protein 5A inhibitor) (G/P), a coformulated once-daily, all oral, ribavirin (RBV)-free, direct-acting antiviral regimen, was evaluated for safety and efficacy in hepatitis C virus genotype 2 (GT2)-infected Japanese patients, including those with compensated cirrhosis. CERTAIN-2 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in treatment-naive and interferon ± RBV treatment-experienced Japanese patients without cirrhosis but with GT2 infection. Patients were randomized 2:1 to receive 8 weeks of G/P (arm A) or 12 weeks of sofosbuvir (400 mg once daily) + RBV (600-1000 mg weight-based, twice daily) (arm B).

Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma.

Glioblastoma (GBM) is a lethal and aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. Molecularly targeted agents hold great promise in treating these genetically heterogeneous tumors, yet have produced disappointing results. One reason for the clinical failure of these novel therapies can be the inability of the drugs to achieve effective concentrations in the invasive regions beyond the bulk tumor.

Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma.

Background: Targeting drug delivery to invasive glioma cells is a particularly difficult challenge because these cells lie behind an intact blood-brain barrier (BBB) that can be observed using multimodality imaging. BBB-associated efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) influence drug distribution to these cells and may negatively impact efficacy. To test the hypothesis that efflux transporters influence brain pharmacokinetics/pharmacodynamics of molecularly targeted agents in glioma treatment, we assessed region-specific penetrance and molecular-targeting capacity for a PI3K/mTOR kinase inhibitor that has high substrate affinity for efflux transporters (GDC-0980) and an analog (GNE-317) that was purposely designed to have reduced efflux.

Sunitinib LC-MS/MS Assay in Mouse Plasma and Brain Tissue: Application in CNS Distribution Studies.

Sunitinib malate is a multi-targeted tyrosine-kinase inhibitor, currently in clinical trials for glioma. Previously developed methods for preclinical studies in species such as mice have either employed high-performance liquid chromatography (HPLC) or did not describe a detailed analytical method, which could be employed by other preclinical laboratories. In this paper, we have developed and validated a simple, sensitive high-performance liquid chromatography tandem mass-spectrometric method (LC-MS/MS) for the determination of sunitinib concentration in mouse plasma and brain tissue homogenate using dasatinib-free base as the internal standard.

Pharmacokinetic assessment of efflux transport in sunitinib distribution to the brain.

This study quantitatively assessed transport mechanisms that limit the brain distribution of sunitinib and investigated adjuvant strategies to improve its brain delivery for the treatment of glioblastoma multiforme (GBM). Sunitinib has not shown significant activity in GBM clinical trials, despite positive results seen in preclinical xenograft studies. We performed in vivo studies in transgenic Friend leukemia virus strain B mice: wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) genotypes were examined.

Determination of cediranib in mouse plasma and brain tissue using high-performance liquid chromatography-mass spectrometry.

A new high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) assay for cediranib, a tyrosine kinase inhibitor for VEGFRs, was developed and validated, for the determination of plasma and brain levels of cediranib in small specimen volumes. Tyrphostin (AG1478) was used as internal standard. Mouse plasma and brain homogenate samples were prepared using liquid-liquid extraction.