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Clinical Pharmacokinetics

Maïlys De Sousa Mendes, Gabrielle Lui, Yi Zheng, Claire Pressiat, Deborah Hirt, Elodie Valade, Naïm Bouazza, Frantz Foissac, Stephane Blanche, Jean-Marc Treluyer, Saik Urien, Sihem Benaboud
BACKGROUND: Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful. METHODS: A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK)...
October 21, 2016: Clinical Pharmacokinetics
Bishoy Kamel, Garry G Graham, Kenneth M Williams, Kevin D Pile, Richard O Day
Febuxostat is a xanthine oxidoreductase inhibitor that has been developed to treat chronic gout. In healthy subjects, the pharmacokinetic parameters of febuxostat after multiple oral dose administration include an oral availability of about 85 %, an apparent oral clearance (CL/F) of 10.5 ± 3.4 L/h and an apparent volume of distribution at steady state (V ss/F) of 48 ± 23 L. The time course of plasma concentrations follows a two-compartment model. The initial half-life (t ½) is approximately 2 h and the terminal t ½ determined at daily doses of 40 mg or more is 9...
October 17, 2016: Clinical Pharmacokinetics
Iris K Minichmayr, André Schaeftlein, Joseph L Kuti, Markus Zeitlinger, Charlotte Kloft
OBJECTIVES: We aimed to assess linezolid pharmacokinetics in the plasma and interstitial space fluid (ISF) of patients with sepsis, diabetic foot infections or cystic fibrosis and healthy volunteers. The impacts of joint characteristics and disease on plasma and target-site exposure were to be identified together with the benefit of dose intensification in critically ill patients. METHODS: Rich plasma (n = 1598) and ISF concentrations in subcutaneous adipose (n = 1430) and muscle tissue (n = 1089) measured by microdialysis were pooled from three clinical trials with 51 individuals receiving 600 mg of intravenous and oral linezolid...
October 17, 2016: Clinical Pharmacokinetics
Luka Verrest, Thomas P C Dorlo
INTRODUCTION: Neglected tropical diseases (NTDs) affect more than one billion people, mainly living in developing countries. For most of these NTDs, treatment is suboptimal. To optimize treatment regimens, clinical pharmacokinetic studies are required where they have not been previously conducted to enable the use of pharmacometric modeling and simulation techniques in their application, which can provide substantial advantages. OBJECTIVES: Our aim was to provide a systematic overview and summary of all clinical pharmacokinetic studies in NTDs and to assess the use of pharmacometrics in these studies, as well as to identify which of the NTDs or which treatments have not been sufficiently studied...
October 15, 2016: Clinical Pharmacokinetics
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
Steven A Lacy, Dale R Miles, Linh T Nguyen
Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq(®)) is approved for the treatment of progressive metastatic medullary thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx™, 60-mg free base equivalent dose) is approved for the treatment of renal cell carcinoma following anti-angiogenic therapy. Cabozantinib displays a long terminal plasma half-life (~120 h) and accumulates ~fivefold by day 15 following daily dosing based on area under the plasma concentration-time curve (AUC)...
October 12, 2016: Clinical Pharmacokinetics
William M Greenberg, Leslie Citrome
Lurasidone hydrochloride, a benzisothiazol derivative, is a second-generation (atypical) antipsychotic agent that has received regulatory approval for the treatment of schizophrenia in the US, Canada, the EU, Switzerland, and Australia, and also for bipolar depression in the US and Canada. In addition to its principal antagonist activity at dopamine D2 and serotonin 5-HT2A receptors, lurasidone has distinctive 5-HT7 antagonistic activity, and displays partial agonism at 5-HT1A receptors, as well as modest antagonism at noradrenergic α2A and α2C receptors...
October 8, 2016: Clinical Pharmacokinetics
Eun Bong Lee, Nikki Daskalakis, Christine Xu, Anne Paccaly, Barry Miller, Roy Fleischmann, Inga Bodrug, Alan Kivitz
INTRODUCTION: Elevated interleukin (IL)-6 occurs in patients with active rheumatoid arthritis (RA), which has been shown to lead to a decrease in cytochrome P450 (CYP) enzyme activity and alterations in drug concentrations metabolized by CYP. IL-6 signaling blockade by IL-6 receptor (IL-6R) antagonists may reverse this effect of IL-6 and restore CYP activity. This study evaluated the pharmacokinetic profile of simvastatin (a CYP3A4 substrate) before and 1 week after a single dose of sarilumab (a human monoclonal antibody [mAb] blocking the IL-6Rα) in patients with RA, to assess potential interaction...
October 8, 2016: Clinical Pharmacokinetics
Jennifer N Clements, Tiffaney Threatt, Eileen Ward, Kayce M Shealy
Concentrated insulin analogs have recently been approved and are available for clinical use in the management of diabetes mellitus. One new product is insulin glargine U-300 (Sanofi), a basal concentrated insulin of 300 U/mL. Several studies have been conducted and completed evaluating blood samples for the pharmacokinetics of insulin glargine U-300 and euglycemic clamp procedures for the pharmacodynamics. This concentrated insulin has a low within-day variability and high day-to-day reproducibility, allowing for a more constant and prolonged duration of action, compared with insulin glargine U-100 (100 U/mL)...
October 4, 2016: Clinical Pharmacokinetics
Matt S Anderson, Sauzanne Khalilieh, Ka Lai Yee, Rachael Liu, Li Fan, Matthew L Rizk, Vedangi Shah, Azra Hussaini, Ivy Song, Lisa L Ross, Joan R Butterton
INTRODUCTION: Doravirine, a non-nucleoside reverse-transcriptase inhibitor in development for the treatment of patients with human immunodeficiency virus-1 infection, has potential to be used concomitantly in antiretroviral therapy with dolutegravir, an integrase strand transfer inhibitor. The pharmacokinetic interactions between these drugs were therefore assessed. METHODS: Oral formulations of doravirine and dolutegravir were dosed both individually and concomitantly once daily in healthy adults...
October 4, 2016: Clinical Pharmacokinetics
Hanne Haahr, Edmond G Fita, Tim Heise
Insulin degludec/insulin aspart (IDegAsp; 70 % IDeg and 30 % IAsp) is a soluble combination of two individual insulin analogues in one product, designed to provide mealtime glycaemic control due to the IAsp component and basal glucose-lowering effect from the IDeg component. The pharmacokinetic and pharmacodynamic characteristics of IDegAsp have been investigated in a series of clinical pharmacology studies with generally comparable designs, methodologies and patient inclusion/exclusion criteria. The glucose-lowering effect profile of IDegAsp during once-daily dosing at steady state shows distinct and clearly separated action from the prandial and basal components of IDegAsp...
October 1, 2016: Clinical Pharmacokinetics
Amanda Long, Emmanuel Chigutsa, Johan Wallin
Necitumumab is a second-generation, recombinant, human immunoglobulin G1, epidermal growth factor (EGFR) receptor antibody that specifically blocks the ligand binding site of EGFR. Necitumumab potentially acts by blocking ligand epidermal growth factor (EGF) binding-mediated activation of the EGFR signaling pathway, inhibiting tumor growth, angiogenesis, and anti-apoptotic mechanisms. Necitumumab inhibited the interaction of EGF and EGFR with a concentration that inhibits binding by 50 % of approximately 0...
September 30, 2016: Clinical Pharmacokinetics
Thomas Müller, Paul Foley
The symptoms of Parkinson's disease (PD) reflect disruptions of a number of brain neurotransmitter systems of varying type and degree. Pharmacological agents with multiple neurochemical mechanisms of action are therefore promising candidates for countering these problems and providing comprehensive symptomatic relief for patients. The pharmacological profile of safinamide includes reversible monoamine oxidase B inhibition, blockage of voltage-dependent Na(+) channels, modulation of Ca(2+) channels, and inhibition of glutamate release...
September 24, 2016: Clinical Pharmacokinetics
Bruce Green, Herta Crauwels, Thomas N Kakuda, Simon Vanveggel, Anne Brochot
BACKGROUND: Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals for treatment-experienced HIV patients ≥6 years of age. Etravirine is primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A. This analysis determined the impact of concomitant antiretrovirals and CYP2C9/CYP2C19 phenotype on the pharmacokinetics of etravirine. METHODS: We used 4728 plasma concentrations from 817 adult subjects collected from four clinical studies to develop the population pharmacokinetic model...
September 24, 2016: Clinical Pharmacokinetics
Daphne Bertholee, Jan Gerard Maring, André B P van Kuilenburg
Cancer treatment is becoming more and more individually based as a result of the large inter-individual differences that exist in treatment outcome and toxicity when patients are treated using population-based drug doses. Polymorphisms in genes encoding drug-metabolizing enzymes and transporters can significantly influence uptake, metabolism, and elimination of anticancer drugs. As a result, the altered pharmacokinetics can greatly influence drug efficacy and toxicity. Pharmacogenetic screening and/or drug-specific phenotyping of cancer patients eligible for treatment with chemotherapeutic drugs, prior to the start of anticancer treatment, can identify patients with tumors that are likely to be responsive or resistant to the proposed drugs...
September 19, 2016: Clinical Pharmacokinetics
Andrea Calcagno, Jessica Cusato, Antonio D'Avolio, Stefano Bonora
BACKGROUND: Antiretroviral treatment is highly effective in enhancing HIV-positive patients' survival and quality of life. Despite an increased tolerability in recent years, a substantial amount of patients experience side effects. Antiretrovirals' efficacy and tolerability have been associated with plasma concentrations and single nucleotide polymorphisms in selected genes involved in drug disposition. OBJECTIVE: Our aim was to review the current knowledge in genetic polymorphisms affecting plasma, intracellular or compartmental concentrations of antiretrovirals...
September 19, 2016: Clinical Pharmacokinetics
Swantje Völler, Georg Hempel, Gudrun Würthwein, Alan V Boddy, Miriam Krischke, Nicolas André, Maurizio D'Incalci, Gianni Bisogno, Joachim Boos
Following the publication of our paper regarding a population-based model of doxorubicin pharmacokinetics in children in Clinical Pharmacokinetics last year (Voller et al. 54:1139-1149, 2015), we have received many inquiries on the practical clinical consequences of this model; however, a population-based model is only one of the aspects to be taken into account when developing dosing algorithms. In addition, any new method of dose calculation would need clinical validation and, subsequently, a new clinical trial...
September 19, 2016: Clinical Pharmacokinetics
Dominik Lott, Thorsten Lehr, Jasper Dingemanse, Andreas Krause
BACKGROUND: Ponesimod is a selective, orally active sphingosine-1-phosphate receptor 1 modulator currently undergoing clinical evaluation for the treatment of multiple sclerosis (MS) in phase III clinical trials. Ponesimod dose-dependently reduces peripheral blood lymphocyte counts by blocking the egress of lymphocytes from lymphoid organs. METHODS: A population pharmacokinetic (PK) analysis was performed based on pooled data from 13 clinical studies. Interindividual variability (IIV) and the impact of key demographic variables and other covariates on ponesimod exposure were assessed quantitatively...
September 15, 2016: Clinical Pharmacokinetics
Kevin J Freise, Aksana K Jones, Doerthe Eckert, Sven Mensing, Shekman L Wong, Rod A Humerickhouse, Walid M Awni, Ahmed Hamed Salem
BACKGROUND: Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies. OBJECTIVE: The objective of this research was to characterize the relationship between venetoclax exposures and efficacy and safety in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). METHODS: A total of 272 and 338 patients from four clinical studies were pooled for the exposure-efficacy and exposure-safety analyses, respectively...
September 15, 2016: Clinical Pharmacokinetics
Catia Marzolini, Rajith Rajoli, Manuel Battegay, Luigia Elzi, David Back, Marco Siccardi
BACKGROUND: Antiretroviral drugs are among the therapeutic agents with the highest potential for drug-drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously. METHODS: This study predicted the magnitude of the DDI between efavirenz, an inducer of CYP3A4 and inhibitor of CYP2C8, and dual CYP3A4/CYP2C8 substrates (repaglinide, montelukast, pioglitazone, paclitaxel) using a physiologically based pharmacokinetic (PBPK) modeling approach integrating concurrent effects on CYPs...
September 7, 2016: Clinical Pharmacokinetics
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