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Ling Xue, Nick Holford, Xiao-Liang Ding, Zhen-Ya Shen, Chen-Rong Huang, Hua Zhang, Jing-Jing Zhang, Zhe-Ning Guo, Cheng Xie, Ling Zhou, Zhi-Yao Chen, Lin-Sheng Liu, Li-Yan Miao
AIMS: The aims of this study are to apply a theory based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin. METHODS: Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population pharmacokinetic parameter with data method was used to describe the international normalized ratio (INR) time course...
October 20, 2016: British Journal of Clinical Pharmacology
Mats O Magnusson, Mahesh N Samtani, Elodie L Plan, E Niclas Jonsson, Stefaan Rossenu, An Vermeulen, Alberto Russu
OBJECTIVES: Our objective was to characterize the population pharmacokinetics of paliperidone after intramuscular administration of its long-acting 3-month formulation palmitate ester at various doses and at different injection sites (deltoid and gluteal muscles). METHODS: This retrospective analysis included pooled data from 651 subjects from one phase I study (single injection of the 3-month formulation) and one phase III study (multiple injections of both 1- and 3-month formulations)...
October 14, 2016: Clinical Pharmacokinetics
Masanobu Takeuchi, Reo Tanoshima, Naoyuki Miyagawa, Takeo Sarashina, Hiromi Kato, Ryosuke Kajiwara, Shinya Ito, Hiroaki Goto
BACKGROUND: Thrombomodulin alfa (TM-α) is a new class of anticoagulant drug for patients with disseminated intravascular coagulation (DIC). This study aimed to determine the pharmacokinetics of TM-α and determine the optimal dose in pediatric patients with hematological malignancy and DIC. PROCEDURE: Pediatric patients with hematological malignancy and DIC were administered TM-α at a dose of 0.06 mg/kg (380 U/kg) over 30 min every 24 hr. Blood samples were taken at steady state before the start, immediately after the end, and 24 hr after the start of the sixth administration...
October 12, 2016: Pediatric Blood & Cancer
Virendra Rambiritch, Poobalan Naidoo, Goonaseelan Pillai
AIM: To determine the effective dose of glibenclamide by quantifying the dose-response relationship in South African type 2 diabetic patients. PATIENTS AND METHODS: A total of 24 type 2 diabetic patients participated in a glibenclamide dose-escalation study during which glibenclamide, glucose, and insulin concentrations were quantified, while the dose of glibenclamide was progressively increased. All except four subjects contributed data on all dose-escalation steps; however, data from all 24 patients were included in the model-based analysis...
2016: Clinical Pharmacology: Advances and Applications
Masato Fukae, Yoshimasa Shiraishi, Takeshi Hirota, Yuka Sasaki, Mika Yamahashi, Koichi Takayama, Yoichi Nakanishi, Ichiro Ieiri
PURPOSE: Docetaxel is used to treat many cancers, and neutropenia is the dose-limiting factor for its clinical use. A population pharmacokinetic-pharmacodynamic (PK-PD) model was introduced to predict the development of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer (NSCLC). METHODS: Forty-seven advanced or recurrent Japanese patients with NSCLC were enrolled. Patients received 50 or 60 mg/m(2) docetaxel as monotherapy, and blood samples for a PK analysis were collected up to 24 h after its infusion...
October 5, 2016: Cancer Chemotherapy and Pharmacology
Andrzej Bienczak, Adrian Cook, Lubbe Wiesner, Veronica Mulenga, Cissy Kityo, Addy Kekitiinwa, A Sarah Walker, Andrew Owen, Diana M Gibb, David Burger, Helen McIlleron, Paolo Denti
OBJECTIVES: To characterize the effects of CYP2B6 polymorphisms, diurnal variation and demographic factors on nevirapine pharmacokinetics in African children. METHODS: Non-linear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration-time data from 414 children aged 0.3-15 years. RESULTS: Nevirapine pharmacokinetics was best described using a one-compartment disposition model with elimination through a well-stirred liver model accounting for a first-pass effect and transit-compartment absorption...
October 5, 2016: Journal of Antimicrobial Chemotherapy
Daniel Fb Wright, Matthew P Doogue, Murray L Barclay, Peter T Chapman, Nicholas B Cross, John H Irvine, Lisa K Stamp
PURPOSE: The aims of this study were to characterise the population pharmacokinetics of oxypurinol in patients receiving haemodialysis and to compare oxypurinol exposure in dialysis and non-dialysis patients. METHODS: Oxypurinol plasma concentrations from 6 gout people receiving haemodialysis and 19 people with gout not receiving dialysis were used to develop a population pharmacokinetic model in NONMEM. Deterministic simulations were used to predict the steady-state area under the oxypurinol plasma concentration time curve over 1 week (AUC7days)...
September 28, 2016: European Journal of Clinical Pharmacology
J K Duong, W de Winter, S Choy, N Plock, H Naik, W Krauwinkel, S A G Visser, K M Verhamme, M C Sturkenboom, B H Stricker, M Danhof
AIM: The Weight-HbA1C-insulin-glucose (WHIG) model described the change in weight on insulin sensitivity (IS) in newly-diagnosed, obese subjects receiving placebo treatment. This model was applied to a wider population of placebo-treated subjects to investigate factors influencing the variability in IS and β-cell function. METHODS: The WHIG model was applied to the WHIG dataset (Study 1) and two other placebo datasets (Studies 2 and 3). Studies 2 and 3 consisted of non-obese subjects and subjects with advanced T2DM...
September 28, 2016: British Journal of Clinical Pharmacology
Qi Pei, Lu Huang, Jie Huang, Jing-Kai Gu, Yun Kuang, Xiao-Cong Zuo, Jun-Jie Ding, Hong-Yi Tan, Cheng-Xian Guo, Shi-Kun Liu, Guo-Ping Yang
AIM: Iloperidone is an atypical antipsychotic drug that is mainly metabolized by CYP2D6, CYP3A4, and cytosolic enzymes. Previous studies show that extensive and poor metabolizers of CYP2D6 exhibit different plasma concentrations of iloperidone and its metabolites. The aim of this study was to develop a parent-metabolite population pharmacokinetic (PPK) model to quantify the effects of CYP2D6(*)10 allele on the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients...
September 26, 2016: Acta Pharmacologica Sinica
Sven Mensing, Doerthe Eckert, Shringi Sharma, Akshanth R Polepally, Amit Khatri, Thomas J Podsadecki, Walid M Awni, Rajeev M Menon, Sandeep Dutta
AIM: To characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir, and dasabuvir) and adjunctive ribavirin and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection. METHODS: Pharmacokinetic data from six phase 3 studies and one phase 2 study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 or 24 weeks were characterized using separate population pharmacokinetic models built using each component of the regimen from non-linear mixed-effects methodology in NONMEM 7...
September 23, 2016: British Journal of Clinical Pharmacology
Atsuko Tanaka, Ikuko Yano, Keiko Shinsako, Eriko Sato, Masahide Fukudo, Satohiro Masuda, Toshinari Yamasaki, Tomomi Kamba, Osamu Ogawa, Kazuo Matsubara
BACKGROUND: Everolimus has been used for the treatment of unresectable or metastatic renal cell carcinoma (RCC). Here, we measured blood concentrations of everolimus to obtain the population pharmacokinetic parameters and to examine the relationship between blood concentration and clinical outcomes. METHODS: Twenty-two Japanese patients were enrolled. Blood samples were collected before and 2, 4, 8, and 24 h after drug administration on days 1 and 8 of everolimus therapy (5 or 10 mg) for inpatients; occasional samples were collected for outpatients...
September 19, 2016: Therapeutic Drug Monitoring
Brenda Cirincione, Donald E Mager
AIM: The aim of this analysis was to develop a core population pharmacokinetic system for the pharmacokinetic properties of immediate-release (IR) exenatide that can be used in subsequent analyses for novel sustained-release formulations. METHODS: Data from eight clinical trials evaluating a wide range of doses and different administration routes were available for analysis. All modelling and simulations were conducted using the nonlinear mixed-effect modelling program NONMEM...
September 21, 2016: British Journal of Clinical Pharmacology
F Bellanti, G C Del Vecchio, M C Putti, A Maggio, A Filosa, C Cosmi, L Mangiarini, M Spino, J Connelly, A Ceci, O Della Pasqua
AIMS: Despite long clinical experience with deferiprone, there is limited information on its pharmacokinetics in children < 6 years of age. Here we assess the impact of developmental growth on the pharmacokinetics of deferiprone in this population using a population approach. Based on pharmacokinetic bridging concepts, we also evaluate whether the recommended doses yield appropriate systemic exposure in this group of patients. METHODS: Data from a study in which 18 paediatric patients were enrolled were available for the purposes of this analysis...
September 19, 2016: British Journal of Clinical Pharmacology
Jinju Guk, Hankil Son, Dong Woo Chae, Kyungsoo Park
Megestrol acetate, an appetite stimulant with low bioavailability, shows increased bioavailability when taken together with food. However, the pharmacokinetic characteristics of megestrol acetate and its relation with food are not well understood. This study aimed to investigate the food effect on the pharmacokinetics (PK) of the recently developed nano-crystallized megestrol acetate (NCMA), using a model-based approach. Data were obtained from an NCMA PK study consisting of a single dose in fasting (39 individuals) and fed conditions (40 individuals)...
September 17, 2016: Basic & Clinical Pharmacology & Toxicology
Romain Guilhaumou, Amélie Marsot, Julien Dupouey, Claire Galambrun, Audrey Boulamery, Carole Coze, Nicolas Simon, Nicolas André
BACKGROUND: In pediatric cancer patients, determination of optimal vancomycin dosage is essential because of high risk of inadequate concentrations and bacterial resistance. The aim of this study was to determine vancomycin pharmacokinetic parameters in this population and propose dosage optimization to achieve optimal concentration. METHODS: We retrospectively reviewed the use of vancomycin in pediatric cancer patients with febrile neutropenia (hematological or solid tumor disease)...
October 2016: Therapeutic Drug Monitoring
Vincent Jullien, Elie Azoulay, Carole Schwebel, Thomas Le Saux, Pierre Emmanuel Charles, Muriel Cornet, Bertrand Souweine, Kadda Klouche, Samir Jaber, Jean-Louis Trouillet, Fabrice Bruneel, Martin Cour, Joel Cousson, Ferhat Meziani, Didier Gruson, Adeline Paris, Michael Darmon, Maité Garrouste-Orgeas, Jean-Christophe Navellou, Arnaud Foucrier, Bernard Allaouchiche, Vincent Das, Jean-Pierre Gangneux, Stéphane Ruckly, Michel Wolff, Jean-François Timsit
OBJECTIVES: To identify the factors associated with the interindividual pharmacokinetic (PK) variability of micafungin and to evaluate the probability of reaching the previously determined PK/pharmacodynamic efficacy thresholds (AUC/MIC >5000 for non-parapsilosis Candida sp. and ≥285 for Candida parapsilosis) with the recommended 100 mg daily dose in ICU patients with sepsis and mechanical ventilation. METHODS: One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software...
September 8, 2016: Journal of Antimicrobial Chemotherapy
Y J Ma, D Q Jiang, J X Meng, M X Li, H H Zhao, Y Wang, L Q Wang
WHAT IS KNOWN AND OBJECTIVE: Numerous population pharmacokinetic studies of theophylline have been conducted in paediatric and adult patients. The purpose of this review was to summarize the published studies concerning population pharmacokinetics of theophylline in patients of different ages and discuss factors that might cause the large variability in the pharmacokinetics of theophylline. METHODS: A literature search was conducted in PubMed using the following keywords: 'theophylline', 'population pharmacokinetic(s)' and 'nonlinear mixed effect model'...
August 31, 2016: Journal of Clinical Pharmacy and Therapeutics
Stéphanie Leroux, Jean-Michel Roué, Jean-Bernard Gouyon, Valérie Biran, Hao Zheng, Wei Zhao, Evelyne Jacqz-Aigrain
Cefotaxime is one of the most frequently prescribed antibiotics in neonates for the treatment of Gram-negative neonatal sepsis. However, a considerable variation of dosing regimens exists in routine clinical practice. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize dosing regimen.Opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed...
August 29, 2016: Antimicrobial Agents and Chemotherapy
Victor Mangas-Sanjuan, Sarin Colon-Useche, Isabel Gonzalez-Alvarez, Marival Bermejo, Alfredo Garcia-Arieta
The objective is to compare the performance of dissolution-profile comparison methods when f 2 is inadequate due to high variability. The 90% confidence region of the Mahalanobis distance and the 90% bootstrap confidence interval (CI) of the f 2 similarity factor (f 2-bootstrap) were explored. A modification of the Mahalanobis distance (new D-Mahalanobis) in which those points >85% were not taken into account for calculation was also used. A population kinetic approach in NONMEM was used to simulate dissolution profiles with the first-order or Weibull kinetic models...
August 29, 2016: AAPS Journal
Naïm Bouazza, Zoubir Djerada, Claire Gozalo, Kanetee Busiah, Jacques Beltrand, Marianne Berdugo, Saik Urien, Jean-Marc Treluyer, Michel Polak
PURPOSE: Glibenclamide (Gb) is used in type II diabetes mellitus but also in the last 10 years, off label, in patients with neonatal syndromic hyperglycemia carrying a mutation of Kir6.2 or SUR1. No studies have reported Gb pharmacokinetics in children. In this study, oral Gb pharmacokinetics was investigated in children in order to describe the concentration time courses, the influence of covariates, and the relationships between drug concentrations and efficacy. METHODS: Gb concentrations were measured in 18 children after the switch from subcutaneous insulin to oral tablets of Gb (crushed tablets for 33 % of patients)...
November 2016: European Journal of Clinical Pharmacology
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