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Clinical Pharmacokinetics

Camille Tron, Florian Lemaitre, Céline Verstuyft, Antoine Petitcollin, Marie-Clémence Verdier, Eric Bellissant
Membrane transporters play an essential role in the pharmacokinetics of drugs as they mediate exchanges between biological compartments. Tacrolimus is characterized by wide interpatient variability in terms of its pharmacokinetics that may in part be due to genetic factors. The pharmacogenetics of drug transporters is therefore a promising area to explore in the clinical pharmacology of tacrolimus. The aim of this review is to provide an overview of currently available data regarding the pharmacogenetics of membrane transporters that may be involved in the interindividual variability of the response to tacrolimus...
November 10, 2018: Clinical Pharmacokinetics
Alper Daskapan, Lusiana R Idrus, Maarten J Postma, Bob Wilffert, Jos G W Kosterink, Ymkje Stienstra, Daniel J Touw, Aase B Andersen, Adrie Bekker, Paolo Denti, Agibothu K Hemanth Kumar, Kidola Jeremiah, Awewura Kwara, Helen McIlleron, Graeme Meintjes, Joep J van Oosterhout, Geetha Ramachandran, Neesha Rockwood, Robert J Wilkinson, Tjip S van der Werf, Jan-Willem C Alffenaar
INTRODUCTION: Contrasting findings have been published regarding the effect of human immunodeficiency virus (HIV) on tuberculosis (TB) drug pharmacokinetics (PK). OBJECTIVES: The aim of this systematic review was to investigate the effect of HIV infection on the PK of the first-line TB drugs (FLDs) rifampicin, isoniazid, pyrazinamide and ethambutol by assessing all published literature. METHODS: Searches were performed in MEDLINE (through PubMed) and EMBASE to find original studies evaluating the effect of HIV infection on the PK of FLDs...
November 8, 2018: Clinical Pharmacokinetics
Carla Carnovale, Marco Pozzi, Faizan Mazhar, Giulia Mosini, Marta Gentili, Gabriëlla G A M Peeters, Emilio Clementi, Sonia Radice
INTRODUCTION: Qualitative studies on drug-drug interactions (DDIs) between anticonvulsants and antibiotics report pharmacokinetic changes that may increase the clinical risks in terms of adverse drug reactions (ADRs) and efficacy. However, no studies have provided a systematic and quantitative analysis of anticonvulsant-antibiotic pharmacokinetic DDIs. To provide such indications, we systematically and critically reviewed the literature on anticonvulsant-antibiotic DDIs in terms of quantitative pharmacokinetic changes and related ADRs...
November 7, 2018: Clinical Pharmacokinetics
Hanne Haahr, Thomas R Pieber, Chantal Mathieu, Theis Gondolf, Masanari Shiramoto, Lars Erichsen, Tim Heise
BACKGROUND: Fast-acting insulin aspart (faster aspart) is an ultra-fast-acting formulation of insulin aspart (IAsp). This post hoc analysis investigated the pharmacokinetics of faster aspart versus IAsp, measured as free or total IAsp, and the relationship between anti-IAsp antibodies and the pharmacokinetics/pharmacodynamics of faster aspart and IAsp. METHODS: Free and total IAsp concentrations and anti-IAsp antibodies were determined in adults with type 1 diabetes mellitus receiving subcutaneous faster aspart and/or IAsp in four single-dose clinical pharmacology trials (n = 175) and a 26-week phase IIIa trial (n = 1040)...
November 7, 2018: Clinical Pharmacokinetics
Sander Bins, Alwin D R Huitema, Pim Laven, Samira El Bouazzaoui, Huixin Yu, Nielka van Erp, Carla van Herpen, Paul Hamberg, Hans Gelderblom, Neeltje Steeghs, Stefan Sleijfer, Ron H N van Schaik, Ron H J Mathijssen, Stijn L W Koolen
BACKGROUND AND OBJECTIVE: As pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib affect systemic pazopanib concentrations. METHODS: The decreased function alleles CYP3A4 15389 C > T (*22), ABCB1 3435 C >T, ABCG2 421 C >A, and ABCG2 34G >A were analyzed within a recently developed population-pharmacokinetic model. RESULTS: Incorporation of CYP3A4*22 in the model resulted in a 35% lower clearance for variant carriers (0...
October 27, 2018: Clinical Pharmacokinetics
Diansong Zhou, Jianguo Li, Khanh Bui, Maria Learoyd, Alienor Berges, Tsveta Milenkova, Nidal Al-Huniti, Helen Tomkinson, Hongmei Xu
BACKGROUND: Olaparib is a first-in-class potent oral poly(ADP-ribose) polymerase inhibitor. OBJECTIVES: The aims of this analysis were to establish an integrated population pharmacokinetic (PK) model of olaparib in patients with solid tumors and to bridge the PK of olaparib between capsule and tablet formulations. METHODS: The population PK model was developed using plasma concentration data from 659 patients in 11 phase I, II, and III studies of olaparib tablets/capsules monotherapy...
October 24, 2018: Clinical Pharmacokinetics
Jurgen B Langenhorst, Thomas P C Dorlo, Erik M van Maarseveen, Stefan Nierkens, Jürgen Kuball, Jaap Jan Boelens, Charlotte van Kesteren, Alwin D R Huitema
BACKGROUND: Fludarabine is often used as an important drug in reduced toxicity conditioning regimens prior to hematopoietic cell transplantation (HCT). As no definitive pharmacokinetic (PK) basis for HCT dosing for the wide age and weight range in HCT is available, linear body surface area (BSA)-based dosing is still used. OBJECTIVE: We sought to describe the population PK of fludarabine in HCT recipients of all ages. METHODS: From 258 HCT recipients aged 0...
October 17, 2018: Clinical Pharmacokinetics
Elise J Smolders, Peter J G Ter Horst, Sharon Wolters, David M Burger
Direct-acting antivirals (DAAs) are known victims (substrate) and perpetrators (cause) of drug-drug interactions (DDIs). These DAAs are used for the treatment of hepatitis C virus (HCV) infections and are highly effective drugs. Drugs used for cardiovascular risk management are frequently used by HCV-infected patients, whom also are treated with DAAs. Therefore, the aim of this review was to describe DDIs between cardiovascular drugs (CVDs) and DAAs. An extensive literature search was performed containing search terms for the marketed DAAs and CVDs (β-blocking agents, ACE inhibitors, angiotensin II antagonists, renin inhibitors, diuretics, calcium channel blockers, statins/ezetimibe, fibrates, platelet aggregation inhibitors, vitamin K antagonists, heparins, direct Xa inhibitors, nitrates, amiodarone, and digoxin)...
September 27, 2018: Clinical Pharmacokinetics
Stephen J Balevic, Thomas P Green, Megan E B Clowse, Amanda M Eudy, Laura E Schanberg, Michael Cohen-Wolkowiez
BACKGROUND: Hydroxychloroquine is an oral drug prescribed to pregnant women with rheumatic disease to reduce disease activity and prevent flares. Physiologic changes during pregnancy may substantially alter drug pharmacokinetics. However, the effect of pregnancy on hydroxychloroquine disposition and the potential need for dose adjustment remains virtually unknown. METHODS: We performed a population-pharmacokinetic analysis using samples from the Duke Autoimmunity in Pregnancy Registry from 2013 to 2016...
September 25, 2018: Clinical Pharmacokinetics
Michael Paulzen, Julia C Stingl, Marc Augustin, Helena Saßmannshausen, Cordula Franz, Gerhard Gründer, Georgios Schoretsanitis
OBJECTIVE: The aim of this study was to measure and investigate correlations of lamotrigine concentrations in maternal as well as umbilical cord blood, amniotic fluid, and breast milk to account for the distribution of the drug. METHODS: Concentrations of lamotrigine were measured in 19 mother-infant pairs at the time of delivery. To account for the penetration ratio into amniotic fluid, cord blood and breast milk, the concentration of lamotrigine in the particular environment was divided by the concentration in maternal serum...
September 25, 2018: Clinical Pharmacokinetics
Michel Tod, S Goutelle, N Bleyzac, L Bourguignon
BACKGROUND AND OBJECTIVE: The In Vivo Mechanistic Static Model (IMSM) is a powerful method used to predict the magnitude of drug-drug interactions (DDIs) mediated by cytochromes. The objective of this study was to extend the IMSM paradigm to DDIs mediated by efflux transporters and cytochromes. METHODS: First, a generic model for this kind of interaction was devised. A flexible approach was then developed to estimate the characteristic parameters [the contribution ratios (CRs) and inhibition or induction potencies (IXs)] from clinical data by non-linear regression...
September 8, 2018: Clinical Pharmacokinetics
Yanhua Gao, Stefanie Hennig, Michael Barras
OBJECTIVES: The objective of this article is to investigate the influence of blood sampling times on tobramycin exposure estimation and clinical decisions and to determine the best sampling times for two estimation methods used for therapeutic drug monitoring. METHODS: Adult patients with cystic fibrosis, treated with once-daily intravenous tobramycin, were intensively sampled over one 24-h dosing interval to determine true exposure (AUC0-24 ). The AUC0-24 s were then estimated using both log-linear regression and Bayesian forecasting methods for 21 different sampling time combinations...
August 24, 2018: Clinical Pharmacokinetics
Felix Stader, Marco Siccardi, Manuel Battegay, Hannah Kinvig, Melissa A Penny, Catia Marzolini
BACKGROUND: Aging is characterized by anatomical, physiological, and biological changes that can impact drug kinetics. The elderly are often excluded from clinical trials and knowledge about drug kinetics and drug-drug interaction magnitudes is sparse. Physiologically based pharmacokinetic modeling can overcome this clinical limitation but detailed descriptions of the population characteristics are essential to adequately inform models. OBJECTIVE: The objective of this study was to develop and verify a population database for aging Caucasians considering anatomical, physiological, and biological system parameters required to inform a physiologically based pharmacokinetic model that included population variability...
August 21, 2018: Clinical Pharmacokinetics
Juliette Berger, Marie Vigan, Bruno Pereira, Thu Thuy Nguyen, Roseline Froissart, Nadia Belmatoug, Florence Dalbiès, Agathe Masseau, Christian Rose, Christine Serratrice, Yves-Marie Pers, Ivan Bertchansky, Fabrice Camou, Monia Bengherbia, Céline Bourgne, Catherine Caillaud, Magali Pettazzoni, Amina Berrahal, Jérôme Stirnemann, France Mentré, Marc G Berger
BACKGROUND AND OBJECTIVES: Intravenous imiglucerase enzyme replacement therapy for Gaucher disease type 1 administered every 2 weeks is at variance with the imiglucerase plasma half-life of a few minutes. We hypothesized that studying the pharmacokinetics of imiglucerase in blood Gaucher disease type 1 monocytes would be more relevant for understanding enzyme replacement therapy responses. METHODS: Glucocerebrosidase intra-monocyte activity was studied by flow cytometry...
August 21, 2018: Clinical Pharmacokinetics
Joseph F Standing, Brian J Anderson, Stefanie Hennig, Nick H Holford, Trevor N Johnston, Catherijne A J Knibbe, Dagan O Lonsdale, Amin Rostami-Hodjegan
No abstract text is available yet for this article.
November 2018: Clinical Pharmacokinetics
Sven C van Dijkman, Nico C B de Jager, Willem M Rauwé, Meindert Danhof, Oscar Della Pasqua
No abstract text is available yet for this article.
November 2018: Clinical Pharmacokinetics
Donald M Black, Darren Bentley, Sunny Chapel, Jongtae Lee, Emily Briggs, Therese Heinonen
The cholesterol ester transfer protein (CETP) inhibitor dalcetrapib has been under evaluation for its potential to prevent cardiovascular (CV) events for almost two decades. The current clinical development program, representing new advances in precision medicine and focused on a genetically defined population with acute coronary syndrome (ACS), is supported by a large body of pharmacokinetic and pharmacodynamic data as well as substantial clinical experience in over 13,000 patients and volunteers. Dalcetrapib treatment of 600 mg/day produces significant inhibition of CETP activity, and has been utilized in phase II and III studies, including CV endpoint trials...
November 2018: Clinical Pharmacokinetics
Ranjeet Prasad Dash, R Jayachandra Babu, Nuggehally R Srinivas
The recent approval of edaravone has provided an intravenous option to treat amyotrophic lateral sclerosis (ALS) in addition to the existing oral agent, riluzole. The present work was primarily undertaken to provide a comprehensive clinical pharmacokinetic summary of the two approved ALS therapeutics. The key objectives of the review were to (i) tabulate the clinical pharmacokinetics of riluzole and edaravone with emphasis on absorption, distribution, metabolism and excretion (ADME) properties; (ii) provide a comparative scenario of the pharmacokinetics of the two drugs wherever possible; and (iii) provide perspectives and introspection on the gathered clinical pharmacokinetic data of the two drugs with appropriate conjectures to quench scientific curiosity...
November 2018: Clinical Pharmacokinetics
Polina German, Anita Mathias, Diana M Brainard, Brian P Kearney
Ledipasvir/sofosbuvir (Harvoni® ), a fixed-dose combination tablet of an NS5A inhibitor ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved for the treatment of chronic hepatitis C virus infection. Ledipasvir/sofosbuvir exhibits a favorable drug-drug interaction profile and can be administered with various medications that may be used by hepatitis C virus-infected patients, including patients with comorbidities, such as co-infection with human immunodeficiency virus or immunosuppression following liver transplantation...
November 2018: Clinical Pharmacokinetics
Ida Robertsen, Jean Debord, Anders Åsberg, Pierre Marquet, Jean-Baptiste Woillard
BACKGROUND AND OBJECTIVE: Intracellular exposure of everolimus may be a better marker of therapeutic effect than trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators based on a limited sampling strategy for estimation of dose interval exposures of everolimus in whole blood and peripheral blood mononuclear cells (PBMCs) in renal transplant recipients. METHODS: Full whole blood and PBMC concentration-time profiles of everolimus were obtained from 12 stable renal transplant recipients on two different occasions, 4 weeks apart...
November 2018: Clinical Pharmacokinetics
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