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Journal of Clinical Pharmacology

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https://www.readbyqxmd.com/read/28194792/semisimultaneous-midazolam-administration-to-evaluate-the-time-course-of-cyp3a-activation-by-a-single-oral-dose-of-efavirenz
#1
Gerd Mikus, Tilman Heinrich, Julia Bödigheimer, Claudia Röder, Anne-Kathrin Matthee, Johanna Weiss, Jürgen Burhenne, Walter E Haefeli
This study aimed to assess whether a single oral dose of the nonnucleoside reverse transcriptase inhibitor efavirenz can alter CYP3A in vivo. In 12 healthy participants individual CYP3A activity was quantified using a semisimultaneous methodology (midazolam orally and 6 hours later intravenously) both alone and during a period of 22 days after a single oral dose of 400 mg efavirenz. Twelve hours after efavirenz administration, midazolam apparent oral clearance was significantly increased by 70%, and midazolam systemic clearance after intravenous administration was significantly increased by 27%...
February 14, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28181260/a-mechanism-based-pharmacokinetic-pharmacodynamic-model-for-bococizumab-a-humanized-monoclonal-antibody-against-proprotein-convertase-subtilisin-kexin-type-9-and-its-application-in-early-clinical-development
#2
Chandrasekhar Udata, Pamela D Garzone, Barry Gumbiner, Tenshang Joh, Hong Liang, Kai-Hsin Liao, Jason H Williams, Xu Meng
Bococizumab (RN316/PF-04950615), a humanized monoclonal antibody, binds to secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents its downregulation of low-density lipoprotein receptor, leading to improved clearance and reduction of low-density lipoprotein cholesterol (LDL-C) in plasma. A mechanism-based drug-target binding model was developed, accounting for bococizumab, PCSK9, and LDL-C concentrations and the effects of concomitant administration of statins. This model was utilized to better understand the pharmacokinetic/pharmacodynamic (PK/PD) data obtained from 3 phase 1 and 2 phase 2a clinical studies...
February 9, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28181259/causative-drugs-of-stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-in-israel
#3
Nicola Maggio, Maria Firer, Huda Zaid, Yana Bederovsky, Mohammed Aboukaoud, Revital Gandelman-Marton, Iris Noyman, Dana Ekstein, Ilan Blatt, Eli Marom, Eyal Schwartzberg, Shoshana Israel, Arieh Ingber, Chaim Brautbar, Sara Eyal
No abstract text is available yet for this article.
February 9, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28181240/cytochrome-p450-genetic-variations-can-predict-mrna-expression-cyclophosphamide-4-hydroxylation-and-treatment-outcomes-in-chinese-patients-with-non-hodgkin-s-lymphoma
#4
Wenying Shu, Lingyan Chen, Xiaoye Hu, Meimei Zhang, Wensheng Chen, Lei Ma, Xiaoyan Liu, Jianing Huang, Tingyuan Pang, Jia Li, Yu Zhang
To investigate the impact of cytochrome P450 (CYP) genetic polymorphisms CYP2B6, CYP2C19, and CYP3A5 on mRNA expression, cyclophosphamide/4-hydroxycyclophosphamide pharmacokinetics, and treatment outcomes of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in Chinese patients with non-Hodgkin's lymphoma, 567 cases were investigated. Plasma concentrations of cyclophosphamide/4-hydroxycyclophosphamide were determined using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters calculated...
February 9, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28168730/continuous-lidocaine-infusion-as-adjunctive-analgesia-in-intensive-care-unit-patients
#5
Yoonsun Mo, Michael C Thomas, Abigail D Antigua, Alex M Ebied, George E Karras
Despite a paucity of data, the role of intravenous lidocaine (IVLI) as adjunctive analgesia in the intensive care unit (ICU) seems promising due to a low potential to contribute to respiratory depression. A retrospective chart review was conducted to evaluate the safety and effectiveness of IVLI for the treatment of pain in ICU patients with varying degrees of organ dysfunction from March 2014 to March 2016. The primary outcomes included the time to a ≥20% reduction in pain scores after the initiation of IVLI and the difference in opioid requirements as well as pain scores prior to and during IVLI therapy...
February 7, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28150316/facilitate-treatment-adjustment-after-overdosing-another-step-toward-21st-century-medicine
#6
Gilbert Koch, Johannes Schropp, Marc Pfister
Overdosing occurs frequently because of prescription errors in neonates, infants, children, adolescents, and adults. Currently there is no quantitative approach that can be used by clinicians to adjust dosing so that toxic drug concentrations can be brought back to levels observed with safe and efficacious therapeutic doses. We present a mathematical solution that offers the time between last overdosing and next therapeutic dose to achieve therapeutic drug concentrations as soon as possible. To facilitate applications of this solution in clinical practice, a minimal amount of information has to be provided, and no simulations are necessary to compute the optimal waiting time...
February 2, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28144958/population-pharmacokinetics-of-ly2623091-in-patients-with-hypertension-and-chronic-kidney-disease
#7
Evan B Wang, Archana Chaudhary, Timothy H Waterhouse, Gemma L Dickinson
LY2623091 is a selective, orally active, nonsteroidal, competitive mineralocorticoid receptor antagonist that blocks the actions of aldosterone and other mineralocorticoid receptor ligands at the receptor level. The aim of this work was to explore and establish a population pharmacokinetic model, quantify the degree of interindividual variability, and identify significant disease-, patient-, and study-specific covariates that alter the disposition of LY2623091. The data included concentrations from 294 healthy subjects and patients with hypertension and/or chronic kidney disease (CKD), sampled in 5 phase 1 and 2 studies...
February 1, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28138963/translational-model-based-strategy-to-guide-the-choice-of-clinical-doses-for-antibody-drug-conjugates
#8
Marion Bouillon-Pichault, Claire Brillac, Céline Amara, Céline Nicolazzi, Nathalie Fagniez, Jean-Baptiste Fau, Kimiko Koiwai, Samira Ziti-Ljajic, Christine Veyrat-Follet
This work proposes a model-based approach to help select the phase 1 dosing regimen for the antibody-drug conjugate (ADC) SAR408701 leveraging the available data for 2 other ADCs of the same construct: SAR3419 and SAR566658. First, monkey and human pharmacokinetic (PK) data of SAR566658 and SAR3419 were used to establish the appropriate allometric approach to be applied to SAR408701 monkey PK data. Second, a population pharmacokinetics-pharmacodynamics (PK-PD) model was developed to describe tumor volume evolution following SAR408701 injection in mice...
January 30, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28134984/conversion-from-sirolimus-to-everolimus-in-long-term-liver-graft-recipients
#9
Nina Weiler, Nigar Bilge, Sven Troetschler, Johannes Vermehren, Andreas Anton Schnitzbauer, Eva Herrmann, Christoph Sarrazin, Stefan Zeuzem, Martin-Walter Welker
Immunosuppression by inhibition of the mechanistic target of rapamycin (mTOR) is a promising approach after liver transplantation. The mTOR inhibitor sirolimus was used in selected liver graft recipients despite safety concerns and lack of approval. Everolimus is another mTOR inhibitor approved after liver transplantation. It is currently unknown, whether conversion of sirolimus to everolimus is safe in long-term liver graft recipients. Long-term liver graft recipients treated with sirolimus were converted to everolimus...
January 30, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28120422/effectiveness-and-tolerability-of-colesevelam-hcl-for-accelerated-elimination-of-teriflunomide-in-healthy-participants
#10
Catherine Lunven, Zuyu Guo, Sandrine Turpault, Astrid Delfolie, Nicolas Fauchoux, Timothy Turner, Francesca Baldinetti
No abstract text is available yet for this article.
January 25, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28117887/electrophysiological-adverse-effects-of-direct-acting-antivirals-in-patients-with-chronic-hepatitis-c
#11
Emanuele Durante-Mangoni, Antonio Parrella, Martina Vitrone, Anna Rago, Pia Clara Pafundi, Gerardo Nigro, Riccardo Utili, Vincenzo Russo
Recently, several cases of symptomatic, sometimes fatal bradycardia during the first days of direct-acting antiviral (DAA) (eg, sofosbuvir [SOF]) administration have been reported. We analyzed in detail electrocardiographic (ECG) changes during SOF- or non-SOF-based chronic hepatitis C (CHC) treatment, specifically focusing on bradyarrhythmias. All 39 consecutive patients treated at our center with any interferon-free regimen between June and December 2015 were included in this study (26 SOF-based therapy vs 13 no-SOF interferon-free regimens)...
January 24, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28114735/effects-of-type-2-diabetes-mellitus-in-patients-on-treatment-with-glibenclamide-and-metformin-on-carvedilol-enantiomers-metabolism
#12
Glauco H B Nardotto, Eduardo B Coelho, Carlos E Paiva, Vera L Lanchote
Carvedilol is available in clinical practice as a racemate in which (S)-(-)-carvedilol is a β- and α1 -adrenergic antagonist and (R)-(+)-carvedilol is only an α1 -adrenergic antagonist. Carvedilol is mainly metabolized by glucuronidation, by CYP2D6 to hydroxyphenylcarvedilol (OHC), and by CYP2C9 to O-desmethylcarvedilol (DMC). This study evaluated the pharmacokinetics of carvedilol enantiomers and their metabolites OHC and DMC in healthy volunteers (n = 13) and in type 2 diabetes mellitus patients with good glycemic control (n = 13)...
January 23, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28111772/preliminary-evidence-for-the-off-label-treatment-of-bulimia-nervosa-with-psychostimulants-six-case-reports
#13
Aaron Keshen, Thomas Helson
Psychostimulants have been assessed in bulimia nervosa patients with comorbid attention deficit/hyperactivity disorder (ADHD), but few studies have examined the impact of psychostimulants on bulimia nervosa patients without comorbid ADHD. The aim of this study was to examine psychostimulants as a potential treatment for bulimia nervosa and to assess the concern of weight loss, given the medication's appetite-suppressing effects. This retrospective study describes 6 case reports of outpatients who were prescribed a psychostimulant specifically for their bulimia nervosa...
January 23, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28105688/medication-adherence
#14
David Lawrence, James H Miller, Charles W Flexner
No abstract text is available yet for this article.
January 20, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28083951/enantioselectivity-in-the-metabolism-of-cyclophosphamide-in-patients-with-multiple-or-systemic-sclerosis
#15
Francine Attié de Castro, Belinda Pinto Simões, Eduardo Barbosa Coelho, Vera Lucia Lanchote
The aim of this study was to evaluate the enantioselective pharmacokinetics of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide and carboxyethylphosphoramide mustard in patients with systemic or multiple sclerosis. Patients with systemic sclerosis (n = 10) or multiple sclerosis (n = 10), genotyped for the allelic variants of CYP2C9*2 and CYP2C9*3 and of the CYP2B6 G516T polymorphism, were treated with 50 mg cyclophosphamide/kg daily for 4 days. Serial blood samples were collected up to 24 hours after administration of the last cyclophosphamide dose...
January 13, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28074489/a-novel-nf-%C3%AE%C2%BAb-inhibitor-edasalonexent-cat-1004-in-development-as-a-disease-modifying-treatment-for-patients-with-duchenne-muscular-dystrophy-phase-1-safety-pharmacokinetics-and-pharmacodynamics-in-adult-subjects
#16
Joanne M Donovan, Michael Zimmer, Elliot Offman, Toni Grant, Michael Jirousek
In Duchenne muscular dystrophy (DMD), NF-κB is activated in skeletal muscle from infancy regardless of the underlying dystrophin mutation and drives inflammation and muscle degeneration while inhibiting muscle regeneration. Edasalonexent (CAT-1004) is a bifunctional orally administered small molecule that covalently links 2 compounds known to inhibit NF-κB, salicylic acid and docosahexaenoic acid (DHA). Edasalonexent is designed to inhibit activated NF-κB upon intracellular cleavage to these bioactive components...
January 11, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28070894/a-phase-1-open-label-randomized-crossover-study-evaluating-the-bioavailability-of-tas-102-trifluridine-tipiracil-tablets-relative-to-an-oral-solution-containing-equivalent-amounts-of-trifluridine-and-tipiracil
#17
Carlos R Becerra, Kenichiro Yoshida, Hirokazu Mizuguchi, Manish Patel, Daniel Von Hoff
TAS-102 (trifluridine/tipiracil) is composed of an antineoplastic thymidine-based nucleoside analogue trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI), at a molar ratio of 1:0.5 (weight ratio, 1:0.471). A phase 1 study evaluated relative bioavailability of TAS-102 tablets compared with an oral solution containing equivalent amounts of FTD and TPI. In an open-label, 2-sequence, 3-period, crossover bioavailability study (part 1), patients 18 years or older with advanced solid tumors were randomized to receive TAS-102 tablets (60 mg; 3 × 20-mg tablets) on day 1 and TAS-102 oral solution (60 mg) on days 8 and 15, or the opposite sequence...
January 9, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28052338/quantitative-prediction-of-the-effect-of-cyp3a-inhibitors-and-inducers-on-venetoclax-pharmacokinetics-using-a-physiologically-based-pharmacokinetic-model
#18
Kevin J Freise, Mohamad Shebley, Ahmed Hamed Salem
The objectives of the analysis were to develop and verify a venetoclax physiologically based pharmacokinetic (PBPK) model to predict the effects of cytochrome P450 3A (CYP3A) inhibitors and inducers on the PK of venetoclax and inform dosing recommendations. A minimal PBPK model was developed based on prior in vitro and in vivo clinical data using a "middle-out" approach. The PBPK model was independently verified against clinical studies of the strong CYP3A inhibitor ketoconazole, the strong CYP3A inducer, multiple-dose rifampin, and the steady-state venetoclax PK in chronic lymphocytic leukemia (CLL) subjects by comparing predicted to observed ratios of the venetoclax maximum concentration (Cmax R) and area under the curve from time 0 to infinity (AUC∞ R) from these studies...
January 4, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28032902/population-pharmacokinetics-of-eplerenone-in-japanese-patients-with-chronic-heart-failure
#19
Masayo Oishi, Yoshiro Tomono, Qinying Zhao, Kevin Sweeney
To characterize eplerenone pharmacokinetics (PK) in Japanese chronic heart failure (CHF) patients and to estimate the impact of factors that may affect eplerenone PK, population pharmacokinetic (PPK) analysis was conducted. In addition, PK of Japanese CHF and Western CHF patients from a previous clinical pharmacology study were compared in the analysis. Eplerenone PK was characterized by a 1-compartment PPK model with first-order absorption and lag time in Japanese CHF patients. The population mean of apparent oral clearance (CL/F) in Japanese CHF patients was estimated as 5...
December 29, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28026013/moderate-hepatic-impairment-does-not-affect-doravirine-pharmacokinetics
#20
Sauzanne Khalilieh, Ka Lai Yee, Rachael Liu, Li Fan, Rosa I Sanchez, Patrice Auger, Ilias Triantafyllou, Daria Stypinski, Kenneth C Lasseter, Thomas Marbury, Marian Iwamoto
Doravirine is a novel, potent, nonnucleoside reverse-transcriptase inhibitor currently in development for HIV-1 infection treatment. As a substrate for CYP3A-mediated metabolism, doravirine could potentially be affected by liver-function changes. As a portion of the HIV-1-infected population has varying degrees of liver impairment, we investigated the effect of moderate hepatic impairment on the pharmacokinetic profile and tolerability of single-dose doravirine 100 mg in otherwise healthy subjects. A total of 16 subjects aged 44-64 years took part in the open-label, single-dose trial: 8 with moderate hepatic impairment (Child-Pugh score, 7-9; 6 men, 2 women) and 8 healthy individuals (mean age and height matched with the impairment group; 6 men, 2 women)...
December 27, 2016: Journal of Clinical Pharmacology
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