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Expert Opinion on Drug Metabolism & Toxicology

Rodrigo M Burgos, Mark J Biagi, Keith A Rodvold, Larry H Danziger
Meropenem/vaborbactam (M/V) represents the first carbapenem and β-lactamase inhibitor combination approved for treatment of cUTI, including pyelonephritis. Vaborbactam is a novel boronic acid, β-lactamase inhibitor with a high affinity for serine β-lactamases, including Klebsiella pneumoniae carbapenemase (KPC). This combination, Vabomere™, was approved in August 2017 by the United States Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections (cUTI) in patients 18 years or older, including pyelonephritis, caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex...
August 14, 2018: Expert Opinion on Drug Metabolism & Toxicology
Melanie Blank, Aliza Thompson, Elizabeth Hausner, Rodney Rouse
Biomarkers are one of the drug development tools that are being developed through collaborative efforts among multiple stakeholder communities to enhance the drug development process. Biomarkers of acute drug-induced renal injury as used in drug development are more commonly referred to as renal safety biomarkers, the focus of this manuscript. Areas covered: This manuscript provides an overview of the history and evolution of the United States Food and Drug Administration's Center for Drug Evaluation and Research's Biomarker Qualification Program...
August 13, 2018: Expert Opinion on Drug Metabolism & Toxicology
Joshua Schrecker, Brandi Puet, Cheryl Hild, David M Schwope
BACKGROUND: Identification of drug-drug interactions (DDIs) typically relies on patient medication lists which are prone to inaccuracies. This study describes use of a mass spectrometry test to detect recently ingested substances in urine with subsequent identification of DDIs. RESEARCH DESIGN AND METHODS: This was a retrospective analysis of the prevalence of DDIs identified in patients with chronic pain, addiction and/or behavioral health conditions in the U.S...
August 9, 2018: Expert Opinion on Drug Metabolism & Toxicology
Shenglei Yan, Lan Yang, Luyang Lu, Qi Guo, Xueyuan Hu, Yuming Yuan, Yao Li, Mingjun Wu, Jingqing Zhang
Anticancer enzymes play important roles in cancer treatment. The anticancer enzyme has been in clinical use to treat acute lymphoblastic leukemia for many years. Other types of anticancer enzymes have been investigated in laboratory studies and clinical trials. Area covered: This paper will provide perspectives on the indications, anticancer mechanisms, enzymatic characteristics (such as molecular weight, organism source, and kinetic parameters) and pharmacokinetic behaviors of anticancer enzymes and their delivery systems by systematically analyzing available literature...
August 6, 2018: Expert Opinion on Drug Metabolism & Toxicology
Eggert Stockfleth, Mike Bastian
Actinic keratosis (AK) is a common skin condition that results from exposure to chronic ultraviolet (UV) radiation. AK is characterized by visible, scaly lesions; sub-clinical lesions may also be present within a field of UV-exposed skin. These lesions exist on a disease continuum with squamous cell carcinoma. Field therapies, such as ingenol mebutate, aim to treat the visible and sub-clinical lesions within an area of sun-damaged skin. Areas covered: According to the SmPC, ingenol mebutate has a proposed dual mechanism of action that induces cell death necrosis with the production of a local pro-inflammatory response and stimulation of apoptosis...
August 3, 2018: Expert Opinion on Drug Metabolism & Toxicology
Lyrialle W Han, Chunying Gao, Qingcheng Mao
P-glycoprotein (P-gp)/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2 are highly expressed in the placenta and fetus throughout gestation and can modulate exposure and toxicity of drugs and xenobiotics to the vulnerable fetus during the sensitive times of growth and development. We aim to provide an update on current knowledge on placental and fetal expressions of the two transporters in different species, and to provide insight on interpreting transporter expression and fetal exposure relative to the concept of fraction of drug transported...
August 3, 2018: Expert Opinion on Drug Metabolism & Toxicology
Antonio Rivero-Juarez, Teresa Brieva, Mario Frias, Antonio Rivero
The combination of daclatasvir (DCV), sofosbuvir (SOF), and ribavirin (RBV) is a direct-acting antiviral (DAA) regimen for the treatment of hepatitis C virus (HCV) infection. The inclusion of newer effective DAAs such as SOF and DCV with high efficacy and excellent tolerance introduced a new scenario in HCV infection therapy: high rates of sustained virological response (SVR), shorter therapies, less toxicity, and interferon-free treatments. This combination was approved for the treatment of HCV in treatment-naive or treatment-experienced patients with chronic HCV genotype 1 or 3 infection...
August 2, 2018: Expert Opinion on Drug Metabolism & Toxicology
Mohamed Ali, Ayman Al-Hendy
No abstract text is available yet for this article.
August 2, 2018: Expert Opinion on Drug Metabolism & Toxicology
Danyi Lu, Dong Dong, Baojian Wu
BACKGROUND: N-glucuronidation is known to be an important metabolic pathway for detoxification and elimination of drugs containing aromatic amines. However, the metabolic pathways for piperazine-containing drugs are not fully established. METHODS: N-glucuronidation potential of four piperazine-containing drugs, namely two antihistamines (i.e. cyclizine and chlorcyclizine) and two tetracyclic antidepressants (i.e. mirtazapine and mianserin), was determined by using expressed UDP-glucuronosyltransferase (UGT) enzymes and liver microsomes from both human and animals...
August 2, 2018: Expert Opinion on Drug Metabolism & Toxicology
Viktorija Dragojević-Simić, Aleksandra Kovačević, Vesna Jaćević, Nemanja Rančić, Snežana Djordjević, Vesna Kilibarda, Momir Mikov, Dubravko Bokonjić
BACKGROUND: The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations. RESEARCH DESIGN AND METHODS: The single-center, open-label, randomized, three-period, three-sequence, reference-replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72...
August 1, 2018: Expert Opinion on Drug Metabolism & Toxicology
Deqing Xiao, Kah Hiing John Ling, Joseph Custodio, Sophia R Majeed, Thomas Tarnowski
Peripheral blood mononuclear cells (PBMCs) are a critical component of the immune system and the target cells for human immunodeficiency virus, type 1 (HIV-1) infection. Nucleoside/nucleotide analogs for the treatment of HIV infection are prodrugs that require cellular activation to triphosphate (TP) metabolites for antiviral activity. A reliable method of PBMC isolation and subsequent cell counting, as well as an accurate bioanalytical determination of the TPs in PBMCs are important for understanding the intracellular pharmacokinetic (PK) of the TPs and its correlation with plasma PK, the drug effect, and dose determination...
July 25, 2018: Expert Opinion on Drug Metabolism & Toxicology
Gueorgui Dubrocq, Natella Rakhmanina
Co-formulated fixed dose combination (FDC) of antiretroviral drugs tenofovir disoproxil fumarate, lamivudine, and reduced dose efavirenz [TDF 300 mg/3TC 300mg/EFV400 mg (TLE-400)] is a single daily tablet recently approved for the treatment of HIV-1 infection. Areas covered: An overview of the pharmacokinetics, pharmacodynamics and role of TLE-400 in the treatment of HIV-1 infection based on the publications from Medline and Pubmed as of February, 2018. Expert opinion: Although TLE-400 has not been formally evaluated in a clinical trial as a new formulation, previous studies have evaluated its components individually and in different doses as other FDCs have shown favorable efficacy and safety results to support continuing its approval and indication in the management of HIV-1 infection...
July 23, 2018: Expert Opinion on Drug Metabolism & Toxicology
Iftekhar Mahmood
Allometry is the study of size and its consequences. The simple hypothesis of allometric scaling is that all physiological parameters are proportional to body size or body mass. This review examines the development of theory-based allometry or fixed exponents (0.75 and 1.0 for basal metabolic rate and volume, respectively) and the evidence for or against the theory. The main focus of this report is to show the readers that there is enough evidence from experimental data that negate the concept of theory-based allometry in biology, physiology, and pharmacokinetics...
July 19, 2018: Expert Opinion on Drug Metabolism & Toxicology
Lucie Cazet, Samuel Bulteau, Adrien Evin, Andrew Spiers, Pascal Caillet, Emmanuelle Kuhn, Jacques Pivette, Anicet Chaslerie, Pascale Jolliet, Caroline Victorri-Vigneau
Co-occurring pain impairs depression's prognosis. Selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) are first-line pharmacotherapies for depression and inhibit many cytochrome 2D6 enzymes. Codeine is a first-line treatment for pain and needs to be metabolized into morphine by cytochrome 2D6 to exert its analgesic effect. Concomitant prescription of both pharmacotherapies leads to inadequate analgesia. Areas covered: We performed a systematic review of the literature to amalgamate the current knowledge regarding the clinical effect of this association and quantified its prevalence in clinical practice in the French Pays de la Loire area using a retrospective observational cohort study design...
July 12, 2018: Expert Opinion on Drug Metabolism & Toxicology
Katharine E Stott, William Hope
Mortality from invasive fungal disease involving the central nervous system (CNS) is excessive. Achieving therapeutic drug concentrations at the site of infection within the CNS is always difficult and its evaluation is complex due to anatomical barriers and variable pathophysiological lesions. Areas covered: This review provides an updated summary of the CNS PK of antifungal therapies. It considers factors that influence the success of antifungal regimens for CNS infection as well as preclinical and clinical data that quantify antifungal pharmacokinetics (PK) in the CNS...
July 9, 2018: Expert Opinion on Drug Metabolism & Toxicology
Mariacarmela Santarpia, Niccola Funel, Asif Ali, Elisa Giovannetti
No abstract text is available yet for this article.
July 4, 2018: Expert Opinion on Drug Metabolism & Toxicology
Cene Skubic, Živa Drakulić, Damjana Rozman
Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease in the world. It describes a term for a group of hepatic diseases including steatosis, fibrosis, and cirrhosis that can finally lead to hepatocellular carcinoma. There are many factors influencing NAFLD initiation and progression, such as obesity, dyslipidemia, insulin resistance, genetic factors, and hormonal changes. However, there is also lean-NAFLD which is not associated with obesity. NAFLD is considered to be a sexually dimorphic disease...
July 3, 2018: Expert Opinion on Drug Metabolism & Toxicology
Laura Cuzzolin, Flamina Bardanzellu, Vassilios Fanos
Patent ductus arteriosus (PDA) persistence is associated, in prematures, to several complications. The optimal PDA management is still under debate, especially regarding the best therapeutic approach and the time to treat. The available drugs are not exempt from contraindications and side effects; ibuprofen itself, although representing the first-choice therapy, can show nephrotoxicity and other complications. Paracetamol seems a valid alternative to classic nonsteroidal anti-inflammatory Drugs, with a lower toxicity...
July 2, 2018: Expert Opinion on Drug Metabolism & Toxicology
Tine A Bækdal, Astrid Breitschaft, Andrea Navarria, Cilie W Hansen
BACKGROUND: Since the first oral glucagon-like peptide-1 analog comprises semaglutide co-formulated with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which induces a transient, localized increase in gastric pH, we have investigated whether a proton pump inhibitor affects the pharmacokinetics of oral semaglutide. RESEARCH DESIGN AND METHODS: A single-center, randomized, open-label, parallel-group trial investigated pharmacokinetic interactions of oral semaglutide with omeprazole (40 mg once-daily) in 54 healthy subjects...
June 30, 2018: Expert Opinion on Drug Metabolism & Toxicology
Elizabeth Jiménez Aguilar, Jon Zugazagoitia Fraile, Luis Paz-Ares Rodríguez
First-line treatment with platinum-based chemotherapy has been the standard treatment for non-small-cell lung cancer (NSCLC) during the past decades. The development of new targeted drugs based on molecular alterations (EGFR, ALK, and ROS1) has led to important outcome benefits, but not for squamous cell carcinoma (SCC). However, the aberrant function of the EGFR pathway in SCC may be important in the development of the tumor and has been explored in preclinical and clinical studies as a potential target. Areas covered: Necitumumab is a human IgG1 anti-EGFR antibody that binds to the receptor and inhibits further pathway activation, thereby inhibiting cell differentiation, proliferation and migration...
August 2018: Expert Opinion on Drug Metabolism & Toxicology
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