Role of Oxidative Stress in Hypersensitivity Reactions to Sulfonamides.
Abstract Antimicrobial sulfonamides are important medications. However, their use is associated with major immune-mediated drug hypersensitivity reactions with a rate that ranges from 3% to 4% in the general population. The pathophysiology of sulfa-induced drug hypersensitivity reactions is not well understood, but accumulation of reactive metabolites (sulfamethoxazole [SMX] hydroxylamine [SMX-HA] and SMX N-nitrosamine [SMX-NO]) is thought to be a major factor. These reactive metabolites contribute to the formation of reactive oxygen species (ROS) known to cause cellular damage and induce cell death through apopto...
Source: The Journal of Clinical Pharmacology - November 10, 2019 Category: Drugs & Pharmacology Authors: Elzagallaai AA, Sultan EA, Bend JR, Abuzgaia AM, Loubani E, Rieder MJ Tags: J Clin Pharmacol Source Type: research

Siponimod and CYP2C9 Allele Prevalence Among Blacks.
PMID: 31701536 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - November 7, 2019 Category: Drugs & Pharmacology Authors: Liu M, Obeng AO Tags: J Clin Pharmacol Source Type: research

Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects With Rheumatoid Arthritis, Crohn's Disease, Ulcerative Colitis, or Atopic Dermatitis: Population Analyses of Phase 1 and 2 Clinical Trials.
Abstract Upadacitinib (ABT-494) is a selective Janus kinase (JAK)1 inhibitor being developed for treatment of several inflammatory disorders. A population pharmacokinetic model was developed for upadacitinib using 11,658 plasma concentrations from 1145 subjects from 4 phase 1 and 5 phase 2 studies in healthy subjects and subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, or atopic dermatitis. A 2-compartment model with first-order absorption and lag time for the immediate-release formulation and mixed zero- and first-order absorption with lag time for the extended-release formulation, and lin...
Source: The Journal of Clinical Pharmacology - November 7, 2019 Category: Drugs & Pharmacology Authors: Nader A, Stodtmann S, Friedel A, Mohamed MF, Othman AA Tags: J Clin Pharmacol Source Type: research

Pharmacokinetics and Placental Transfer of Bupivacaine Enantiomers in HIV-Infected Parturient Women on Antiretroviral Therapy.
In this study, HIV-infected parturient women (n = 10) treated with zidovudine, lamivudine, lopinavir, and ritonavir were investigated. Anesthesia and/or analgesia was achieved by the administration of 0.5% racemic bupivacaine hydrochloride with 1:200000 epinephrine in the epidural space at doses of 2.5 to 22.5 mg. Maternal serial blood samples were obtained at the time immediately before and 5, 15, 30, 45, and 60 minutes and 2, 4, 6, 8, 10, 12, and 14 hours after administration of the bupivacaine. At the time of delivery, samples of maternal and umbilical cord vein blood were also collected. The results suggest that bupiva...
Source: The Journal of Clinical Pharmacology - November 6, 2019 Category: Drugs & Pharmacology Authors: Souza MCO, Marques MP, Duarte G, Lanchote VL Tags: J Clin Pharmacol Source Type: research

Pharmacokinetics of Para-Aminosalicylic Acid and Its 2 Major Metabolites: A Potential Relationship to the Development of Gastrointestinal Intolerance.
The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow-release enteric coated formulation, and its metabolites acetyl-PAS and glycine-PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug-resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow-release enteric-coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue ...
Source: The Journal of Clinical Pharmacology - November 4, 2019 Category: Drugs & Pharmacology Authors: Adams KT, Donald PR, Abulfathi AA, Diacon AH, Stander MA, Reuter H Tags: J Clin Pharmacol Source Type: research

Use of Propofol Plus Dexmedetomidine in Patients Experiencing Severe Alcohol Withdrawal in the Intensive Care Unit.
Abstract Alcohol abuse and alcohol withdrawal syndrome are major problems in the United States. This retrospective chart review assessed efficacy and safety of propofol plus dexmedetomidine used in combination as adjunctive therapy to benzodiazepines compared with either agent used alone in the treatment of severe alcohol withdrawal. Patients admitted to the intensive care unit and experiencing severe alcohol withdrawal between September 1, 2015 and September 30, 2018 were assessed for eligibility. Primary end points were change in the revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar) sc...
Source: The Journal of Clinical Pharmacology - October 29, 2019 Category: Drugs & Pharmacology Authors: Love K, Zimmermann AE Tags: J Clin Pharmacol Source Type: research

Association of ABCC Gene Polymorphism With Susceptibility to Antituberculosis Drug-Induced Hepatotoxicity in Western Han Patients With Tuberculosis.
Abstract Six-month combination regimens could lead to serious hepatotoxicity, which may limit the clinical use of antituberculosis drugs. ABCC transporters are critical to the influx and efflux of compounds into and out of cells. The aim of this study was to explore whether the genetic variants in ABCC genes were related to the development of antituberculosis drug-induced hepatotoxicity. Here, we screened and genotyped 39 single-nucleotide polymorphisms of 13 ABCC genes in 746 eligible patients treated by first-line antituberculosis drugs in Western China Hospital. Genomic DNA was extracted from a peripheral blood...
Source: The Journal of Clinical Pharmacology - October 24, 2019 Category: Drugs & Pharmacology Authors: Bai H, Wu T, Jiao L, Wu Q, Zhao Z, Song J, Liu T, Lv Y, Lu X, Ying B Tags: J Clin Pharmacol Source Type: research

Effects of the Fluoroquinolones Moxifloxacin and Levofloxacin on the QT Subintervals: Sex Differences in Ventricular Repolarization.
a A Abstract Women are associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. The purpose of this study was to characterize the differences in cardiac electrophysiology between moxifloxacin and levofloxacin in men and women and to assess the balance of inward and outward currents through the analysis of QT subintervals. Data from 2 TQT studies were used to investigate the impact of moxifloxacin (400 mg) and levofloxacin (1000 and 1500 mg) on QT subintervals using algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Concentration-effect an...
Source: The Journal of Clinical Pharmacology - October 21, 2019 Category: Drugs & Pharmacology Authors: Täubel J, Prasad K, Rosano G, Ferber G, Wibberley H, Cole ST, Van Langenhoven L, Fernandes S, Djumanov D, Sugiyama A Tags: J Clin Pharmacol Source Type: research

More Frequent Premature Antibiotic Discontinuations and Acute Kidney Injury in the Outpatient Setting With Vancomycin Compared to Daptomycin.
Abstract Vancomycin and daptomycin are often used in outpatient parenteral antimicrobial therapy for gram-positive coverage. Vancomycin's narrow therapeutic window poses challenges. We retrospectively assessed acute kidney injury (AKI) and other adverse drug events in outpatient parenteral antimicrobial therapy patients receiving vancomycin or daptomycin at home after hospital discharge. Among 191 patients included, AKI was the most common adverse drug event. Early antibiotic discontinuation and AKI were more frequent in the vancomycin group. Vancomycin use (odds ratio [OR], 4.57; 95% confidence interval [CI], 1.0...
Source: The Journal of Clinical Pharmacology - October 20, 2019 Category: Drugs & Pharmacology Authors: Tuerff D, Nunez M Tags: J Clin Pharmacol Source Type: research

What Drug Development Sponsors, Contract Research Organizations, and Investigators Can Do to Increase Diversity in Clinical Trials.
PMID: 31608451 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - October 13, 2019 Category: Drugs & Pharmacology Authors: Symes YR, Modell JG Tags: J Clin Pharmacol Source Type: research

Effect of Plasma Protein Binding on the Pharmacokinetics of Erdafitinib: Results of an Integrated Cross-Study Analysis.
Abstract Erdafitinib, a potent oral fibroblast growth factor receptor inhibitor, is a low extraction ratio drug highly bound to alpha-1-acid glycoprotein (AGP) with free fraction (fu ) varying across populations. This analysis aimed to characterize the impact of plasma protein binding on erdafitinib pharmacokinetics (PK). Plasma protein-binding data (fu , AGP, albumin) and PK parameters were pooled from 6 phase 1 studies in healthy participants and 1 first-in-human study in patients with cancer. Binding kinetics were characterized using a nonlinear mixed-effects model. Mean (coefficient of variation, CV%) fu was 0...
Source: The Journal of Clinical Pharmacology - October 10, 2019 Category: Drugs & Pharmacology Authors: Li LY, Guo Y, Gonzalez M, Ouellet D Tags: J Clin Pharmacol Source Type: research

A Population Pharmacokinetic Model of Oral Docetaxel Coadministered With Ritonavir to Support Early Clinical Development.
In conclusion, a semiphysiological PK model for docetaxel and ritonavir was successfully developed. Coadministration of ritonavir resulted in increased plasma concentrations of docetaxel after administration of the oral formulations of ModraDoc. Furthermore, the oral ModraDoc formulations showed lower variability in plasma concentrations between and within patients compared to the drinking solution. Comparable exposure could be reached with the oral ModraDoc formulations compared to IV administration. PMID: 31595980 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - October 9, 2019 Category: Drugs & Pharmacology Authors: Yu H, Janssen JM, Sawicki E, van Hasselt JGC, de Weger VA, Nuijen B, Schellens JHM, Beijnen JH, Huitema ADR Tags: J Clin Pharmacol Source Type: research

Evaluation of Occipital Nerve Blocks for Acute Pain Relief of Migraines.
Abstract Migraines are a debilitating neurological disease affecting as many as 1 of 6 adults in the United States. Occipital nerve block, consisting of a local anesthetic and/or corticosteroid, has shown to be an effective treatment for the management of migraines. Occipital nerve block has been reported to reduce migraine pain scores, frequency, and duration. We aimed to evaluate the impact of occipital nerve block for acute pain relief in patients with migraines. This was a single-center retrospective observational study conducted at a 1162-bed academic medical center in Gainesville, Florida. Included patients ...
Source: The Journal of Clinical Pharmacology - October 8, 2019 Category: Drugs & Pharmacology Authors: Ebied AM, Nguyen DT, Dang T Tags: J Clin Pharmacol Source Type: research

The Case for an Unblinded Modeler in Early Clinical Development.
This article discusses guidance of such early clinical studies by modeling and simulation. The ability to make use of all available information each time new data become available during the study requires the modeling scientist to be unblinded. This must of course not jeopardize the blinding of the clinical team, and this article discusses how unblinding can be prevented. Although modeling and simulation are established for guidance of the drug development process overall, they are not frequently used for guidance on a small scale, that is, during studies with the largest uncertainty, the first-in-human studies. Applicati...
Source: The Journal of Clinical Pharmacology - September 25, 2019 Category: Drugs & Pharmacology Authors: Krause A, Henrich A, Dingemanse J Tags: J Clin Pharmacol Source Type: research

CYP2B6*6 Genotype Specific Differences in Artemether-Lumefantrine Disposition in Healthy Volunteers.
Abstract Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of the antimalarial drugs artemether and lumefantrine. Here we investigated the effect of CYP2B6*6 on the plasma pharmacokinetics of artemether, lumefantrine, and their metabolites in healthy volunteers. Thirty healthy and previously genotyped adult volunteers-15 noncarriers (CYP2B6*1/*1) and 15 homozygote carriers (CYP2B6*6/*6)-selected from a cohort of 150 subjects from the Ilorin metropolitan area were administered the complete 3-day course of artemether and lumefantrine (80 and 480 mg twice daily, respectively). Intensive pharmacokinetic sampl...
Source: The Journal of Clinical Pharmacology - September 23, 2019 Category: Drugs & Pharmacology Authors: Abdullahi ST, Soyinka JO, Olagunju A, Bolarinwa RA, Olarewaju OJ, Bakare-Odunola MT, Winterberg M, Tarning J, Owen A, Khoo S Tags: J Clin Pharmacol Source Type: research

Pharmacokinetic Drug-Drug Interactions Between Trospium Chloride and Ranitidine Substrates of Organic Cation Transporters in Healthy Human Subjects.
Abstract Trospium chloride, a muscarinic receptor blocker, is poorly absorbed with different rates from areas in the jejunum and the cecum/ascending colon. To evaluate whether organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion (MATE) 1 and MATE2-K are involved in pharmacokinetics, competitions with ranitidine, a probe inhibitor of the cation transporters, were evaluated in transfected HEK293 cells. Furthermore, a drug interaction study with trospium chloride after intravenous (2 mg) and oral dosing (30 mg) plus ranitidine (300 mg) was performed in 12 healthy subjects and evaluated by noncom...
Source: The Journal of Clinical Pharmacology - September 22, 2019 Category: Drugs & Pharmacology Authors: Abebe BT, Weiss M, Modess C, Tadken T, Wegner D, Meyer MJ, Schwantes U, Neumeister C, Scheuch E, Schulz HU, Tzvetkov M, Siegmund W Tags: J Clin Pharmacol Source Type: research

Pharmacokinetics of Neoadjuvant Axitinib Influenced the Efficacy in Patients With Advanced Renal Cell Carcinoma.
This study aimed to evaluate the relationship between axitinib pharmacokinetics and clinical efficacy in patients with advanced renal cell carcinoma treated in a neoadjuvant setting. We retrospectively reviewed 16 patients who underwent neoadjuvant axitinib treatment from prospective phase 2 study cohorts treated with axitinib and assessed whether the drug concentration was associated with clinical efficacy for primary tumors of advanced metastatic/oligometastatic clear cell renal cell carcinoma. Axitinib was administered orally at a starting dose of 5 mg twice daily for 2 months in principle before the operation, and the ...
Source: The Journal of Clinical Pharmacology - September 19, 2019 Category: Drugs & Pharmacology Authors: Yamamoto Y, Otori T, Inoue R, Yano S, Hirata H, Matsumoto H, Matsuyama K, Matsuyama H Tags: J Clin Pharmacol Source Type: research

Effect of Aromatase Inhibition (Exemestane) on Urine Concentration of Osteoprotegerin in Healthy Postmenopausal Women.
Abstract This pilot study examined how exemestane (an aromatase inhibitor [AI]) affected osteoprotegerin (OPG) urine concentrations in postmenopausal women. Exemestane (25 mg, single dose) was given to 14 disease-free women past menopause in this nonrandomized, open-label study. Before dosing, urine specimens were gathered. Three days later, these women returned to provide urine specimens for pharmacokinetic (measurement of major parent drug and enzymatic product) and pharmacodynamic (profiling of OPG) analysis. Urine concentrations of the major parent drug (exemestane) and enzymatic product (17-hydroexemestane) w...
Source: The Journal of Clinical Pharmacology - September 18, 2019 Category: Drugs & Pharmacology Authors: Garcia AP, Hatvany JB, Murphy MA, Atchley DH, Gurley BJ, Kamdem LK Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics of Glecaprevir/Pibrentasvir in HCV-infected Japanese Subjects in Phase 3 CERTAIN-1 and CERTAIN-2 Trials.
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. Pharmacokinetics of GLE/PIB were characterized using a nonlinear mixed-effects modeling. The analyses evaluated the impact of covariates (concomitant medications and demographic and clinical covariates such as renal impairment, effect of cirrhotic status) on GLE/PIB PK. GLE and PIB PK were described by 1- and 2-compartment models, respectively. Presence of cirrhosis, age, and body weigh...
Source: The Journal of Clinical Pharmacology - September 12, 2019 Category: Drugs & Pharmacology Authors: Suleiman AA, Lin CW, Liu W, Eckert D, Mensing S, Burroughs M, Kato K, Chayama K, Kumada H, Oberoi RK Tags: J Clin Pharmacol Source Type: research

Model-Based Comparison of Dose-Response Profiles of Tofacitinib in Japanese Versus Western Rheumatoid Arthritis Patients.
Abstract Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this analysis was to characterize the relationship between tofacitinib dose and efficacy, as measured by American College of Rheumatology (ACR) response rates, and to compare this between Japanese and Western patients with RA. Efficacy data were pooled from 2 double-blind, dose-ranging phase 2 studies of tofacitinib monotherapy 1-15 mg twice daily in patients with RA with an inadequate response to disease-modifying antirheumatic drugs (DMARDs). NCT00550446 was carried out in mostly Western patient...
Source: The Journal of Clinical Pharmacology - September 12, 2019 Category: Drugs & Pharmacology Authors: Suzuki M, Shoji S, Miyoshi S, Krishnaswami S Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics of Talazoparib in Patients With Advanced Cancer.
Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to treat cancers associated with somatic BRCA mutations and germline genetic aberrations involved in the DNA damage response. The efficacy, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) profile of talazoparib, a potent small-molecule PARP inhibitor, was established in 4 clinical studies in cancer patients (2 phase 1 studies PRP-001 and PRP-002, the phase 2 ABRAZO trial, and the phase 3 EMBRACA trial). The current study aimed to describe the population PK of talazoparib and identify covariates that affect talazoparib PK in patien...
Source: The Journal of Clinical Pharmacology - September 6, 2019 Category: Drugs & Pharmacology Authors: Yu Y, Durairaj C, Shi H, Wang DD Tags: J Clin Pharmacol Source Type: research

Physiologically Based Pharmacokinetic Models to Predict Maternal Pharmacokinetics and Fetal Exposure to Emtricitabine and Acyclovir.
Abstract Pregnancy is associated with physiological changes that may impact drug pharmacokinetics (PK). The goals of this study were to build maternal-fetal physiologically based pharmacokinetic (PBPK) models for acyclovir and emtricitabine, 2 anti(retro)viral drugs with active renal net secretion, and to (1) evaluate the predicted maternal PK at different stages of pregnancy; (2) predict the changes in PK target parameters following the current dosing regimen of these drugs throughout pregnancy; (3) evaluate the predicted concentrations of these drugs in the umbilical vein at delivery; (4) compare the model perfo...
Source: The Journal of Clinical Pharmacology - September 6, 2019 Category: Drugs & Pharmacology Authors: Liu XI, Momper JD, Rakhmanina N, van den Anker JN, Green DJ, Burckart GJ, Best BM, Mirochnick M, Capparelli EV, Dallmann A Tags: J Clin Pharmacol Source Type: research

Effects of Adding Pentoxifylline to Captopril on Primary Hypertension: A Pilot Randomized Clinical Trial.
Abstract Because of the key role blood viscosity plays in the regulation of blood pressure (BP) and the hemorheological effects of pentoxifylline (PTX), this study was conducted to evaluate whether PTX can reduce BP when added to captopril in patients with stage 1 hypertension. In this randomized clinical trial 62 patients with stage 1 hypertension were entered. The intervention group (n = 30) received 1200 mg PTX in 3 divided doses plus 25 mg captopril 3 times a day, whereas the control group (n = 32) received only 75 mg captopril in 3 divided doses. Measurements of BP were done at baseline an...
Source: The Journal of Clinical Pharmacology - September 5, 2019 Category: Drugs & Pharmacology Authors: Namdar H, Khani E, Pourrashid MH, Entezari-Maleki T Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics of Galcanezumab, an Anti-CGRP Antibody, Following Subcutaneous Dosing to Healthy Individuals and Patients With Migraine.
In conclusion, galcanezumab exhibits PK parameters typical for an IgG mAb administered subcutaneously. The population PK model developed in this study demonstrates that galcanezumab exhibits linear PK that was not influenced in a clinically relevant manner by the patient factors evaluated. PMID: 31482569 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - September 4, 2019 Category: Drugs & Pharmacology Authors: Kielbasa W, Quinlan T Tags: J Clin Pharmacol Source Type: research

Physiologically Based Pharmacokinetic Modeling to Evaluate Formulation Factors Influencing Bioequivalence of Metoprolol Extended-Release Products.
Authors: PMID: 31368538 [PubMed - in process] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - August 3, 2019 Category: Drugs & Pharmacology Tags: J Clin Pharmacol Source Type: research

Survey of Japanese Orphan Drug Program: Factors Related to Successful Marketing Approval.
In this study, we analyzed recent outcomes of development for orphan drugs designated from 1993 to 2017 in Japan, considering their development and approval status in the United States. Our analysis showed that success for orphan drug development in Japan was apparently associated with prior approval status in the United States. Company size, orphan development experience, and patient enrichment were also positively associated with successful marketing approval. Although similar designations and priority review systems for orphan drugs have been enacted, economic incentives and regulatory conditions provided by the systems...
Source: The Journal of Clinical Pharmacology - July 31, 2019 Category: Drugs & Pharmacology Authors: Harada K, Toriyabe K, Ono S Tags: J Clin Pharmacol Source Type: research

Effect of Lercanidipine on the Pharmacokinetics-Pharmacodynamics of Carvedilol Enantiomers in Patients With Chronic Kidney Disease.
This study evaluates the carvedilol-lercanidipine drug interaction, and the influence of chronic kidney disease (CKD) on both drugs. Patients with high blood pressure (8 with normal renal function [control] and 8 with CKD with estimated glomerular filtration rate categories of G3b to G5 [12-38 mL/min/1.73 m2 ]) were included and prescribed 3 different treatment regimens, a single oral dose of racemic carvedilol 25 mg (CAR), a single oral dose of racemic lercanidipine 20 mg (LER), and single oral doses of CAR plus LER. Blood samples were collected and variations in heart rate were assessed (using isometric exercise with han...
Source: The Journal of Clinical Pharmacology - July 28, 2019 Category: Drugs & Pharmacology Authors: Hanauer Schaab E, Lanchote VL, Balthazar Nardotto GH, Marques Pereira MP, Dantas M, Paiva CE, Barbosa Coelho E Tags: J Clin Pharmacol Source Type: research

Optimizing Vancomycin Use Through 2-Point AUC-Based Therapeutic Drug Monitoring in Pediatric Patients.
In conclusion, EqA based on the 2 measured serum concentrations was sufficiently accurate for AUC24 estimation. Ctrough>10 mg/L correlated highly to AUC24 ≥400 mg⋅h/L. PMID: 31342543 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - July 24, 2019 Category: Drugs & Pharmacology Authors: Suchartlikitwong P, Anugulruengkitt S, Wacharachaisurapol N, Jantarabenjakul W, Sophonphan J, Theerawit T, Chatsuwan T, Wattanavijitkul T, Puthanakit T Tags: J Clin Pharmacol Source Type: research

Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis.
Abstract Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin protein. Patisiran is an RNA interference therapeutic comprising a novel, small interfering ribonucleic acid (ALN-18328) formulated in a lipid nanoparticle targeted to inhibit hepatic transthyretin protein synthesis. The lipid nanoparticle also contains 2 novel lipid excipients (DLin-MC3-DMA and PEG2000 -C-DMG). Here we report patisiran pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response analyses from the phase 3 APOLLO trial, i...
Source: The Journal of Clinical Pharmacology - July 19, 2019 Category: Drugs & Pharmacology Authors: Zhang X, Goel V, Attarwala H, Sweetser MT, Clausen VA, Robbie GJ Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetics of Milrinone in Infants, Children, and Adolescents.
tee Abstract Milrinone is a type 3 phosphodiesterase inhibitor used to improve cardiac output in critically ill infants and children. Milrinone is primarily excreted unchanged in the urine, raising concerns for toxic accumulation in the setting of renal dysfunction of critical illness. We developed a population pharmacokinetic model of milrinone using nonlinear mixed-effects modeling in NONMEM to perform dose-exposure simulations in children with variable renal function. We included children aged
Source: The Journal of Clinical Pharmacology - July 17, 2019 Category: Drugs & Pharmacology Authors: Hornik CP, Yogev R, Mourani PM, Watt KM, Sullivan JE, Atz AM, Speicher D, Al-Uzri A, Adu-Darko M, Payne EH, Gelber CE, Lin S, Harper B, Melloni C, Cohen-Wolkowiez M, Gonzalez D, Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Commi Tags: J Clin Pharmacol Source Type: research

Characterization of Severe Adverse Drug Reactions at a Free-Standing Children's Hospital.
Abstract We performed a retrospective chart review on severe adverse drug reactions (ADRs) detected by a pharmacovigilance program at a free-standing pediatric hospital from January 2011 through September 2014. The pharmacist-led program identifies ADRs using electronic medical record triggers. A systematic approach was used to classify ADR type and severity and assure accurate documentation. Data collection included demographics, implicated medication, type of ADR, Naranjo probability scale, ADR-associated International Classification of Diseases, 9th Revision E codes, 30-day mortality, and health care visit cost...
Source: The Journal of Clinical Pharmacology - July 15, 2019 Category: Drugs & Pharmacology Authors: Yu D, Sheets J, Suppes S, Goldman J Tags: J Clin Pharmacol Source Type: research

Efficacy, Safety, and Tolerability of ONO-4474, an Orally Available Pan-Tropomyosin Receptor Kinase Inhibitor, in Japanese Patients With Moderate to Severe Osteoarthritis of the Knee: A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group Comparative Study.
We examined the efficacy, safety, and tolerability of ONO-4474 in Japanese patients with osteoarthritis (OA) of the knee. In this multicenter, placebo-controlled, randomized, double-blind, parallel-group comparative study, patients with moderate to severe OA who were refractory to nonsteroidal anti-inflammatory drugs were orally administered 100 mg of ONO-4474 twice daily for 28 days. The primary end point was knee pain during walking, assessed by visual analog scale over 24 hours (VAS24 ). Treatment-emergent adverse events (TEAEs) and adverse drug reactions were reported for safety. In total, 110 patients were randomized ...
Source: The Journal of Clinical Pharmacology - July 8, 2019 Category: Drugs & Pharmacology Authors: Ishiguro N, Oyama S, Higashi R, Yanagida K Tags: J Clin Pharmacol Source Type: research

Effect of Itraconazole or Rifampin on Itacitinib Pharmacokinetics When Administered Orally in Healthy Subjects.
Abstract Itacitinib is a potent, selective JAK-1 inhibitor currently in phase 3 development for the treatment of acute and chronic graft-versus-host disease (GVHD) in combination with corticosteroids. Itacitinib is primarily eliminated via metabolism by cytochrome P-450 (CYP)3A4 with minimal renal elimination. A drug-drug interaction study was conducted to evaluate the impact of the strong CYP3A inhibitor itraconazole or the strong CYP3A4 inducer rifampin on the pharmacokinetics of itacitinib in healthy volunteers. In cohort 1, subjects received 200 mg sustained release (SR) tablets of itacitinib on days 1 and 6 a...
Source: The Journal of Clinical Pharmacology - July 8, 2019 Category: Drugs & Pharmacology Authors: Barbour AM, Punwani N, Epstein N, Landman R, Cimino E, Yuska B, Wang P, He K, Chen X, Yeleswaram S Tags: J Clin Pharmacol Source Type: research

Population Pharmacokinetic Modeling of Gentamicin in Pediatrics.
Abstract The primary objective of this work was to characterize the pharmacokinetics (PK) of gentamicin across the whole pediatric age spectrum from premature neonates to young adults with a single model by identifying significant clinical predictors. A nonlinear mixed-effect population PK model was developed with retrospective therapeutic drug-monitoring data. A total of 6459 drug concentration measurements from 3370 hospitalized patients were collected for model building (n = 2357) and evaluation (n = 1013). In agreement with previously reported models, a 2-compartment model with first-order ...
Source: The Journal of Clinical Pharmacology - July 8, 2019 Category: Drugs & Pharmacology Authors: Wang H, Sherwin C, Gobburu JVS, Ivaturi V Tags: J Clin Pharmacol Source Type: research

A Multicenter, Randomized, Placebo-Controlled Study of Pseudoephedrine for the Temporary Relief of Nasal Congestion in Children With the Common Cold.
Abstract This multicenter, double-blind, placebo-controlled, randomized study was designed to evaluate the efficacy and safety of pseudoephedrine hydrochloride 30-mg tablets in children aged 6 to 11 years for the temporary relief of nasal congestion due to the common cold. The primary efficacy end point was the weighted sum of the change from baseline in instantaneous nasal congestion severity score over the period from 1 to 8 hours following the first dose of study drug on day 1. Safety assessments included adverse events, sleepiness ratings, and vital signs. Pseudoephedrine was superior to placebo in reduci...
Source: The Journal of Clinical Pharmacology - July 5, 2019 Category: Drugs & Pharmacology Authors: Gelotte CK, Albrecht HH, Hynson J, Gallagher V Tags: J Clin Pharmacol Source Type: research

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib.
This study investigated the time course and magnitude of the pharmacokinetic interaction between capecitabine and the cytochrome P450 (CYP) 2C9 substrate celecoxib, with implications for coadministration of fluoropyrimidines with CYP2C9 substrates such as warfarin. Patients received celecoxib 200 mg orally twice daily continuously, with capecitabine (1000 mg/m2 orally twice daily for 14 days every 21 days) starting 7 days later. Assessment of the drug-drug interaction (DDI) potential was performed using equivalence testing, which assumes that there is no clinically relevant DDI when the calculated 90% confidence intervals ...
Source: The Journal of Clinical Pharmacology - July 5, 2019 Category: Drugs & Pharmacology Authors: Ramírez J, House LK, Karrison TG, Janisch LA, Turcich M, Salgia R, Ratain MJ, Sharma MR Tags: J Clin Pharmacol Source Type: research

2018 reviewer thank you list.
Authors: PMID: 31162680 [PubMed - in process] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - June 5, 2019 Category: Drugs & Pharmacology Tags: J Clin Pharmacol Source Type: research

Association of Metformin Use With End-Stage Renal Disease in Patients With Type 2 Diabetes Mellitus: A Nationwide Cohort Study Under the Pay-for-Performance Program.
Abstract Animal studies have demonstrated that metformin exerts a renoprotective effect. Human studies of patients with diabetes mellitus (DM) regarding the association of metformin use with end-stage renal disease (ESRD) are lacking. Patients with type 2 DM and without a history of kidney disease who were enrolled under the pay-for-performance program of the National Health Insurance in Taiwan were identified. Those who received ≥90 cumulative defined daily doses of metformin within 1 year were selected (metformin users) and compared with a 1:1 propensity score-matched metformin nonuser cohort. Primary and sec...
Source: The Journal of Clinical Pharmacology - June 4, 2019 Category: Drugs & Pharmacology Authors: Lee MC, Lee CH, Chang LY, Chang CH, Zhang JF, Lee MR, Wang JY, Chen SM Tags: J Clin Pharmacol Source Type: research

Alternative Magnesium Sulfate Dosing Regimens for Women With Preeclampsia: A Population Pharmacokinetic Exposure-Response Modeling and Simulation Study.
The objectives of this study were to develop a robust exposure-response model for the relationship between serum magnesium exposure and eclampsia using data from large studies of women with preeclampsia who received magnesium sulfate, and to predict eclampsia probabilities for standard and alternative (shorter treatment duration and/or fewer intramuscular injections) regimens. Exposure-response modeling and simulation were applied to existing data. A total of 10 280 women with preeclampsia who received magnesium sulfate or placebo were evaluated. An existing population pharmacokinetic model was used to estimate i...
Source: The Journal of Clinical Pharmacology - June 3, 2019 Category: Drugs & Pharmacology Authors: Du L, Wenning LA, Carvalho B, Duley L, Brookfield KF, Witjes H, de Greef R, Lumbiganon P, Titapant V, Kongwattanakul K, Long Q, Sangkomkamhang US, Gülmezoglu AM, Oladapo OT Tags: J Clin Pharmacol Source Type: research

Effects of Ketoconazole, a CYP4F2 Inhibitor, and CYP4F2*3 Genetic Polymorphism on Pharmacokinetics of Vitamin K1.
This study revealed that ketoconazole and CYP4F2*3 polymorphism substantially increased the exposure of vitamin K1 in humans. These findings provide a plausible explanation for variations in warfarin dose requirements resulting from interindividual variations in vitamin K1 exposure due to CYP4F2-related drug interactions and genetic polymorphisms. PMID: 31134657 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - May 28, 2019 Category: Drugs & Pharmacology Authors: Park JW, Kim KA, Park JY Tags: J Clin Pharmacol Source Type: research

Effects of Sitagliptin on Lipid Profile in Patients With Type 2 Diabetes Mellitus After 7 Years of Therapy.
Abstract The aim of this study was to investigate whether the effects of sitagliptin on lipid profile were maintained even after 7 years of treatment. We treated 591 patients who had not been well controlled by current therapy with the addition of sitagliptin 100 mg/d. Data were compared with those of 612 patients treated with sulfonylureas plus metformin, pioglitazone plus metformin, and pioglitazone plus sulfonylureas. We observed that, compared with patients treated with sulfonylureas plus metformin, patients receiving sitagliptin in addition to metformin experienced a greater decrease of total cholesterol and ...
Source: The Journal of Clinical Pharmacology - May 26, 2019 Category: Drugs & Pharmacology Authors: Derosa G, Tritto I, Romano D, D'Angelo A, Catena G, Maffioli P Tags: J Clin Pharmacol Source Type: research

Model-Based Population Pharmacokinetic Analysis of Nivolumab in Chinese Patients With Previously Treated Advanced Solid Tumors, Including Non-Small Cell Lung Cancer.
Abstract Nivolumab is the first anti-programmed death-1 agent approved in China for treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Here, we characterize the population pharmacokinetics (PPK) of nivolumab monotherapy in Chinese patients with previously treated advanced/recurrent solid tumors, including NSCLC and nasopharyngeal cancer (NPC), using data from 2 predominantly Chinese (CheckMate 077 and 078), and 5 global (MDX1106-01, CA209-003, and CheckMate 017, 057, and 063) studies. The PPK model was developed by reestimating parameters of a prior global population model with Chinese...
Source: The Journal of Clinical Pharmacology - May 22, 2019 Category: Drugs & Pharmacology Authors: Zhang J, Cai J, Bello A, Roy A, Sheng J Tags: J Clin Pharmacol Source Type: research

Loperamide: A Readily Available but Dangerous Opioid Substitute.
Abstract The antidiarrheal over-the-counter drug loperamide is increasingly being used to control opioid withdrawal or for opioid abuse. Taking many times above the normally recommended dose is dangerous with cardiovascular, respiratory, and neurological adverse events. Cytochrome P-450 (CYP)2C8, CYP3A, and P-glycoprotein inhibitors can increase the plasma and central nervous system concentrations and radically alter the risk profile of loperamide. Online forums suggest using over-the-counter metabolic enzyme blockers to enhance the effects. Public health options include switching over-the-counter loperamide to bl...
Source: The Journal of Clinical Pharmacology - May 22, 2019 Category: Drugs & Pharmacology Authors: White CM Tags: J Clin Pharmacol Source Type: research

Quantitative Comparison of the Efficacies of 5 First-Line Drugs for Primary Restless Leg Syndrome.
Abstract Comparative analyses of the efficacies of dopaminergic agonists (pramipexole, ropinirole, and rotigotine patch) and α-2-δ ligands (gabapentin enacarbil and pregabalin) for treatment of primary restless leg syndrome (RLS) are lacking because of the few head-to-head clinical trials. A model-based meta-analysis approach was employed to quantitatively compare the efficacies of these 5 first-line RLS drugs. Longitudinal efficacy data of RLS drugs were collected from published eligible literature. Mean changes in both the International Restless Leg Syndrome Study Group (IRLS) rating scale and Clinic...
Source: The Journal of Clinical Pharmacology - May 20, 2019 Category: Drugs & Pharmacology Authors: Zhang N, Li Y, Lv Y, Xu L, Chen J, Liu H, Li L, Zheng Q Tags: J Clin Pharmacol Source Type: research

The Effect of Selenomethionine on Thyroid Autoimmunity in Euthyroid Men With Hashimoto Thyroiditis and Testosterone Deficiency.
Abstract Hashimoto (autoimmune) thyroiditis develops much less frequently in men than in women, suggesting that androgens have a protective effect against thyroid autoimmunity. The current study was aimed at investigating whether the effect of selenomethionine on thyroid antibody titers and thyroid function tests in euthyroid men with autoimmune thyroid disease depends on testosterone levels. The study population consisted of 2 age-matched, weight-matched, and thyroid antibody titer-matched groups of euthyroid men with Hashimoto thyroiditis and testosterone deficiency: 18 patients receiving intramuscular ...
Source: The Journal of Clinical Pharmacology - May 20, 2019 Category: Drugs & Pharmacology Authors: Krysiak R, Kowalcze K, Okopień B Tags: J Clin Pharmacol Source Type: research

Is Moxifloxacin a Treatment Option for Pancreatic Infections? A Pharmacometric Analysis of Serum and Pancreatic Juice.
In conclusion, penetration of MXF into pancreatic juice was substantial. The PK/PD analysis indicated that treatment of pancreatic infections by isolates with MIC ≤ 0.25 mg/L (gram-negative) and ≤1 mg/L (gram-positive) should be evaluated in further studies. PMID: 31111505 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - May 20, 2019 Category: Drugs & Pharmacology Authors: Wicha SG, Mundkowski RG, Klock A, Hopt UT, Drewelow B, Kloft C, Wellner UF, Keck T, Wittel UA Tags: J Clin Pharmacol Source Type: research

Acetaminophen Protein Adducts in Hospitalized Children Receiving Multiple Doses of Acetaminophen.
Abstract Previous reports have questioned the safety of multiple doses of acetaminophen administered to ill children. Acetaminophen protein adducts (adducts) are a biomarker of acetaminophen-induced liver injury and reflect the oxidative metabolism of acetaminophen, a known mechanism in acetaminophen toxicity. In this prospective observational study, we analyzed adduct concentrations in 1034 blood samples obtained from 181 hospitalized children (1 to 18 years inclusive) who received 2 or more doses of acetaminophen. Linear regression analysis showed that serum adduct concentrations increased as a function of ...
Source: The Journal of Clinical Pharmacology - May 17, 2019 Category: Drugs & Pharmacology Authors: Jiang S, Vozmediano V, Abdel-Rahman SM, Schmidt S, James LP Tags: J Clin Pharmacol Source Type: research

Membrane-Spanning Protein Genetic Polymorphisms Related to Methotrexate Therapeutic Outcomes in a Chinese Rheumatoid Arthritis Population.
Abstract Methotrexate (MTX) is a first-line disease-modifying antirheumatic drug for rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. The differences in drug efficacy and adverse drug reactions may be caused by genetic variations. We investigated the effects of single-nucleotide polymorphisms (SNPs) in 2 genes encoding membrane-spanning proteins, namely, reduced folate carrier-1 RFC-1/SLC19A1 (G>A [rs7499], A>G [rs2838956] and 180G>A [rs1051266]) and adenosine triphosphate-binding cassette B1 (rs1045642). Tagged SNPs were genotyped in 162 patients with RA in C...
Source: The Journal of Clinical Pharmacology - May 17, 2019 Category: Drugs & Pharmacology Authors: Lv S, Fan H, Yang H, Huang J, Li J, Shu X, Zhang L, Xu Y, Li X, Zuo J, Lv C, Kong X, Xiao C Tags: J Clin Pharmacol Source Type: research

Recently Registered Midazolam Doses for Preterm Neonates Do Not Lead to Equal Exposure: A Population Pharmacokinetic Model.
SHP Abstract Although midazolam is a frequently used sedative in neonatal intensive care units, its use in preterm neonates has been off-label. Recently, a new dosing advice for midazolam for sedation on intensive care units has been included in the label (0.03 mg/[kg·h] for preterm neonates 32 weeks). Concentration-time data of a prospective multicenter study (29 patients, median gestational age 26.7 [range 24.0-31.1 weeks]) were combined with previously published data (26 patients, median gestational age 28.1 [range 26.3-33.6 weeks]), and a population pharmacokinetic model describing the maturat...
Source: The Journal of Clinical Pharmacology - May 15, 2019 Category: Drugs & Pharmacology Authors: Völler S, Flint RB, Beggah F, Reiss I, Andriessen P, Zimmermann LJI, van den Anker JN, Liem KD, Koch BCP, de Wildt S, Knibbe CAJ, Simons SHP Tags: J Clin Pharmacol Source Type: research

An Integrated Bioinformatics and Quantitative Modeling Approach to Investigate Potential Claims of Oral Generic Drug Product Bioinequivalence: Introduction.
PMID: 31087551 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology)
Source: The Journal of Clinical Pharmacology - May 14, 2019 Category: Drugs & Pharmacology Authors: Lesko LJ, Fang L, Schmidt S, Trame MN Tags: J Clin Pharmacol Source Type: research