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Journal of Clinical Pharmacology

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https://www.readbyqxmd.com/read/28628225/utilization-of-the-bridging-strategy-for-the-development-of-new-drugs-in-oncology-to-avoid-drug-lag
#1
Seiji Kogure, Nobuyuki Koyama, Shinji Hidaka
Global trial (GT) strategy and bridging (BG) strategy are currently the main clinical development strategies of oncology drugs in Japan, but the relationship between development style and drug lag and how the bridging strategy has contributed to the solution of drug lag have not been clear. We investigated the potential factors that influenced submission lag (SL), and also compared the differences in SL among early-initiation BG strategy, late-initiation BG strategy, and GT strategy. A stepwise linear regression analysis identified the potential factors that shorten SL: development start lag and development style...
June 19, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28618035/population-pharmacokinetics-of-imatinib-in-nigerians-with-chronic-myeloid-leukemia-clinical-implications-for-dosing-and-resistance
#2
Babatunde Ayodeji Adeagbo, Tiwalade Adewale Olugbade, Muheez Alani Durosinmi, Rahman Ayodele Bolarinwa, Kayode Ogungbenro, Oluseye Oladotun Bolaji
Imatinib, a tyrosine kinase inhibitor, is the drug of choice for the treatment of chronic myeloid leukemia in Nigeria. Several studies have established interindividual and interpopulation variations in imatinib disposition although no pharmacokinetic study have been conducted in an African population since the introduction of the drug. This study explored a population pharmacokinetic approach to investigate the disposition of imatinib in Nigerians and examined the involvement of some covariates including genetic factors in the variability of the drug disposition with a view to optimize the use of the drug in this population...
June 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28618007/an-exploratory-study-in-healthy-male-subjects-of-the-mechanism-of-mirabegron-induced-cardiovascular-effects
#3
Marcel van Gelderen, Matthias Stölzel, John Meijer, Virginie Kerbusch, Christiane Collins, Cees Korstanje
To explore the role of β1 -adrenoceptors (ARs) in the heart rate response to the selective β3 -adrenoceptor agonist mirabegron, 12 young male volunteers received single oral doses of the nonselective β1/2 -AR antagonist propranolol (160 mg), the selective β1 -AR antagonist bisoprolol (10 mg), or placebo on days 1 and 5 of each period in a 3-period crossover study. On day 5, dosing was followed by a supratherapeutic dose of mirabegron (200 mg). Vital signs, impedance cardiography, and plasma renin activity were collected...
June 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28618006/lucerastat-an-iminosugar-for-substrate-reduction-therapy-pharmacokinetics-tolerability-and-safety-in-subjects-with-mild-moderate-and-severe-renal-function-impairment
#4
Nicolas Guérard, Christian Zwingelstein, Jasper Dingemanse
Lucerastat, an inhibitor of glucosylceramide synthase, has the potential for substrate reduction therapy in glycosphingolipid storage disorders such as Fabry disease. In pharmacokinetic studies in rats, dogs, and healthy subjects, the main route of elimination was renal. The pharmacokinetics, tolerability, and safety of lucerastat were evaluated in subjects with mild (group A), moderate (group B), and severe (group C) renal impairment. Group D included healthy subjects. Thirty-two subjects (8 per group) were included in this single-center, open-label study and received a single oral dose of 1000 mg lucerastat in groups A and B and 500 mg in groups C and D...
June 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28618005/bace1-inhibitor-lanabecestat-azd3293-in-a-phase-1-study-of-healthy-japanese-subjects-pharmacokinetics-and-effects-on-plasma-and-cerebrospinal-fluid-a%C3%AE-peptides
#5
Kei Sakamoto, Shunji Matsuki, Kyoko Matsuguma, Tatsuya Yoshihara, Naoki Uchida, Fumihiko Azuma, Muir Russell, Glen Hughes, Samantha Budd Haeberlein, Robert C Alexander, Susanna Eketjäll, Alan R Kugler
Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat...
June 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28614613/population-pharmacokinetic-and-exposure-response-analysis-of-weekly-teriparatide-in-osteoporosis-patients
#6
Atsushi Ose, Masashi Serada, Keiko Yamashita, Kazuyuki Tsurui, Yusuke Tanigawara
Teriparatide is a potent therapeutic agent for the treatment of osteoporosis. One of the aims of this analysis was to develop a population pharmacokinetic (PPK) model to understand the pharmacokinetic characteristics of the once-weekly formulation of teriparatide. Another aim was to develop an exposure-response model to describe the relationship between change in bone mineral density (BMD) and teriparatide exposure after weekly subcutaneous administration. The PPK analysis showed that apparent total body clearance was significantly influenced by estimated creatinine clearance and the presence of osteoporosis...
June 14, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28614591/core-entrustable-professional-activities-in-clinical-pharmacology-for-entering-residency-biologics
#7
Vera S Donnenberg, Maja Mandic, John C Rhee, Timothy F Burns, Bernd Meibohm, Joan M Korth-Bradley
Biologicals are a rapidly expanding class of medications used in the treatment of many different conditions. This article reviews the common characteristics of this class and the requirements for safe and effective use in patients. Several vignettes are included to illustrate common challenges.
June 14, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28609567/safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-the-novel-crth2-antagonist-bi-1021958-at-single-oral-doses-in-healthy-men-and-multiple-oral-doses-in-men-and-women-with-well-controlled-asthma
#8
Andy Fowler, Rüdiger Koenen, James Hilbert, Jon Blatchford, Dominik Kappeler, Ewald Benediktus, Chester Wood, Abhya Gupta
BI 1021958, a novel antagonist of the chemoattractant-receptor-homologous molecule (CRTH2), targets airway inflammation in asthma by inhibiting prostaglandin binding to CRTH2 receptors. Two phase 1 studies assessed BI 1021958 safety/tolerability and pharmacokinetics (PK)/pharmacodynamics (PD) following single doses in healthy men and multiple doses in men/women with well-controlled asthma. Studies 1 had 2 parts: a placebo-controlled, fixed-sequence, single-blind, single-rising-dose part (n = 56) and a randomized, 2-way crossover, open-label, repeated-dose part studying the food effect on PK/PD (n = 12)...
June 13, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28597922/pharmacokinetic-characterization-and-dose-selection-of-a-novel-sumatriptan-nasal-spray-formulation-dfn-02
#9
Arindam Pal, Anirudh Gautam, Sagar Munjal
This 3-way, single-dose, randomized crossover study evaluated the pharmacokinetics (PK) and dose proportionality of 5-, 10-, and 15-mg doses of intranasal sumatriptan (DFN-02) coformulated with a permeation enhancer (DDM) in 18 healthy adults. The objective was to determine which DFN-02 dose approximates the PK of a 6-mg dose of sumatriptan delivered via subcutaneous injection in the deltoid muscle of the arm. Sumatriptan plasma concentrations peaked with DFN-02 between 10 and 15 minutes postdose, declining thereafter, with a t1/2 of about 2...
June 9, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28597919/an-open-label-dose-finding-study-of-allopurinol-to-target-defined-reduction-in-urate-levels-in-hemodialysis-patients
#10
Elaine Rutherford, Graham Stewart, J Graeme Houston, Alan G Jardine, Patrick B Mark, Allan D Struthers
No abstract text is available yet for this article.
June 9, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28589614/optimization-of-maternal-magnesium-sulfate-administration-for-fetal-neuroprotection-application-of-a-prospectively-constructed-pharmacokinetic-model-to-the-beam-cohort
#11
Kathleen F Brookfield, Mohammed Elkomy, Felice Su, David R Drover, Brendan Carvalho
The aim of the study was to identify the optimal therapeutic maternal magnesium drug exposure and maternal serum concentration to prevent cerebral palsy in the extremely preterm fetus. We applied a previously constructed pharmacokinetic model adjusted for indication to a large cohort of pregnant women receiving magnesium sulfate to prevent cerebral palsy in their preterm offspring at 20 different US academic centers between December 1997 and May 2004. We simulated the population-based individual maternal serum magnesium concentration at the time of delivery and the total magnesium dose for each woman who received magnesium sulfate to determine the relationship between maternal serum magnesium level at the time of delivery and the development of cerebral palsy...
June 6, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28581633/population-pharmacokinetic-analysis-of-zolmitriptan-and-its-metabolite-in-adults-and-adolescents-to-support-dose-selection-in-children-with-migraine
#12
Wangda Zhou, Jianguo Li, Bruce Birmingham, Hongmei Xu, Stefan Lillieborg, Diansong Zhou, Nidal Al-Huniti
Zolmitriptan is a serotonin (5-HT) 1B/1D receptor agonist effective for the treatment of migraine. This analysis aimed to develop a population pharmacokinetic (PK) model for zolmitriptan and its active metabolite in adults and adolescents and provide appropriate dosing regimens to be used in clinical trials for children 6-11 years old. The data from a single-dose clinical study of 5.0-mg zolmitriptan nasal spray (ZNS) conducted in adult and adolescent patients with migraine between migraine attacks was applied...
June 5, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28569994/physiologically-based-pharmacokinetic-modeling-for-predicting-the-effect-of-intrinsic-and-extrinsic-factors-on-darunavir-or-lopinavir-exposure-coadministered-with-ritonavir
#13
Christian Wagner, Ping Zhao, Vikram Arya, Charu Mullick, Kimberly Struble, Stanley Au
Management of comorbidities and medications is complex in HIV-1-infected patients. The overall objective of this project was to develop separate physiologically based pharmacokinetic (PBPK) substrate models for the protease inhibitors darunavir and lopinavir. These protease inhibitors are used in the treatment of HIV infection. Both darunavir and lopinavir are coadministered with another medication that inhibits cytochrome (CYP) 3A. The current project focused on PBPK modeling for darunavir and lopinavir coadministered with ritonavir...
June 1, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28561918/dose-finding-of-lenvatinib-in-subjects-with-advanced-hepatocellular-carcinoma-based-on-population-pharmacokinetic-and-exposure-response-analyses
#14
Toshiyuki Tamai, Seiichi Hayato, Seiichiro Hojo, Takuya Suzuki, Takuji Okusaka, Kenji Ikeda, Hiromitsu Kumada
Hepatocellular carcinoma (HCC) accounts for up to 90% of primary liver cancer occurrences worldwide. Lenvatinib, a multikinase inhibitor, was approved in radioiodine-refractory differentiated thyroid cancer. In this phase 2 study (study 202), we aimed to identify the lenvatinib optimal dose for subjects with advanced HCC Child-Pugh class A. Pooled data from phase 1 studies in healthy adults and in subjects with mixed tumor types, and from study 202 in subjects with HCC, were analyzed using a population pharmacokinetic approach...
May 31, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28561902/safety-and-pharmacokinetics-of-bendamustine-rapid-infusion-formulation
#15
Eric M Cheung, William J Edenfield, Bassam Mattar, Stephen P Anthony, Peter J Mutch, Brian Chanas, Mark Smith, Adrian Hepner
Bendamustine hydrochloride (BDM) is approved in the United States to treat chronic lymphocytic leukemia and relapsed indolent B-cell non-Hodgkin lymphoma. The first formulation marketed in the United States (original BDM) was a lyophilized product requiring reconstitution prior to dilution to the final admixture. A liquid formulation of BDM was subsequently introduced that did not require reconstitution before dilution. Both formulations are administered as a 500 mL admixture with a recommended infusion time of 30 or 60 minutes for chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma, respectively...
May 31, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28543950/approach-to-fingolimod-induced-lymphopenia-in-multiple-sclerosis-patients-do-we-have-a-roadmap
#16
Jagannadha Avasarala, Sandip Jain, Enrique Urrea-Mendoza
No abstract text is available yet for this article.
May 25, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28543601/influence-of-meals-and-glycemic-changes-on-qt-interval-dynamics
#17
Brenda Cirincione, Philip T Sager, Donald E Mager
Thorough QT/QTc studies have become an integral part of early drug development programs, with major clinical and regulatory implications. This analysis expands on existing pharmacodynamic models of QT interval analysis by incorporating the influence of glycemic changes on the QT interval in a semimechanistic manner. A total of 21 healthy subjects enrolled in an open-label phase 1 pilot study and provided continuous electrocardiogram monitoring and plasma glucose and insulin concentrations associated with a 24-hour baseline assessment...
May 22, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28543393/model-based-evaluation-of-exenatide-effects-on-the-qt-interval-in-healthy-subjects-following-continuous-iv-infusion
#18
Brenda Cirincione, Frank LaCreta, Philip Sager, Donald E Mager
Investigation of the cardiovascular proarrhythmic potential of a new chemical entity is now an integral part of drug development. Studies suggest that meals and glycemic changes can influence QT intervals, and a semimechanistic model has been developed that incorporates the effects of changes in glucose concentrations on heart rate (HR) and QT intervals. This analysis aimed to adapt the glucose-HR-QT model to incorporate the effects of exenatide, a drug that reduces postprandial increases in glucose concentrations...
May 22, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28543352/effect-of-albiglutide-on-cholecystokinin-induced-gallbladder-emptying-in-healthy-individuals-a-randomized-crossover-study
#19
Bonnie C Shaddinger, Malcolm A Young, Julia Billiard, David A Collins, Azra Hussaini, Antonio Nino
The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) exenatide and lixisenatide reduce cholecystokinin (CCK)-induced gallbladder emptying in healthy subjects. It is unknown if all GLP-1 RAs share this effect; therefore, the effect of the GLP-1 RA albiglutide on gallbladder function was assessed. In this randomized, double-blind, 2-way crossover study, a single dose of subcutaneous albiglutide 50 mg or placebo was administered to 17 healthy subjects, and CCK-induced gallbladder contractility was measured by ultrasonography...
May 19, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28543084/population-pharmacokinetics-and-exposure-response-assessment-of-cc-292-a-potent-btk-inhibitor-in-patients-with-chronic-lymphocytic-leukemia
#20
Yan Li, Francisco Ramírez-Valle, Yongjun Xue, Judith I Ventura, Olivier Gouedard, Jay Mei, Kenichi Takeshita, Maria Palmisano, Simon Zhou
CC-292, a potent Bruton tyrosine kinase inhibitor, is under development for the treatment of B-cell malignancies. An analysis was performed to develop a population pharmacokinetic model of CC-292 and assess the influence of demographics and disease-related covariates on CC-292 exposure and to assess the exposure-response (overall response rate) relationship in patients with chronic lymphocytic leukemia. Population pharmacokinetic analysis was based on a 2-compartment base model conducted in NONMEM. Categorical exposure-response analysis was performed using logistic regression in SAS...
May 19, 2017: Journal of Clinical Pharmacology
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