535 results match your criteria Clinical Pharmacology in Drug Development [Journal]


Absolute Oral Bioavailability of Glasdegib (PF-04449913), a Smoothened Inhibitor, in Randomized Healthy Volunteers.

Clin Pharmacol Drug Dev 2019 Apr 12. Epub 2019 Apr 12.

Pfizer Inc, Groton, CT, USA.

Glasdegib (PF-04449913) is an oral small-molecule inhibitor of the Hedgehog signaling pathway under development for treating myeloid malignancies. This was an open-label phase 1, randomized, 2-sequence, 2-treatment, 2-period, crossover study evaluating the absolute bioavailability of glasdegib in healthy volunteers under fasting condition (NCT03270878). In period 1, 12 eligible subjects received either a single oral dose of glasdegib 100 mg (tablet) or a single intravenous (IV) dose of glasdegib 50 mg. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.692DOI Listing
April 2019
1 Read

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine.

Clin Pharmacol Drug Dev 2019 Apr 12. Epub 2019 Apr 12.

Shionogi & Co, Ltd, Osaka, Japan.

Naldemedine is a peripherally acting μ-opioid-receptor antagonist for the treatment of opioid-induced constipation. Two phase 1 single-dose studies investigated the pharmacokinetics and safety of a 0.2-mg oral dose of naldemedine in subjects with renal impairment (mild, n = 9; moderate, n = 9; severe, n = 6; and end-stage renal disease, n = 8) or hepatic impairment (mild or moderate, n = 8 each) and demographically matched healthy subjects with normal renal and hepatic function (n = 8, both studies). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.690DOI Listing
April 2019
1 Read

Evaluation of the Pharmacokinetics of Metformin Following Coadministration With Doravirine in Healthy Volunteers.

Clin Pharmacol Drug Dev 2019 Apr 11. Epub 2019 Apr 11.

Merck & Co., Inc., Kenilworth, NJ, USA.

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, type 2 diabetes mellitus is often treated with metformin. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.685DOI Listing
April 2019
3 Reads

First-in-Human Pharmacokinetics and Safety Study of GSK3008356, a Selective DGAT1 Inhibitor, in Healthy Volunteers.

Clin Pharmacol Drug Dev 2019 Apr 5. Epub 2019 Apr 5.

GlaxoSmithKline, Collegeville, PA, USA.

Diacylglycerol acyltransferase (DGAT) enzymes are involved in triglyceride (TG) biosynthesis. GSK3008356 is a potent and selective DGAT1 inhibitor that was administered orally in a 2-part study as double-blind, randomized, placebo-controlled single doses (SDs) and repeat doses (RDs) in healthy subjects to investigate its pharmacokinetics, pharmacodynamics, and safety/tolerability. Gastrointestinal adverse events were considered drug related and increased with dose and when given as multiple doses. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.691DOI Listing

Population Pharmacokinetics and Pharmacodynamics of Teicoplanin and C-Reactive Protein in Hospitalized Patients With Gram-Positive Infections.

Clin Pharmacol Drug Dev 2019 Apr 1. Epub 2019 Apr 1.

Department of Medical Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

Teicoplanin is an antibiotic agent used for the treatment of Gram-positive infections. The clinical benefit of teicoplanin is associated with its blood concentrations, but the optimal dosing regimen is not yet known. To explore the optimal individual dosing regimen, we performed a population pharmacokinetic (PK) and pharmacodynamic (PD) analysis targeting a large-scale population, including patients with a wide range of ages, body weights, and renal functions. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.684DOI Listing

Pharmacokinetic Properties of Single and Multiple Doses of Ertugliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects.

Clin Pharmacol Drug Dev 2019 Apr 1. Epub 2019 Apr 1.

Pfizer Inc., Groton, CT, USA.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus, prevents renal glucose reabsorption resulting in urinary glucose excretion. This open-label, parallel cohort, randomized study conducted in healthy Chinese adults residing in China assessed the pharmacokinetics, tolerability, and safety of 5 mg and 15 mg of ertugliflozin following single (fasted condition) and multiple-dose (fed condition) administration. Sixteen subjects were randomized and completed the study. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.686DOI Listing

Assessment of Azeliragon QTc Liability Through Integrated, Model-Based Concentration QTc Analysis.

Clin Pharmacol Drug Dev 2019 Apr 1. Epub 2019 Apr 1.

vTv Therapeutics LLC, High Point, NC, USA.

Azeliragon is an inhibitor of the receptor for advanced glycation end products being developed for the treatment of Alzheimer's disease. The objective of the current analysis was to evaluate the relationship between plasma azeliragon concentrations and QT interval. Simultaneous QT values and plasma concentrations were available from 711 subjects (6236 records), pooled from 5 studies in healthy volunteers, 2 studies in patients with mild to moderate Alzheimer's disease, and 1 study in patients with type 2 diabetes and persistent albuminuria. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.689DOI Listing

Effect of Food on the Pharmacokinetics of a Combination of Olanzapine and Samidorphan.

Clin Pharmacol Drug Dev 2019 Mar 28. Epub 2019 Mar 28.

Alkermes, Inc., Waltham, MA, USA.

ALKS 3831 is a combination of olanzapine and samidorphan (OLZ/SAM), intended to provide the antipsychotic efficacy of OLZ while mitigating its known weight gain and metabolic effects. This randomized, 2-way crossover study evaluated the effect of food on the pharmacokinetics (PK) of OLZ and SAM (both are Biopharmaceutics Classification System class 3 compounds) given in combination as OLZ/SAM. Thirty-six healthy volunteers were randomized to receive a single dose of OLZ/SAM (10 mg OLZ/10 mg SAM) in either fasted or fed conditions. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.688DOI Listing

Safety Profiles, Pharmacokinetics, and Changes in Bone Turnover Markers After Twice-Weekly Subcutaneous Administration of Teriparatide in Healthy Japanese Postmenopausal Women: A Single-Blind Randomized Study.

Clin Pharmacol Drug Dev 2019 Mar 28. Epub 2019 Mar 28.

Internal Medicine 1, Shimane University Faculty of Medicine, Shimane, Japan.

Once-weekly injection of 56.5-μg teriparatide formulation is a potent therapeutic agent for osteoporosis treatment. However, this treatment has an issue of difficulty in continuing the treatment by its adverse side effects including nausea, vomiting, and headaches. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.687DOI Listing
March 2019
2 Reads

Pharmacokinetic Profile of a Generic Formulation of Sofosbuvir and Its Metabolite GS-331007 in Healthy Chinese Subjects.

Clin Pharmacol Drug Dev 2019 Mar 22. Epub 2019 Mar 22.

Phase I Clinical Trial Unit, China-Frontage USA, The First Hospital of Jilin University, Jilin University, Changchun, People's Republic of China.

Sofosbuvir is an NS5B nucleotide inhibitor for the treatment of hepatitis C viral infection. In this study the pharmacokinetics (PK) and safety of single and multiple doses of generic sofosbuvir were investigated in healthy Chinese subjects. Twelve subjects (6 male and 6 female) were enrolled in this study. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.674DOI Listing
March 2019
1 Read

Pharmacokinetic Properties of Ibuprofen (IBU) From the Fixed-Dose Combination IBU/Caffeine (400/100 mg; FDC) in Comparison With 400 mg IBU as Acid or Lysinate Under Fasted and Fed Conditions-Data From 2 Single-Center, Single-Dose, Randomized Crossover Studies in Healthy Volunteers.

Clin Pharmacol Drug Dev 2019 Mar 21. Epub 2019 Mar 21.

Consumer Health Care, Global Medical Affairs, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.

Rapid onset of analgesic action is linked with rapid absorption of analgesics (high maximum concentration [C ] and short time to maximum concentration [t ]). After overnight fasting, ibuprofen lysinate reaches higher peak plasma levels (C ) earlier than ibuprofen acid (t ) with comparable exposure (area under the plasma concentration-time curve [AUC]); however, subjects usually take ibuprofen with or within a short time of a meal. Therefore, pharmacokinetic (PK) studies under fed conditions may better characterize properties under real-life conditions. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.672DOI Listing

Drug-Drug Interactions of Tacrolimus or Cyclosporine With Glecaprevir and Pibrentasvir in Healthy Subjects.

Clin Pharmacol Drug Dev 2019 Mar 12. Epub 2019 Mar 12.

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.

A fixed-dose combination of glecaprevir and pibrentasvir is approved for treatment of chronic infection with hepatitis C virus (HCV) genotypes 1-6. Three phase 1 open-label studies were conducted in healthy volunteers to evaluate the potential for clinically relevant drug-drug interactions of the glecaprevir 300-mg and pibrentasvir 120-mg combination with the immunosuppressants tacrolimus (1 mg) or cyclosporine (100 and 400 mg). Glecaprevir and pibrentasvir exposure was unaffected by tacrolimus, whereas the tacrolimus area under the curve (AUC) value was 45% higher with glecaprevir and pibrentasvir. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.671DOI Listing
March 2019
10 Reads

A Randomized, Double-Blind, Placebo-Controlled, First-Time-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects.

Clin Pharmacol Drug Dev 2019 Mar 12. Epub 2019 Mar 12.

GlaxoSmithKline, Research Triangle Park, North Carolina, USA.

GSK3389404 is a liver-targeted antisense oligonucleotide that inhibits synthesis of hepatitis B surface antigen and all other hepatitis B virus proteins. This first-in-human, randomized, double-blind, phase 1 study assessed the safety and pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy subjects. Four single ascending-dose cohorts (10 mg, 30 mg, 60 mg, and 120 mg) and 3 multiple ascending-dose cohorts (30 mg, 60 mg, and 120 mg once weekly for 4 weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects randomized to placebo. Read More

View Article

Download full-text PDF

Source
http://doi.wiley.com/10.1002/cpdd.670
Publisher Site
http://dx.doi.org/10.1002/cpdd.670DOI Listing
March 2019
3 Reads

Pharmacokinetics of Tacrolimus Coadministered With Letermovir in Allogeneic Hematopoietic Stem Cell Transplantation Patients.

Clin Pharmacol Drug Dev 2019 Apr 6;8(3):411-412. Epub 2019 Mar 6.

Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.669DOI Listing
April 2019
2 Reads

A Phase 1 Study to Evaluate the Pharmacokinetics and Safety of Cabotegravir in Patients With Hepatic Impairment and Healthy Matched Controls.

Clin Pharmacol Drug Dev 2019 Feb 27. Epub 2019 Feb 27.

ViiV Healthcare, Research Triangle Park, NC, USA.

Cabotegravir is an investigational integrase inhibitor in development for the treatment and pre-exposure prophylaxis of HIV-1 infection. Liver disease is a major cause of morbidity and mortality in HIV-infected individuals and can impact the pharmacokinetics (PK) of HIV medications. This phase 1 study evaluated the PK of cabotegravir in individuals with moderate hepatic impairment (n = 8) versus healthy controls (n = 8). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.655DOI Listing
February 2019
2 Reads

A Phase I Study to Evaluate the Pharmacokinetics and Safety of Cabotegravir in Adults With Severe Renal Impairment and Healthy Matched Control Participants.

Clin Pharmacol Drug Dev 2019 Feb 27. Epub 2019 Feb 27.

ViiV Healthcare, Research Triangle Park, NC, USA.

This study investigates the impact of severe renal impairment on the pharmacokinetics of cabotegravir, an investigational HIV-1 integrase inhibitor. This was a phase I, open-label, parallel-group, multicenter study conducted in 8 participants with severe renal impairment (creatinine clearance <30 mL/min; no renal replacement therapy) and 8 healthy participants (creatinine clearance >90 mL/min; 2 women/group; 6 men/group) matched for sex, age (±10 years), and body mass index (±25%). Participants received a single 30-mg oral cabotegravir tablet to determine total and unbound plasma cabotegravir concentrations. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.664DOI Listing
February 2019
1 Read

Study on Drug-Drug Interactions Between Chiglitazar, a Novel PPAR Pan-Agonist, and Metformin Hydrochloride in Healthy Subjects.

Clin Pharmacol Drug Dev 2019 Feb 27. Epub 2019 Feb 27.

Drug Clinical Trials Institution, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, P.R.China.

Chiglitazar (CHI) is a potent and selective peroxisome proliferator-activated receptor potentially for the treatment of patients with type 2 diabetes mellitus (T2DM). An open-label, randomized, 3-period crossover and self-controlled study was conducted to investigate drug-drug interaction potential between CHI and metformin hydrochloride (MET). Eligible subjects received a single oral dose of CHI (48 mg), MET (1000 mg), or a combination in each period, followed by serial blood sampling collected for up to 48 hours postdose, and safety was assessed throughout the trial. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.668DOI Listing
February 2019

A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects.

Clin Pharmacol Drug Dev 2019 Feb 21. Epub 2019 Feb 21.

Greenwich Biosciences, Inc., Carlsbad, CA, USA.

GW Pharmaceuticals' formulation of highly purified cannabidiol oral solution is approved in the United States for seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open-label, fixed-sequence, drug-drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady-state pharmacokinetics of clobazam (and N-desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant cannabidiol had little effect on clobazam exposure (maximum concentration [C ] and area under the concentration-time curve [AUC], 1. Read More

View Article

Download full-text PDF

Source
http://doi.wiley.com/10.1002/cpdd.665
Publisher Site
http://dx.doi.org/10.1002/cpdd.665DOI Listing
February 2019
6 Reads

A Phase 3, Randomized, Placebo-Controlled Evaluation of the Safety of Intravenous Meloxicam Following Major Surgery.

Clin Pharmacol Drug Dev 2019 Feb 20. Epub 2019 Feb 20.

Tampa General Hospital, Tampa, FL, USA.

An intravenous (IV) formulation of meloxicam is being studied for moderate to severe pain management. This phase 3, randomized, multicenter, double-blind, placebo-controlled trial evaluated the safety of once-daily meloxicam IV 30 mg in subjects following major elective surgery. Eligible subjects were randomized (3:1) to receive meloxicam IV 30 mg or placebo administered once daily. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.666DOI Listing
February 2019
1 Read

Pharmacokinetics, Food Effect, Ketoconazole Interaction, and Safety of JTK-853, a Novel Nonnucleoside HCV Polymerase Inhibitor, After Ascending Single and Multiple Doses in Healthy Subjects.

Clin Pharmacol Drug Dev 2019 Apr 19;8(3):371-384. Epub 2019 Feb 19.

Clinical Pharmacology, Akros Pharma Inc., Princeton, NJ, USA.

Pharmacokinetics, safety, and tolerability of JTK-853, a novel HCV polymerase inhibitor, were evaluated in single and multiple ascending dose (SAD, MAD) studies, with food- and ketoconazole-related effects on exposure to JTK-853 and its active (CYP3A4 mediated) metabolite M2. JTK-853 was safe and well tolerated in both studies. In the SAD study, at doses >1600 mg (with standard breakfast [SBF]), JTK-853 exposure did not increase further, was substantially higher (AUC increase: 3- to 8-fold) with SBF (vs fasted), with a moderate increase in AUC (approximately 1. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.656DOI Listing
April 2019
4 Reads

The Relative Bioavailability and Effects of Food and Acid-Reducing Agents on Filgotinib Tablets in Healthy Subjects.

Clin Pharmacol Drug Dev 2019 Feb 15. Epub 2019 Feb 15.

Horizon Pharma, Brisbane, CA, USA.

Filgotinib is a potent, selective Janus kinase-1 inhibitor being developed to treat chronic inflammatory diseases. This phase 1 study in healthy subjects evaluated the relative bioavailability of filgotinib maleate tablets versus the reference tablet (filgotinib hydrochloride) and effects of food and acid-reducing agents (ARAs) on the pharmacokinetics of filgotinib and its major metabolite. Noncompartmental pharmacokinetic parameters of filgotinib and its major metabolite were compared between the 2 tablets at 100- and 200-mg doses and with or without food or ARAs. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.659DOI Listing
February 2019

Lesinurad: Evaluation of Pharmacokinetic and Pharmacodynamic Interactions With Warfarin in Healthy Volunteers.

Clin Pharmacol Drug Dev 2019 Feb 13. Epub 2019 Feb 13.

AstraZeneca, Gaithersburg, MD, USA.

Lesinurad is a selective uric acid reabsorption inhibitor approved for use in combination with xanthine oxidase inhibitors for the treatment of hyperuricemia associated with gout. In vitro, lesinurad was shown to be a weak inhibitor of cytochrome P450 (CYP)2C9 and a weak inducer of CYP3A4. Warfarin is a widely prescribed oral coumarin-based anticoagulant commonly prescribed in gout patients. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.662DOI Listing
February 2019
4 Reads

Effects of Food and Antacids on Pharmacokinetics and Pharmacodynamics of Lesinurad, a Selective Urate Reabsorption Inhibitor.

Clin Pharmacol Drug Dev 2019 Feb 12. Epub 2019 Feb 12.

AstraZeneca, Gaithersburg, MD, USA.

Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg lesinurad. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.663DOI Listing
February 2019
1 Read

A Cocktail Interaction Study Evaluating the Drug-Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels.

Clin Pharmacol Drug Dev 2019 Feb 7. Epub 2019 Feb 7.

Department of Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe BV, Leiden, The Netherlands.

ASP8477 (molecular weight 325.36 g/mol) is a fatty acid amide hydrolase inhibitor intended for the treatment of neuropathic pain. Results from in vitro studies indicated that ASP8477 is a direct inhibitor of cytochrome P450 (CYP) 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes at expected efficacious concentrations, with the strongest effect on CYP2C19; a phase 1 study confirmed ASP8477 to be a CYP2C19 inhibitor. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.660DOI Listing
February 2019
5 Reads

Designer Benzodiazepines: A Review of Published Data and Public Health Significance.

Clin Pharmacol Drug Dev 2019 Apr 7;8(3):266-269. Epub 2019 Feb 7.

Tufts University School of Medicine, Boston, MA, USA.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.667DOI Listing

Randomized Phase I Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Topical Daprodustat in Healthy Volunteers and in Patients With Diabetic Foot Ulcers.

Clin Pharmacol Drug Dev 2019 Feb 5. Epub 2019 Feb 5.

University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.

Daprodustat, a small-molecule inhibitor of prolyl hydroxylases, prevents breakdown of hypoxia-inducible factor (HIF), leading to increased transcription of HIF-responsive genes. This randomized, placebo-controlled study evaluated the safety, tolerability, and pharmacokinetics of a topical formulation of daprodustat in healthy volunteers (intact skin) and in patients with diabetic foot ulcers (DFUs) following single and/or 14-day repeat-dose administration. In the diabetic patients, exploratory assessments of wound area, volume, and depth were made to qualitatively assess effectiveness. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.654DOI Listing
February 2019
4 Reads

Use of Population Pharmacokinetic Analyses Among FDA-Approved Biologics.

Clin Pharmacol Drug Dev 2019 Feb 1. Epub 2019 Feb 1.

Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Biologics, especially monoclonal antibodies, are increasingly important in the pharmaceutical marketplace. Population pharmacokinetic (PK) analyses could be useful to guide the need for dose adjustments among special populations, yet it is unknown how commonly such analyses are performed during biologics development. We summarized the characteristics of population PK models of biologics and examined their role in informing the drug labels. Read More

View Article

Download full-text PDF

Source
http://doi.wiley.com/10.1002/cpdd.658
Publisher Site
http://dx.doi.org/10.1002/cpdd.658DOI Listing
February 2019
9 Reads

Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety.

Clin Pharmacol Drug Dev 2019 Apr 24;8(3):281-289. Epub 2019 Jan 24.

Amgen Inc., Thousand Oaks, CA, USA.

We evaluated the pharmacokinetics, pharmacodynamics, and safety of evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open-label, parallel-design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140-mg dose of evolocumab. The effects of evolocumab treatment on low-density lipoprotein cholesterol (LDL-C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups. Geometric mean C and AUC values in the severe RI and ESRD hemodialysis groups compared with the normal renal function group were lower but within 37% of the normal renal function group (Jonckheere-Terpstra trend test; C , P = . Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.650DOI Listing
April 2019
1 Read

Exposure-Response Analysis for Efficacy of Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV-Infected Patients.

Clin Pharmacol Drug Dev 2019 Jan 22. Epub 2019 Jan 22.

Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA.

The combination regimen of daclatasvir, asunaprevir, and beclabuvir (3DAA regimen) was developed as a fixed-dose combination for the treatment of hepatitis C virus (HCV) infection in Japan. The objectives of this analysis were to characterize the relationship between drug exposure and sustained virologic response at posttreatment week 12 (SVR12) in HCV-infected subjects and to evaluate the impact of demographic covariates and clinical factors on the exposure-response (E-R) relationship. The E-R efficacy analysis was performed with data from phase 2 and phase 3 studies in HCV-infected subjects treated with the 3DAA regimen. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.646DOI Listing
January 2019

Pharmacokinetics of Once-Daily Extended-Release Tacrolimus Tablets Versus Twice-Daily Capsules in De Novo Liver Transplant.

Clin Pharmacol Drug Dev 2019 Jan 22. Epub 2019 Jan 22.

Veloxis Pharmaceuticals, Inc., Cary, NC, USA.

The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.657DOI Listing
January 2019
2 Reads

Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of ELX-02, a Potential Treatment for Genetic Disorders Caused by Nonsense Mutations, in Healthy Volunteers.

Clin Pharmacol Drug Dev 2019 Jan 16. Epub 2019 Jan 16.

SGS Life Sciences, Clinical Pharmacology Unit, Antwerp, Belgium.

ELX-02 is an investigational synthetic eukaryotic ribosome-selective glycoside optimized as a translational read-through molecule that induces read through of nonsense mutations, resulting in normally localized full-length functional proteins. ELX-02 is being developed as a therapy for genetic diseases caused by nonsense mutations. Two phase 1a, randomized, double-blind placebo-controlled, single-ascending-dose studies were conducted in healthy human subjects to evaluate the safety and pharmacokinetics of ELX-02. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.647DOI Listing
January 2019
3 Reads

A Phase 1 Study of Intravenous Plazomicin in Healthy Adults to Assess Potential Effects on the QT/QTc Interval, Safety, and Pharmacokinetics.

Clin Pharmacol Drug Dev 2019 Jan 16. Epub 2019 Jan 16.

Achaogen, Inc, South San Francisco, CA, USA.

Plazomicin is an aminoglycoside with in vitro activity against multidrug-resistant Enterobacteriaceae. A phase 1, randomized, double-blind, crossover study assessed the potential effects of plazomicin on cardiac repolarization (NCT01514929). Fifty-six healthy adults (24 men, 32 women) received a single therapeutic dose of plazomicin (15 mg/kg administered by 30-minute intravenous infusion), a single supratherapeutic dose of plazomicin (20 mg/kg administered by 30-minute intravenous infusion), placebo, or oral moxifloxacin (400 mg). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.653DOI Listing
January 2019
3 Reads

A Phase 1b Trial to Assess the Pharmacokinetics of Ezutromid in Pediatric Duchenne Muscular Dystrophy Patients on a Balanced Diet.

Clin Pharmacol Drug Dev 2019 Jan 16. Epub 2019 Jan 16.

Summit Therapeutics, Abingdon, UK.

Ezutromid (SMT C1100) is a small-molecule utrophin modulator that was developed to treat Duchenne muscular dystrophy (DMD). Previous clinical trials of this agent revealed lower exposure in DMD patients compared with healthy volunteers, which may reflect differences in diet. This study evaluated the pharmacokinetics of ezutromid in patients with DMD who followed a balanced diet. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.642DOI Listing
January 2019
1 Read

A Phase 1 Randomized, Placebo-Controlled Trial With a Topical Inhibitor of Stearoyl-Coenzyme A Desaturase 1 Under Occluded and Nonoccluded Conditions.

Clin Pharmacol Drug Dev 2019 Apr 16;8(3):270-280. Epub 2019 Jan 16.

CMAX, a division of IDT Australia Limited, Adelaide, South Australia, Australia.

Stearoyl-coenzyme A desaturase 1 (SCD-1) in sebaceous glands is a key enzyme in the synthesis of monounsaturated fatty acids essential for acne development. GSK1940029 gel, a novel SCD-1 inhibitor, is being developed as a potential treatment for acne. To assess the irritation potential, pharmacokinetics (PK), and safety of topical GSK1940029 to the skin of healthy adults, two interdependent studies were conducted in parallel. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.644DOI Listing
April 2019
2 Reads

Ataluren Pharmacokinetics in Healthy Japanese and Caucasian Subjects.

Clin Pharmacol Drug Dev 2019 Feb 10;8(2):172-178. Epub 2019 Jan 10.

PTC Therapeutics, Inc, South Plainfield, NJ, USA.

To evaluate the potential for ethnicity-related differences in ataluren pharmacokinetics (PK) and safety, a phase 1 single-dose study was conducted in 48 healthy (24 Japanese and 24 Caucasian subjects), nonsmoking male volunteers who were equally divided into 3 cohorts of oral doses at 5, 10, and 20 mg/kg. Blood samples were collected until 48 hours postdose. PK results demonstrated rapid absorption of ataluren, with peak plasma levels (C ) being attained between 0. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.645DOI Listing
February 2019
3 Reads

Population Pharmacokinetic Analysis of Daclatasvir, Asunaprevir, and Beclabuvir Combination in HCV-Infected Subjects.

Clin Pharmacol Drug Dev 2019 Jan 10. Epub 2019 Jan 10.

Bristol-Myers Squibb, Princeton, NJ, USA.

A fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor) was approved for hepatitis C virus treatment in Japan. The objectives of the analyses were to develop the daclatasvir, asunaprevir, and beclabuvir population pharmacokinetic models for the combination regimen. First, an original population pharmacokinetic model was developed using the data in non-Japanese hepatitis C virus-infected subjects. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.649DOI Listing
January 2019
6 Reads

An Open-Label, Randomized, Pivotal Bioequivalence Study of Oral Rolapitant.

Clin Pharmacol Drug Dev 2019 Feb 9;8(2):152-159. Epub 2019 Jan 9.

TESARO, Inc., Waltham, MA, USA.

Rolapitant, a selective and long-acting neurokinin-1 receptor antagonist, is approved in an oral formulation for prevention of delayed chemotherapy-induced nausea and vomiting in adults. This pivotal open-label, randomized, single-dose, multicenter, parallel-group study assessed the bioequivalence of a single oral dose of 180 mg of rolapitant administered in tablet (2 × 90-mg tablets) or capsule (4 × 45-mg capsules) form in healthy male and female subjects. Blood samples for pharmacokinetic analysis were collected predose and at times up to 912 hours postdose. Read More

View Article

Download full-text PDF

Source
http://doi.wiley.com/10.1002/cpdd.651
Publisher Site
http://dx.doi.org/10.1002/cpdd.651DOI Listing
February 2019
22 Reads

No Effect of Plazomicin on the Pharmacokinetics of Metformin in Healthy Subjects.

Clin Pharmacol Drug Dev 2019 Jan 3. Epub 2019 Jan 3.

Achaogen, Inc., South San Francisco, CA, USA.

Plazomicin is an aminoglycoside that was engineered to overcome aminoglycoside-modifying enzymes, which are the most common aminoglycoside resistance mechanism in Enterobacteriaceae. Because plazomicin is predominantly eliminated via renal pathways, an in vitro study was conducted to determine whether plazomicin inhibits the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion (MATE1 and MATE2-K) transporters, using metformin as a probe substrate. Plazomicin inhibited OCT2, MATE1, and MATE2-K transporters with half-maximal inhibition of the transporter values of 5120, 1300, and 338 μg/mL, respectively. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.648DOI Listing
January 2019
4 Reads

Ketoconazole and Liver Injury: A Five-Year Update.

Clin Pharmacol Drug Dev 2019 Jan;8(1):6-8

Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.

View Article

Download full-text PDF

Source
http://doi.wiley.com/10.1002/cpdd.652
Publisher Site
http://dx.doi.org/10.1002/cpdd.652DOI Listing
January 2019
2 Reads

Quantitative Assessment of the Effect of Chronic Kidney Disease on the Nonrenal Clearance of 10 Drugs After Intravenous Administration.

Clin Pharmacol Drug Dev 2019 Feb 27;8(2):138-151. Epub 2018 Dec 27.

Department of Pharmaceutics, University of Florida, Gainesville, FL, USA.

The investigation identified 10 publications that reported the individual values of total clearance (CL), renal clearance (CLr), nonrenal clearance (CLnr), and the glomerular filtration rate (GFR), in subjects with varying renal functions. We used these data to estimate extent and prevalence of changes in CLnr in chronic kidney disease (CKD) by examining the relationship between clearances and renal function. The investigation was restricted to drugs given intravenously and eliminated by mixed renal and nonrenal pathways. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.635DOI Listing
February 2019
2 Reads

The Effect of a High-Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers.

Clin Pharmacol Drug Dev 2018 Dec 20. Epub 2018 Dec 20.

ARIAD Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90-mg tablets) after a 10-hour fast or after a high-fat meal in a 2-period, 2-sequence crossover study. Read More

View Article

Download full-text PDF

Source
http://doi.wiley.com/10.1002/cpdd.641
Publisher Site
http://dx.doi.org/10.1002/cpdd.641DOI Listing
December 2018
12 Reads

Elagolix Pharmacokinetic Profiles in Women With Renal or Hepatic Impairment.

Clin Pharmacol Drug Dev 2018 Dec 20. Epub 2018 Dec 20.

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.

The aim of these studies was to assess the safety and pharmacokinetics of elagolix, an oral nonpeptide gonadotropin-releasing hormone antagonist following oral administration in women with renal or hepatic impairment. Two phase 1 studies were conducted in adult women with normal renal function versus renal impairment (reduced study), and normal hepatic function versus hepatic impairment (full study design). All women received a single dose of elagolix 200 mg (renal) or 150 mg (hepatic). Read More

View Article

Download full-text PDF

Source
http://doi.wiley.com/10.1002/cpdd.640
Publisher Site
http://dx.doi.org/10.1002/cpdd.640DOI Listing
December 2018
21 Reads

Effect of Rifampicin on the Pharmacokinetics of a Single Dose of Vemurafenib in Patients With BRAF Mutation-Positive Metastatic Malignancy.

Clin Pharmacol Drug Dev 2018 Dec 20. Epub 2018 Dec 20.

Genentech, Inc., South San Francisco, CA, USA.

Vemurafenib prolongs survival in patients with BRAF -mutated advanced melanoma. In vitro studies show cytochrome P450 (CYP) 3A4 is involved in vemurafenib metabolism, but the effect of strong inducers or inhibitors of CYP3A4 on vemurafenib exposure in vivo is unknown. This phase 1, open-label, multicenter study evaluated the effect of rifampicin, a CYP3A4 inducer, on the pharmacokinetics of single-dose vemurafenib in 27 patients with BRAF mutation-positive metastatic malignancy. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.643DOI Listing
December 2018
6 Reads

Evaluation of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Intravenous Dose of Miridesap in Healthy Japanese Subjects.

Clin Pharmacol Drug Dev 2018 Dec 17. Epub 2018 Dec 17.

Medicines Development, Japan Development Division, GlaxoSmithKline K.K., Tokyo, Japan.

This phase 1 study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of miridesap (GSK2315698) following an intravenous (IV) infusion in healthy Japanese men. Subjects in Cohort 1 received 1-hour IV infusions of 10, 20, and 40 mg of miridesap or placebo, and subjects in Cohort 2 received a 15-hour IV infusion of 20 mg/h of miridesap or placebo. No treatment-related adverse events were reported. Read More

View Article

Download full-text PDF

Source
http://doi.wiley.com/10.1002/cpdd.631
Publisher Site
http://dx.doi.org/10.1002/cpdd.631DOI Listing
December 2018
8 Reads

Single-Dose Pharmacokinetic Properties and Relative Bioavailability of Different Formulations of Posaconazole Oral Suspension in Healthy Volunteers.

Clin Pharmacol Drug Dev 2018 Dec 10. Epub 2018 Dec 10.

University of Zagreb, Faculty of Pharmacy and Biochemistry, Department of Pharmaceutical Technology, Zagreb, Croatia.

The rate and extent of absorption of drugs belonging to Biopharmaceutics Classification System class II are rate-limited by dissolution and highly dependent on the performance of the formulated product. The purpose of the present study was to investigate the potential impact of a surfactant and the particle size of the active substance on the in vitro drug dissolution profiles and in vivo pharmacokinetics of the poorly soluble drug posaconazole. A comparative physicochemical evaluation was conducted, and 3 formulations of posaconazole oral suspension were tested in various dissolution media compared with the reference product. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.636DOI Listing
December 2018
5 Reads

Pharmacokinetics, Safety, and Tolerability Evaluation of Single and Multiple Doses of GSK3342830 in Healthy Volunteers.

Clin Pharmacol Drug Dev 2018 Dec 10. Epub 2018 Dec 10.

GlaxoSmithKline, Clinical Pharmacology Modeling & Simulation, Collegeville, PA, USA.

This was a first-time-in-human randomized, double-blind, single-center, placebo-controlled dose-escalation study to determine the safety, tolerability, and pharmacokinetic (PK) profiles of GSK3342830 after single and repeat intravenous doses in healthy adult subjects (NCT0271424). Sixty-two subjects were enrolled: 48 subjects in part 1 (single dose) and 14 subjects in part 2 (multiple doses). Following single intravenous infusions, total systemic exposure of GSK3342830 was dose proportional over the 250- to 6000-mg dose range evaluated, whereas peak exposure was approximately dose proportional over the dose range. Read More

View Article

Download full-text PDF

Source
https://onlinelibrary.wiley.com/doi/abs/10.1002/cpdd.637
Publisher Site
http://dx.doi.org/10.1002/cpdd.637DOI Listing
December 2018
9 Reads

Impact of Splitting or Crushing on the Relative Bioavailability of the Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen.

Clin Pharmacol Drug Dev 2018 Dec 3. Epub 2018 Dec 3.

Janssen Research & Development, Beerse, Belgium.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is an oral once-daily single-tablet regimen for the treatment of human immunodeficiency virus-1 infection. Different administration modalities for the D/C/F/TAF fixed-dose combination tablet were explored in this phase 1 randomized, open-label, 3-period, 3-treatment crossover study enrolling 30 healthy adults. The primary objective was to assess the relative bioavailability of each component after a single dose of D/C/F/TAF (800/150/200/10 mg) administered as a split or crushed tablet (tests) versus swallowed whole (reference). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.632DOI Listing
December 2018
4 Reads

Effects of Rifamycin Coadministration on Bedaquiline Desmethylation in Healthy Adult Volunteers.

Clin Pharmacol Drug Dev 2018 Nov 30. Epub 2018 Nov 30.

Department of Pediatrics, University of Toledo College of Medicine, Toledo, OH, USA.

There is an urgent need to identify safe and effective combination treatments for multidrug-resistant (MDR) Mycobacterium tuberculosis infection (TB). Bedaquiline, a new diarylquinoline, is approved for the treatment of MDR pulmonary TB in combination with other drugs, which could include rifabutin, which is also used to treat drug-resistant TB. Both rifabutin and bedaquiline are metabolized via cytochrome P450 3A4, and rifabutin is an inducer of this enzyme. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.639DOI Listing
November 2018
3 Reads

Toward Dynamic Prescribing Information: Codevelopment of Companion Model-Informed Precision Dosing Tools in Drug Development.

Clin Pharmacol Drug Dev 2018 Nov 30. Epub 2018 Nov 30.

Certara, Princeton, NJ, USA.

Model-informed precision dosing (MIPD) is biosimulation in healthcare to predict the drug dose for a given patient based on their individual characteristics that is most likely to improve efficacy and/or lower toxicity compared with traditional dosing. Despite widespread use of biosimulation in drug development, MIPD has not been adopted beyond academic-hospital centers. A reason for this is that MIPD requires more supporting evidence in the language that everyday doctors understand-evidence-based medicine. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.638DOI Listing
November 2018
3 Reads

Pharmacokinetic Interaction Study Between Saxagliptin and Omeprazole, Famotidine, or Magnesium and Aluminum Hydroxides Plus Simethicone in Healthy Subjects: An Open-Label Randomized Crossover Study.

Clin Pharmacol Drug Dev 2018 Nov 30. Epub 2018 Nov 30.

Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gaithersburg, MD, USA.

Saxagliptin is an orally administered, highly potent, and selective dipeptidyl peptidase-4 inhibitor for the management of type 2 diabetes mellitus. This study was conducted to determine the effect of magnesium and aluminum hydroxides plus simethicone, famotidine, and omeprazole on the pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin. This was an open-label, randomized, 5-treatment, 5-period, 3-way crossover study in 15 healthy subjects. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpdd.634DOI Listing
November 2018
8 Reads