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Clinical Pharmacology in Drug Development

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https://www.readbyqxmd.com/read/28430398/impact-of-acid-reducing-agents-on-the-pharmacokinetics-of-palbociclib-a-weak-base-with-ph-dependent-solubility-with-different-food-intake-conditions
#1
Wan Sun, Karen J Klamerus, Lisa M Yuhas, Sylvester Pawlak, Anna Plotka, Melissa O'Gorman, Leonid Kirkovsky, Maha Kosa, Diane Wang
Palbociclib free base capsule is a weak base drug with highly pH-dependent solubility. In vitro and in vivo studies evaluated the impact of acid-reducing agents on exposure of palbociclib and determined whether the impact, if any, can be mitigated by food. A drug-drug interaction study (study 1) was conducted first under fasted conditions and showed that coadministration of multiple doses of the proton-pump inhibitor rabeprazole substantially reduced palbociclib mean area under the concentration-time curve from time 0 to infinity and maximum observed plasma concentration by 62% and 80%, respectively...
April 21, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28419778/single-and-multiple-dose-pharmacokinetics-of-once-daily-formulations-of-raltegravir
#2
Rajesh Krishna, Matthew L Rizk, Patrick Larson, Valerie Schulz, Filippos Kesisoglou, Radu Pop
A new once-daily formulation of raltegravir, an integrase strand transfer inhibitor indicated in combination with other antiretroviral drugs for the treatment of human immunodeficiency virus-1 infection, is under development. Single-dose and steady-state pharmacokinetics of 1200 mg for 2 formulations of raltegravir were characterized in 2 open-label phase 1 studies in healthy male and female subjects aged 18 to 55 years. The new raltegravir 600-mg formulation had a higher relative bioavailability compared with the 400-mg tablets...
April 17, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28419747/a-randomized-placebo-and-positive-controlled-single-dose-crossover-thorough-qt-qtc-study-assessing-the-effect-of-daprodustat-on-cardiac-repolarization-in-healthy-subjects
#3
Stephen Caltabiano, Jon Collins, Gul Serbest, Lisa Morgan, Deborah A Smith, Ramiya Ravindranath, Alexander R Cobitz
Daprodustat (GSK1278863) is a prolyl hydroxylase inhibitor in phase 3 clinical studies for the treatment of anemia associated with chronic kidney disease. This study was conducted to evaluate the effect of daprodustat on cardiac repolarization and enrolled 55 healthy adult male (29) and female (26) subjects who received single-dose 75 and 500 mg daprodustat, 400 mg moxifloxacin, and placebo. Mean placebo-corrected change from baseline QT interval for daprodustat showed no statistically significant increase...
April 17, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28419732/a-phase-1-randomized-placebo-controlled-study-assessing-the-pharmacokinetics-safety-and-tolerability-of-retosiban-in-healthy-nonpregnant-japanese-subjects
#4
Stephen Caltabiano, Mindy He Magee, Feng Liu, Kathleen J Beach
This study characterized the pharmacokinetics, safety, and tolerability of retosiban in healthy, nonpregnant Japanese women prior to the enrollment of Japanese women in preterm labor in phase 3 trials. This study had 2 cohorts. Cohort 1 was a double-blind, sponsor-open, randomized study in Japanese women. Cohort 2 was an open-label study in white women to compare the pharmacokinetics with those of Japanese women. Retosiban was administered as a 6 mg/h infusion for 24 hours, followed by a 12 mg/h infusion over the next 24 hours; each infusion was preceded by a 6 mg loading dose administered over 5 minutes...
April 17, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28409893/spotlight-on-anti-cgrp-monoclonal-antibodies-in-migraine-the-clinical-evidence-to-date
#5
REVIEW
Lanfranco Pellesi, Simona Guerzoni, Luigi Alberto Pini
Migraine, a common neurovascular brain disorder, represents a severe and widespread health problem; along with medication-induced (medication-overuse) headache, it is the third-leading cause of disability worldwide. Currently, its therapeutic management remains unsatisfactory for several reasons; up to 40% of migraineurs are eligible for prophylactic treatment, but there are issues of efficacy, safety, and adherence. In recent years the evidence on the role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology has been consolidated, so new and promising treatments for migraine pain and its possible prevention have been developed...
April 14, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28403576/no-pharmacokinetic-drug-drug-interaction-between-prasugrel-and-vorapaxar-following-multiple-dose-administration-in-healthy-volunteers
#6
Matt S Anderson, Teddy Kosoglou, Paul Statkevich, Jing Li, Jennifer Rotonda, Alan G Meehan, David L Cutler
Vorapaxar is a first-in-class antagonist of the protease-activated receptor-1, the primary thrombin receptor on human platelets, which mediates the downstream effects of thrombin in hemostasis and thrombosis. Prasugrel is a platelet inhibitor that acts as a P2Y12 receptor antagonist through an active metabolite, R-138727. This study investigated the interaction of these 2 platelet antagonists when coadministered. This was a randomized, open-label, multiple-dose study in 54 healthy volunteers consisting of a fixed-sequence crossover and a parallel group design...
April 12, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28394491/randomized-blinded-placebo-and-positive-controlled-crossover-study-to-determine-the-effect-of-deferiprone-on-the-qtc-interval-in-healthy-subjects
#7
Caroline Fradette, Anna Rozova, Anne Stilman, Yu Chung Tsang, Mark J Allison, Fernando Tricta
This study evaluated whether deferiprone, an oral iron chelator, acts to prolong the QT interval. Fifty healthy volunteers received single doses of each of the following: therapeutic dose of deferiprone (33 mg/kg), supratherapeutic dose (50 mg/kg), placebo, or moxifloxacin, a positive control known to significantly prolong QT interval. Following each dose, subjects underwent cardiac monitoring, pharmacokinetics assessments, and safety assessments. Based on the QT interval obtained using the Fridericia correction for heart rate (QTcF), the upper bound of the 1-sided 95% confidence interval of the mean difference between deferiprone and placebo was <10 milliseconds (the threshold of concern defined by authorities) at all time points for both doses: maximum difference of 3...
April 10, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28388014/food-effect-on-oral-bioavailability-old-and-new-questions
#8
Jing-He Yan
No abstract text is available yet for this article.
April 7, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28371488/bioequivalence-study-of-warfarin-in-healthy-chinese-volunteers-with-a-validated-high-performance-liquid-chromatography-mass-spectrometry-method
#9
Wenlong Li, Fanlong Bu, Rong Li, Benjie Wang, Abdul Sami Shaikh, Yunyun Zhang, Ruichen Guo, Rui Zhang
This study was designed to investigate the pharmacokinetics of an innovative film-coated warfarin sodium tablet and to compare it with the marketed sugar-coated warfarin sodium tablet in humans. A single-dose, open-label, randomized, two-way crossover study was performed in 24 healthy Chinese male volunteers. They were administered 2.5 mg of innovative film-coated warfarin sodium tablets or the marketed sugar-coated warfarin sodium tablets. Blood samples were collected at different time points after dosing for investigation of the pharmacokinetics of warfarin in human plasma...
April 3, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28371303/a-comparative-pharmacokinetic-study-of-2-pemetrexed-formulations-in-indian-adult-chemonaive-patients-with-adenocarcinoma-stage-iii-iv-non-small-cell-lung-cancer
#10
Krunal Kavathiya, Murari Gurjar, Anand Patil, Madhura Naik, Vanita Noronha, Amit Joshi, Vikram Gota, Kumar Prabhash
The study aimed to compare the pharmacokinetics of 2 pemetrexed formulations (Pemgem, Dr. Reddy's Laboratories w.r.t; Alimta, Eli Lilly) in adult chemonaive subjects with adenocarcinoma stage III/IV non-small cell lung cancer. All patients received 500 mg/m(2) pemetrexed (Alimta or Pemgem) as a 10-minute infusion on day 1 of a 21-day cycle. Plasma pemetrexed concentrations were determined on day 1 of cycle 1. Area under the concentration-time curve (AUC0-inf ) and the maximum plasma concentration (Cmax ) were estimated using noncompartment analysis and compared between the 2 arms...
March 29, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28339166/pharmacokinetics-pharmacodynamics-pharmacogenomics-safety-and-tolerability-of-avatrombopag-in-healthy-japanese-and-white-subjects
#11
Maiko Nomoto, Gina Pastino, Bhaskar Rege, Jagadeesh Aluri, Jim Ferry, David Han
Avatrombopag, an orally administered, small-molecule thrombopoietin receptor (c-Mpl) agonist, is currently in clinical development for the potential treatment of severe thrombocytopenia in patients with chronic liver disease undergoing an elective procedure. The objectives of this study were to characterize and compare the pharmacokinetics (including the food effect) and pharmacodynamics (platelet count) of avatrombopag following single doses in Japanese and white subjects. Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5 to 8 hours and subsequently declined with a half-life of 16 to 18 hours in Japanese and white subjects...
March 24, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28339149/effect-of-food-intake-on-the-pharmacodynamics-of-tenapanor-a-phase-1-study
#12
Susanne A Johansson, Mikael Knutsson, Maria Leonsson-Zachrisson, David P Rosenbaum
Tenapanor (RDX5791/AZD1722) is a minimally systemic small-molecule inhibitor of the sodium/hydrogen exchanger NHE3. Tenapanor acts in the gut to reduce absorption of sodium and phosphate. This phase 1 open-label, 3-way crossover study (NCT02226783) evaluated the effect of food on the pharmacodynamics of tenapanor. Eighteen volunteers completed a randomized sequence of three 4-day treatments with tenapanor hydrochloride 15 mg twice daily: before food, after food, and while fasting. Participants received a diet standardized for sodium content...
March 24, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28301098/pharmacokinetics-of-a-novel-anagrelide-extended-release-formulation-in-healthy-subjects-food-intake-and-comparison-with-a-reference-product
#13
Petro E Petrides, Christian Schoergenhofer, Rudolf Widmann, Bernd Jilma, Christoph S Klade
Anagrelide is an established therapy for essential thrombocythemia. Common adverse effects have been linked to peak plasma concentrations of anagrelide and its 3OH metabolite. Our study was performed to investigate the pharmacokinetics (PK) of a novel anagrelide extended-release (AER) formulation and its active metabolites. Thirty healthy volunteers were randomized to receive either 2 mg AER (under fasting and fed conditions) or 2 mg commercially available reference product (CARP) in an open-label, 3-way crossover trial with washout periods of 6 days...
March 16, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28301096/effects-of-tenapanor-on-cytochrome-p450-mediated-drug-drug-interactions
#14
Susanne Johansson, David P Rosenbaum, Marie Ahlqvist, Helen Rollison, Mikael Knutsson, Bergur Stefansson, Marie Elebring
Tenapanor (RDX5791, AZD1722) is an inhibitor of sodium/hydrogen exchanger isoform 3 in development for the treatment of constipation-predominant irritable bowel syndrome and the treatment of hyperphosphatemia in patients with chronic kidney disease on dialysis. We aimed to investigate whether tenapanor inhibits or induces cytochrome P450s (CYPs). In vitro experiments assessing the potential of tenapanor to affect various CYPs indicated that it could inhibit CYP3A4/5 (IC50 0.4-0.7 μM). An open-label, phase 1 clinical study (NCT02140268) evaluated the pharmacokinetics of the CYP3A4 substrate midazolam when administered with and without tenapanor...
March 16, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28301092/pharmacokinetics-and-safety-of-dw1029m-a-botanical-drug-for-the-treatment-of-diabetic-nephropathy-following-single-doses-in-healthy-subjects
#15
Yunjeong Kim, Ji-Young Jeon, Eun-Young Kim, Cheol-Hee Lim, Hwan Bong Jang, Min-Gul Kim
DW1029M is a botanical extract of Morus albalinne root bark and Puerariae radix that is used for the treatment of diabetic nephropathy. This study evaluated the safety and pharmacokinetics of DW1029M following its administration in healthy Korean subjects. We conducted a randomized, open-label, single-dose, crossover phase 1 clinical study. During each period, subjects received 300, 600, or 1200 mg oral doses of DW1029M. Plasma concentrations of puerarin, daidzin, and daidzein were analyzed using a liquid chromatography-tandem mass spectrometry...
March 16, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28301084/the-effect-of-verapamil-a-p-glycoprotein-inhibitor-on-the-pharmacokinetics-of-peficitinib-an-orally-administered-once-daily-jak-inhibitor
#16
Tong Zhu, Corrie Howieson, Tomasz Wojtkowski, Jay P Garg, David Han, Ogert Fisniku, James Keirns
Peficitinib is an orally administered, once-daily Janus kinase inhibitor currently in development for the treatment of rheumatoid arthritis. It has been shown to be a P-glycoprotein (P-gp) substrate in vitro. The effects of verapamil, an inhibitor of the efflux pump P-gp, on the pharmacokinetic profile of peficitinib were assessed in this open-label, single-center, single-sequence, crossover drug-interaction study. Twenty-four healthy volunteers received a single 150-mg dose of peficitinib on days 1 and 12 of a 14-day treatment period and received verapamil 80 mg 3 times daily on days 5-14...
March 16, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28176487/lornoxicam-immediate-release-tablets-formulation-and-bioequivalence-study-in-healthy-mediterranean-volunteers-using-a-validated-lc-ms-ms-method
#17
Abdel Naser Zaid, Ayman Mousa, Nidal Jaradat, Rana Bustami
This study aimed to demonstrate interchangeability between 2 lornoxicam tablet formulations under fasting conditions among Mediterranean Arabs by using a newly validated high-pressure liquid chromatography-tandem mass spectrometry method. A single-oral solid dosage form (8 mg/tablet), randomized, open-label, 2-way crossover study was conducted on 30 healthy male volunteers. Blood samples were collected prior to dosing and over a 24-hour period, and the washout period was 9 days. Statistical comparison of the main pharmacokinetic parameters showed no significant difference between generic and branded products...
February 8, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28176470/effect-of-sustained-elevated-gastric-ph-levels-on-gefitinib-exposure
#18
Weifeng Tang, Helen Tomkinson, Eric Masson
This open-label, randomized, phase 1 crossover study investigated the effect of elevated gastric pH level (>5) on the relative bioavailability and pharmacokinetic profile of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. Healthy male volunteers (n = 26) were randomized to gefitinib 250 mg (fasted), either alone on day 1 (unmodified gastric pH) or 1 hour following the second of 2 oral doses of the H2 -receptor antagonist ranitidine 450 mg (elevated gastric pH). After a 3-week washout period, volunteers crossed to the other treatment...
February 8, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28168828/relative-bioavailability-of-a-dolutegravir-dispersible-tablet-and-the-effects-of-low-and-high-mineral-content-water-on-the-tablet-in-healthy-adults
#19
Ann M Buchanan, Michael Holton, Ian Conn, Mark Davies, Mike Choukour, Brian R Wynne
Dolutegravir (DTG) is approved in the United States to treat HIV-1-infected patients weighing ≥30 kg. A dispersible DTG tablet formulation was recently developed for pediatric patients. This study compares the pharmacokinetics (PK) of the dispersible tablet with that of a previously evaluated granule formulation. In this randomized, open-label, crossover study, 15 healthy adults received single oral doses of DTG 20 mg every 7 days across 5 treatment arms: granules consumed immediately after mixture with purified water, dispersible DTG consumed immediately after reconstitution in low-mineral-content (LMC) or high-mineral-content (HMC) water, and dispersible DTG consumed 30 minutes after dispersal in LMC or HMC water...
February 7, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28127948/bioequivalence-studies-of-a-reformulated-dutasteride-and-tamsulosin-hydrochloride-combination-capsule-and-a-commercially-available-formulation
#20
Renee Kurczewski, Chet Bowen, David Collins, John Zhu, Gulyeter Serbest, Michael Manyak
A dutasteride 0.5 mg and tamsulosin hydrochloride 0.4 mg combination (DTC) capsule (Duodart(®) ) was reformulated to reduce the capsule size and enhance product stability. Bioequivalence of the reformulated DTC capsule with the commercial formulation was evaluated in 2 single-dose, open-label, randomized, 2-way crossover studies in healthy adult male volunteers. Subjects in a fasted or fed state received a single oral dose of either the reformulated DTC or the commercial formulation followed by a 28-day washout period between treatments...
January 27, 2017: Clinical Pharmacology in Drug Development
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