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Clinical Pharmacokinetics

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https://www.readbyqxmd.com/read/28540640/a-population-pharmacokinetic-and-pharmacodynamic-analysis-of-abemaciclib-in-a-phase-i-clinical-trial-in-cancer-patients
#1
Sonya C Tate, Amanda K Sykes, Palaniappan Kulanthaivel, Edward M Chan, P Kellie Turner, Damien M Cronier
BACKGROUND AND OBJECTIVES: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated clinical activity in a number of different cancer types. The objectives of this study were to characterize the pharmacokinetics of abemaciclib in cancer patients using population pharmacokinetic (popPK) modeling, and to evaluate target engagement at clinically relevant dose levels. METHODS: A phase I study was conducted in cancer patients which incorporated intensive pharmacokinetic sampling after single and multiple oral doses of abemaciclib...
May 24, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28540639/exploiting-pharmacokinetic-models-of-tamoxifen-and-endoxifen-to-identify-factors-causing-subtherapeutic-concentrations-in-breast-cancer-patients
#2
Lena Klopp-Schulze, Markus Joerger, Sebastian G Wicha, Rob Ter Heine, Chantal Csajka, Zinnia P Parra-Guillen, Charlotte Kloft
BACKGROUND AND OBJECTIVES: A better understanding of the highly variable pharmacokinetics (PK) of tamoxifen and its active metabolite endoxifen in breast cancer patients is crucial to support individualised treatment. This study used a modelling and simulation approach to quantitatively assess the influence of cytochrome P450 (CYP) 2D6 activity and other relevant factors on tamoxifen and endoxifen PK to identify subgroups at risk for subtherapeutic endoxifen concentrations. METHODS: Simulations were performed using two previously published PK models jointly describing tamoxifen and endoxifen with CYP2D6 and CYP3A4/5 enzyme activities implemented as covariates...
May 24, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28540638/in-silico-dose-prediction-for-long-acting-rilpivirine-and-cabotegravir-administration-to-children-and-adolescents
#3
Rajith K R Rajoli, David J Back, Steve Rannard, Caren Freel Meyers, Charles Flexner, Andrew Owen, Marco Siccardi
BACKGROUND AND OBJECTIVES: Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3-18 years) using physiologically-based pharmacokinetic modelling...
May 24, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28528396/penetration-of-vancomycin-into-the-cerebrospinal-fluid-a-systematic-review
#4
REVIEW
Jessica E Beach, Jerrold Perrott, Ricky D Turgeon, Mary H H Ensom
INTRODUCTION: Infectious disease and pharmacokinetic textbooks indicate that vancomycin has poor penetration into the central nervous system due to its hydrophilic nature and high molecular weight. Recent literature suggests that penetration of vancomycin into cerebrospinal fluid (CSF) is higher than previously reported; therefore, we conducted a systematic review to assess the penetration of vancomycin into CSF. METHODS: We searched the MEDLINE, EMBASE, and CENTRAL electronic databases for English-language human studies evaluating serum and CSF concentrations of intravenous vancomycin...
May 20, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28527109/erratum-to-clinical-pharmacokinetics-of-sacubitril-valsartan-lcz696-a-novel-angiotensin-receptor-neprilysin-inhibitor
#5
Surya Ayalasomayajula, Thomas Langenickel, Parasar Pal, Sreedevi Boggarapu, Gangadhar Sunkara
Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a twofold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, ~1...
May 19, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28523450/a-review-of-the-clinical-pharmacokinetics-pharmacodynamics-and-immunogenicity-of-vedolizumab
#6
REVIEW
Maria Rosario, Nathanael L Dirks, Catherine Milch, Asit Parikh, Michael Bargfrede, Tim Wyant, Eric Fedyk, Irving Fox
Vedolizumab is a humanized anti-α4β7 integrin monoclonal antibody that selectively blocks trafficking of memory T cells to inflamed gut tissue by inhibiting the α4β7-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction. Approved for treating patients with moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), vedolizumab is administered as a 300 mg intravenous infusion. Vedolizumab undergoes a rapid, saturable, non-linear, target-mediated elimination process at low concentrations and a slower, linear, non-specific elimination process at higher concentrations...
May 18, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28512699/an-open-label-crossover-study-of-the-pharmacokinetics-of-the-60-mg-edoxaban-tablet-crushed-and-administered-either-by-a-nasogastric-tube-or-in-apple-puree-in-healthy-adults
#7
Kenneth Duchin, Anil Duggal, George J Atiee, Motonori Kidokoro, Tadanobu Takatani, Nicole Lazarus Shipitofsky, Ling He, George Zhang, Tarundeep Kakkar
BACKGROUND: Edoxaban is an orally active, direct factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation and for the treatment of venous thromboembolism. OBJECTIVES: This study assessed the pharmacokinetics, safety, and tolerability of the edoxaban 60-mg tablet crushed and administered via a nasogastric tube in a water suspension or orally mixed in apple puree. METHODS: This phase 1, open-label, crossover study randomized 30 healthy adults to receive three edoxaban treatment regimens (oral 60-mg edoxaban tablet, or 60-mg edoxaban tablet crushed and administered via a nasogastric tube or orally in apple puree) in one of six treatment sequences...
May 17, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28510797/influence-of-morbid-obesity-on-the-pharmacokinetics-of-morphine-morphine-3-glucuronide-and-morphine-6-glucuronide
#8
Sjoerd de Hoogd, Pyry A J Välitalo, Albert Dahan, Simone van Kralingen, Michael M W Coughtrie, Eric P A van Dongen, Bert van Ramshorst, Catherijne A J Knibbe
INTRODUCTION: Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers. METHODS: In this analysis, data from 20 morbidly obese patients [mean body mass index 49.9 kg/m(2) (range 37...
May 16, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28508936/phase-i-clinical-study-of-zyan1-a-novel-prolyl-hydroxylase-phd-inhibitor-to-evaluate-the-safety-tolerability-and-pharmacokinetics-following-oral-administration-in-healthy-volunteers
#9
Kevinkumar A Kansagra, Deven Parmar, Rajendra H Jani, Nuggehally R Srinivas, Jason Lickliter, Harilal V Patel, Devang P Parikh, Heather Heading, Hardik B Patel, Rahul J Gupta, Chintan Y Shah, Maulik R Patel, Vyom N Dholakia, Raghav Sukhadiya, Mukul R Jain, Krupi V Parmar, Kinjal Barot
OBJECTIVE: This phase I study of ZYAN1 was conducted to evaluate the safety, tolerability, and pharmacokinetics following oral administration in healthy volunteers. METHODS: The study was a randomized, double-blind, placebo-controlled phase I study carried out in two parts in addition to a third part involving an open-label study to evaluate the food/sex effect. A total of 100 subjects were enrolled into the study as follows: part I-single-dose study with ZYAN1 10, 25, 50, 100, 150, 200, and 300 mg (n = 56); part II-multiple-dose study with every other day dosing of ZYAN1 100, 150, 200, and 300 mg (n = 32); and part III-sex and food effect study with ZYAN1 150 mg (n = 12; open-label)...
May 16, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28508378/population-pharmacokinetic-and-pharmacodynamic-modeling-of-etelcalcetide-in-patients-with-chronic-kidney-disease-and-secondary-hyperparathyroidism-receiving-hemodialysis
#10
Ping Chen, Adimoolam Narayanan, Benjamin Wu, Per Olsson Gisleskog, John P Gibbs, Andrew T Chow, Murad Melhem
INTRODUCTION: Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). METHODS: To assess titrated dosing regimens, population pharmacokinetic (PK) and PK/pharmacodynamic (PKPD) modeling of etelcalcetide was performed using NONMEM 7.2. In this analysis, plasma etelcalcetide, serum parathyroid hormone (PTH) and calcium (Ca) concentration-time data were collected from five phase I, II, and III clinical trials following single or multiple intravenous doses of etelcalcetide ranging from 2...
May 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28497260/a-physiologically-based-pharmacokinetic-perspective-on-the-clinical-utility-of-albumin-based-dose-adjustments-in-critically-ill-patients
#11
Huybrecht T'jollyn, An Vermeulen, Jan Van Bocxlaer, Pieter Colin
INTRODUCTION: In hypo-albuminemia, the extent of albumin binding of a drug decreases. The resulting change in plasma protein binding only rarely leads to clinically relevant changes in unbound drug exposure. Nevertheless, in the critically ill, a tendency to increase dosing of anti-infective therapy is seen in patients experiencing hypo-albuminemia. To reconcile basic pharmacological principles with current clinical practice, this work presents a pharmacologically-based pharmacokinetic simulation study to emphasize the (lack of) effect of altered plasma protein binding on a drug's concentration-time profile and associated pharmacokinetic parameters...
May 11, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28497259/safety-and-tolerability-of-intravenous-valproic-acid-in-healthy-subjects-a-phase-i-dose-escalation-trial
#12
Patrick E Georgoff, Vahagn C Nikolian, Tess Bonham, Manjunath P Pai, Celia Tafatia, Ihab Halaweish, Kathleen To, Kuanwong Watcharotone, Aishwarya Parameswaran, Ruijuan Luo, Duxin Sun, Hasan B Alam
BACKGROUND: Valproic acid, a histone deacetylase inhibitor, has beneficial effects in the setting of cancer, neurologic diseases, and traumatic injuries. In animal models of traumatic injury, a single dose of valproic acid has been shown to reduce mortality. The purpose of this trial was to determine the maximum tolerated single dose of intravenous valproic acid in healthy humans. METHODS: A double-blinded, placebo-controlled, dose-escalation trial design was used to identify dose-limiting toxicities in healthy subjects who received a single dose of intravenous valproic acid...
May 11, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28497258/clinical-pharmacokinetics-and-mass-balance-of-veliparib-in-combination-with-temozolomide-in-subjects-with-nonhematologic-malignancies
#13
Silpa Nuthalapati, Wijith Munasinghe, Vincent Giranda, Hao Xiong
BACKGROUND AND OBJECTIVES: Veliparib is an orally active potent poly(ADP-ribose) polymerase (PARP) inhibitor currently in phase III clinical trials in solid tumors. This phase I study evaluated the pharmacokinetics and mass balance of veliparib administered alone and in combination with temozolomide, and assessed any potential pharmacokinetic drug-drug interaction between veliparib and temozolomide. METHODS: This was an open-label, dose-escalation study of veliparib in combination with temozolomide in 42 subjects with nonhematologic malignancies...
May 11, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28470545/relationship-between-adherence-rate-threshold-and-drug-forgiveness
#14
Alan Morrison, Melissa E Stauffer, Anna S Kaufman
The medication adherence rate (A) is the proportion of prescribed drug doses consumed within a given time period. It is often assumed that there is an adherence rate threshold (A th) at or above which the therapeutic effect of the medication is maintained. Drug forgiveness (F) is the number of consecutive doses that can be missed while still maintaining a therapeutic effect. At a given value for A, the therapeutic effect of the drug will be continuously maintained if there is no possibility of >F missed doses...
May 3, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28425029/comparison-of-a-novel-formulation-of-abiraterone-acetate-vs-the-originator-formulation-in-healthy-male-subjects-two-randomized-open-label-crossover-studies
#15
Ronald Goldwater, Azra Hussaini, Bill Bosch, Paul Nemeth
BACKGROUND AND OBJECTIVE: Abiraterone acetate is approved for the treatment of metastatic castration-resistant prostate cancer. The originator abiraterone acetate (OAA) formulation is poorly absorbed and exhibits large pharmacokinetic variability in abiraterone exposure. Abiraterone acetate fine particle (AAFP) is a proprietary formulation (using SoluMatrix Fine Particle Technology™) designed to increase the oral bioavailability of abiraterone acetate. Here, we report on two phase I studies in healthy male subjects aged 18-50 years...
April 19, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28417439/clinical-pharmacokinetics-of-sacubitril-valsartan-lcz696-a-novel-angiotensin-receptor-neprilysin-inhibitor
#16
REVIEW
Surya Ayalasomayajula, Thomas Langenickel, Parasar Pal, Sreedevi Boggarapu, Gangadhar Sunkara
Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a two-fold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, ~1...
April 17, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28409488/a-joint-model-for-vitamin-k-dependent-clotting-factors-and-anticoagulation-proteins
#17
Qing Xi Ooi, Daniel F B Wright, R Campbell Tait, Geoffrey K Isbister, Stephen B Duffull
BACKGROUND: Warfarin acts by inhibiting the reduction of vitamin K (VK) to its active form, thereby decreasing the production of VK-dependent coagulation proteins. The aim of this research is to develop a joint model for the VK-dependent clotting factors II, VII, IX and X, and the anticoagulation proteins, proteins C and S, during warfarin initiation. METHODS: Data from 18 patients with atrial fibrillation who had warfarin therapy initiated were available for analysis...
April 13, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28405936/population-pharmacokinetics-some-observations-in-pediatric-modeling-for-drug-clearance
#18
Iftekhar Mahmood, Million A Tegenge
The objective of this study is to evaluate the predictive performance of several models to predict drug clearance in preterm and term neonates. Five models using different types of allometric and linear models were developed. Two sets of data were used to develop these models (data from preterm neonates to adults and data from preterm and term neonates). Models were also developed with (normalized to 70 kg) or without body weight normalization (body weight 1 kg). From the literature, clearance values for four drugs from neonates to adults were obtained...
April 12, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28401480/target-mediated-drug-disposition-pharmacokinetic-pharmacodynamic-model-of-bosentan-and-endothelin-1
#19
Anke-Katrin Volz, Andreas Krause, Walter Emil Haefeli, Jasper Dingemanse, Thorsten Lehr
BACKGROUND AND OBJECTIVES: Bosentan is a competitive antagonist on endothelin receptor A and B (ETA and ETB), displacing the endogenous binding partner endothelin-1 (ET-1) from its binding sites. After administration of escalating single doses of 10-750 mg as an intravenous (i.v.) infusion, bosentan showed dose-dependent pharmacokinetics (PK). The aim of this analysis was to develop a PK model of bosentan after i.v. administration including competitive antagonism with ET-1 and to analyze its influence on blood pressure and heart rate with a combined pharmacokinetic/pharmacodynamic (PK/PD) model...
April 11, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28401479/gestation-specific-changes-in-the-anatomy-and-physiology-of-healthy-pregnant-women-an-extended-repository-of-model-parameters-for-physiologically-based-pharmacokinetic-modeling-in-pregnancy
#20
REVIEW
André Dallmann, Ibrahim Ince, Michaela Meyer, Stefan Willmann, Thomas Eissing, Georg Hempel
BACKGROUND: In the past years, several repositories for anatomical and physiological parameters required for physiologically based pharmacokinetic modeling in pregnant women have been published. While providing a good basis, some important aspects can be further detailed. For example, they did not account for the variability associated with parameters or were lacking key parameters necessary for developing more detailed mechanistic pregnancy physiologically based pharmacokinetic models, such as the composition of pregnancy-specific tissues...
April 11, 2017: Clinical Pharmacokinetics
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