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Clinical Pharmacokinetics

Thomas Tängdén, Pier Giorgio Cojutti, Jason A Roberts, Federico Pea
BACKGROUND AND OBJECTIVES: Valganciclovir is used as oral prophylaxis for cytomegalovirus (CMV) infection in kidney transplant recipients. However, limited pharmacokinetic data exist to guide dosing in this patient group. This study aimed to describe the population pharmacokinetics of valganciclovir in a large sample of kidney transplant recipients and predict optimal dosing based on Monte Carlo simulations. METHODS: Therapeutic drug monitoring (TDM) data from adult kidney transplant recipients who received valganciclovir prophylaxis during a 10-year study period were collected retrospectively...
March 15, 2018: Clinical Pharmacokinetics
Femke M de Man, Andrew K L Goey, Ron H N van Schaik, Ron H J Mathijssen, Sander Bins
Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose-limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences...
March 8, 2018: Clinical Pharmacokinetics
Stein Schalkwijk, Rob Ter Heine, Angela C Colbers, Alwin D R Huitema, Paolo Denti, Kelly E Dooley, Edmund Capparelli, Brookie M Best, Tim R Cressey, Rick Greupink, Frans G M Russel, Mark Mirochnick, David M Burger
BACKGROUND: Reducing the dose of efavirenz can improve safety, reduce costs, and increase access for patients with HIV infection. According to the World Health Organization, a similar dosing strategy for all patient populations is desirable for universal roll-out; however, it remains unknown whether the 400 mg daily dose is adequate during pregnancy. METHODS: We developed a mechanistic population pharmacokinetic model using pooled data from women included in seven studies (1968 samples, 774 collected during pregnancy)...
March 8, 2018: Clinical Pharmacokinetics
Erik Mogalian, Diana M Brainard, Anu Osinusi, Lisa Moorehead, Bernard Murray, Kah Hiing John Ling, Robert Perry, Craig Curtis, Eric Lawitz, Kenneth Lasseter, Thomas Marbury, Anita Mathias
BACKGROUND: The pharmacokinetics and safety of velpatasvir, a potent pangenotypic hepatitis C virus NS5A inhibitor, were evaluated in two hepatic impairment studies: a phase I study in hepatitis C virus-uninfected subjects and a phase III study (ASTRAL-4) in hepatitis C virus-infected patients. METHODS: In the phase I study, subjects with moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C), and demographically matched subjects with normal hepatic function received a single dose of velpatasvir 100 mg...
March 8, 2018: Clinical Pharmacokinetics
Sathej Gopalakrishnan, Sven Mensing, Rajeev M Menon, Jiuhong Zha
BACKGROUND: The clinical development program of the direct-acting antiviral (DAA) combination therapy of paritaprevir (coadministered with ritonavir) and ombitasvir, with and without dasabuvir (3-DAA [3D] and 2-DAA [2D] regimens, respectively) used in the treatment of chronic hepatitis C infection has generated a robust dataset across various dosing regimens and patient populations. OBJECTIVE: The current analysis aimed to characterize the population pharmacokinetics in patients without cirrhosis ('non-cirrhotic') and with compensated cirrhosis ('cirrhotic'), while accounting for differences across hepatitis C virus (HCV) genotypes (GT) 1, 2, and 4, multiple regimens (3D regimen ± ribavirin for GT1 in global studies, 2D regimen for subgenotype 1b in Japan, 2D regimen + ribavirin for GT2 in Japan, and 2D regimen + ribavirin for GT4), and ethnicities...
March 7, 2018: Clinical Pharmacokinetics
Luc J J Derijks, Dennis R Wong, Daniel W Hommes, Adriaan A van Bodegraven
According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved...
March 6, 2018: Clinical Pharmacokinetics
Pieter J Colin, Stijn Jonckheere, Michel M R F Struys
OBJECTIVES: In this in-silico study, we investigate the clinical utility of target-controlled infusion for antibiotic dosing in an intensive care unit setting using vancomycin as a model compound. We compared target-controlled infusion and adaptive target-controlled infusion, which combines target-controlled infusion with data from therapeutic drug monitoring, with conventional (therapeutic drug monitoring-based) vancomycin dosing strategies. METHODS: A clinical trial simulation was conducted...
March 6, 2018: Clinical Pharmacokinetics
Insa Winzenborg, Ahmed Nader, Akshanth R Polepally, Mohan Liu, Jacob Degner, Cheri E Klein, Nael M Mostafa, Peter Noertersheuser, Juki Ng
INTRODUCTION: Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well-characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters...
February 23, 2018: Clinical Pharmacokinetics
Jennifer H Martin, Jennifer Schneider, Catherine J Lucas, Peter Galettis
In the original publication, Page 3, Sect. 4.3, the first sentence was incorrectly published.
February 21, 2018: Clinical Pharmacokinetics
Nithya Srinivas, Kaitlyn Maffuid, Angela D M Kashuba
Despite contributing significantly to the burden of global disease, the translation of new treatment strategies for diseases of the central nervous system (CNS) from animals to humans remains challenging, with a high attrition rate in the development of CNS drugs. The failure of clinical trials for CNS therapies can be partially explained by factors related to pharmacokinetics/pharmacodynamics (PK/PD), such as lack of efficacy or improper selection of the initial dosage. A focused assessment is needed for CNS-acting drugs in first-in-human studies to identify the differences in PK/PD from animal models, as well as to choose the appropriate dose...
February 20, 2018: Clinical Pharmacokinetics
Patrick J Marroum, Silpa Nuthalapati, Apurvasena Parikh, Mohamad Shebley, David Hoffman, Jiuhong Zha, Amit Khatri, Walid M Awni
Investigating the effect of food on bioavailability during the development of an oral drug product is of prime importance because it has major implications on the study design of the clinical trials and dosing and administration recommendations. For modified-release formulations that exhibit dose dumping when administered with food, this may result in clinical concerns around safety and efficacy. In this article, we provide an overview of the various considerations in our opinion that impact the design and conduct of food-effect studies...
February 19, 2018: Clinical Pharmacokinetics
Chia-Hsiang Hsueh, Vicky Hsu, Yuzhuo Pan, Ping Zhao
BACKGROUND: Physiologically-based pharmacokinetic (PBPK) modeling in predicting metabolic drug-drug interactions (mDDIs) is routinely used in drug development. Currently, the US FDA endorses the use of PBPK to potentially support dosing recommendations for investigational drugs as enzyme substrates of mDDIs, and to inform a lack of mDDIs for investigational drugs as enzyme modulators. METHODS: We systematically evaluated the performance of PBPK modeling in predicting mDDIs published in the literature...
February 17, 2018: Clinical Pharmacokinetics
Niloufar Marsousi, Youssef Daali, Pierre Fontana, Jean-Luc Reny, Virginie Ancrenaz-Sirot, Alexandra Calmy, Serge Rudaz, Jules Alexandre Desmeules, Caroline Flora Samer
BACKGROUND AND OBJECTIVES: Prasugrel and clopidogrel are inhibitors of the ADP-P 2 Y 12 platelet receptor used in acute coronary syndrome patients. They require bioactivation via isoenzymes such as cytochrome P450 (CYP) 3A4, CYP2C19 and CYP2B6. Ritonavir and cobicistat are potent CYP3A inhibitors, prescribed as pharmacokinetic (PK) enhancers in the treatment of human immunodeficiency virus (HIV) infection. METHODS: In this study, the impact of boosted antiretroviral therapies (ARTs) on the PK of clopidogrel and prasugrel active metabolites (AMs), and on the efficacy of prasugrel and clopidogrel, were evaluated in a randomized crossover clinical trial...
February 16, 2018: Clinical Pharmacokinetics
Idoia Bilbao-Meseguer, Alicia Rodríguez-Gascón, Helena Barrasa, Arantxazu Isla, María Ángeles Solinís
BACKGROUND: Traditionally, renal function in critically ill patients has been assessed to identify renal dysfunction, and dose adjustment is generally accepted in such a context. Nevertheless, augmented renal clearance (ARC) is a less well-studied phenomenon that could lead to faster elimination of drugs, resulting in subtherapeutic concentrations and poorer clinical outcomes when standard dosage guidelines are followed. OBJECTIVE: The aim of this systematic review was to gather and summarise all the available evidence on ARC in critically ill patients, including its definition, underlying mechanisms, epidemiology, diagnosis and impact on both drug pharmacokinetics and clinical outcomes...
February 13, 2018: Clinical Pharmacokinetics
Sven C van Dijkman, Nico C B de Jager, Willem M Rauwé, Meindert Danhof, Oscar Della Pasqua
BACKGROUND AND AIMS: In this study, we evaluate the performance of allometric concepts to predict the implications of age and size on the pharmacokinetics of lamotrigine, and assess the dose rationale across different age groups from 0.2 to 91 years. METHODS: An allometrically scaled pharmacokinetic model was developed using adolescent and adult data, taking into account the effect of comedications. Model parameters were then used to extrapolate lamotrigine pharmacokinetics to older adults (> 65 years), children (4-12 years) and infants and toddlers (0...
January 23, 2018: Clinical Pharmacokinetics
Laura A Hart, Gail D Anderson
International guidelines recommend the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method to monitor kidney function in chronic kidney disease using either creatinine- or cystatin C-based estimation methods. The choice of an estimation method to determine dosage for renally eliminated drugs is not as clear. For the majority of currently marketed drugs, the Cockcroft-Gault equation with the Jaffe method, a non-isotope dilution mass spectrometry, standardized serum creatinine, was used to estimate kidney function to recommend dosing adjustment in kidney impairment...
January 22, 2018: Clinical Pharmacokinetics
Sreeneeranj Kasichayanula, Anita Grover, Maurice G Emery, Megan A Gibbs, Ransi Somaratne, Scott M Wasserman, John P Gibbs
Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhibits nonlinear kinetics as a result of binding to PCSK9. Elimination is predominantly through saturable binding to PCSK9 at lower concentrations and a nonsaturable proteolytic pathway at higher concentrations. The effective half-life of evolocumab is 11-17 days...
January 20, 2018: Clinical Pharmacokinetics
Yash Gandhi, Timothy Eley, Aberra Fura, Wenying Li, Richard J Bertz, Tushar Garimella
Daclatasvir is a first-in-class, highly selective, hepatitis C virus, non-structural protein 5a polymerase replication complex inhibitor with picomolar potency and broad genotypic coverage in vitro. Daclatasvir undergoes rapid absorption, with a time to reach maximum plasma concentration of 1-2 h and an elimination half-life of ~ 10 to 14 h observed in single-ascending dose studies. Steady state was achieved by day 4 in multiple-ascending dose studies. Daclatasvir can be administered without regard to food or pH modifiers...
January 20, 2018: Clinical Pharmacokinetics
Mukul Minocha, Jiewei Zeng, Jeroen K Medema, Ahmed A Othman
BACKGROUND AND OBJECTIVE: Venetoclax is an oral selective Bcl-2 inhibitor approved for the treatment of patients with chronic lymphocytic leukemia with 17p deletion. Mechanistic and preclinical evidence warranted evaluation of venetoclax for the treatment of systemic lupus erythematosus (SLE). This work characterized the pharmacokinetics of venetoclax in female subjects with SLE. METHODS: Single (10-500 mg) and multiple (30-600 mg) escalating doses of venetoclax or matching placebo were evaluated using randomized, double-blind, placebo-controlled designs (6 active and 2 placebo per dose with 73 unique SLE patients enrolled, 25 of whom enrolled twice)...
January 15, 2018: Clinical Pharmacokinetics
Valentin Al Jalali, Markus Zeitlinger
Telavancin was discovered by modifying the chemical structure of vancomycin and belongs to the group of lipoglycopeptides. It employs its antimicrobial potential through two distinct mechanisms of action: inhibition of bacterial cell wall synthesis and induction of bacterial membrane depolarization and permeabilization. In this article we review the clinically relevant pharmacokinetic and pharmacodynamic data of telavancin. For comparison, the pharmacokinetic and pharmacodynamic data of the other glycopeptides are presented...
January 13, 2018: Clinical Pharmacokinetics
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