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Clinical Pharmacokinetics

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https://www.readbyqxmd.com/read/28290122/scientific-rationale-for-determining-the-bioequivalence-of-inhaled-drugs
#1
REVIEW
Omar S Usmani, Mathieu Molimard, Vaibhav Gaur, Jaideep Gogtay, Gur Jai Pal Singh, Geena Malhotra, Eric Derom
In recent years, pathways for the development and approval of bioequivalent inhaled products have been established for regulated markets, including the European Union (EU), and a number of orally inhaled products (OIPs) have been approved in the EU solely on the basis of in vitro and pharmacokinetic data. This review describes how these development pathways are structured and their implications for the treatment of airway diseases such as asthma. The EU guidance follows a stepwise approach that includes in vitro criteria as the first step...
March 13, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28290121/population-pharmacokinetic-analysis-of-ixazomib-an-oral-proteasome-inhibitor-including-data-from-the-phase-iii-tourmaline-mm1-study-to-inform-labelling
#2
Neeraj Gupta, Paul M Diderichsen, Michael J Hanley, Deborah Berg, Helgi van de Velde, R Donald Harvey, Karthik Venkatakrishnan
Ixazomib is an oral proteasome inhibitor, approved in USA, Canada, Australia and Europe in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. We report a population pharmacokinetic model-based analysis for ixazomib that was pivotal in describing the clinical pharmacokinetics of ixazomib, to inform product labelling. Plasma concentration-time data were collected from 755 patients who received oral or intravenous ixazomib in once- or twice-weekly schedules in ten trials, including the global phase III TOURMALINE-MM1 study...
March 13, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28290120/development-of-a-pediatric-physiologically-based-pharmacokinetic-model-of-clindamycin-using-opportunistic-pharmacokinetic-data
#3
Christoph P Hornik, Huali Wu, Andrea N Edginton, Kevin Watt, Michael Cohen-Wolkowiez, Daniel Gonzalez
Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool used to characterize maturational changes in drug disposition to inform dosing across childhood; however, its use is limited in pediatric drug development. Access to pediatric pharmacokinetic data is a barrier to widespread application of this model, which impedes its development and optimization. To support the development of a pediatric PBPK model, we sought to leverage opportunistically-collected plasma concentrations of the commonly used antibiotic clindamycin...
March 13, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28290119/time-to-seizure-modeling-of-lacosamide-used-in-monotherapy-in-patients-with-newly-diagnosed-epilepsy
#4
Andreas Lindauer, Christian Laveille, Armel Stockis
OBJECTIVES: To quantify the relationship between exposure to lacosamide monotherapy and seizure probability, and to simulate the effect of changing the dose regimen. METHODS: Structural time-to-event models for dropouts (not because of a lack of efficacy) and seizures were developed using data from 883 adult patients newly diagnosed with epilepsy and experiencing focal or generalized tonic-clonic seizures, participating in a trial (SP0993; ClinicalTrials.gov identifier: NCT01243177) comparing the efficacy of lacosamide and carbamazepine controlled-release monotherapy...
March 13, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28258380/clinical-pharmacokinetics-of-dasabuvir
#5
REVIEW
Jennifer R King, Jiuhong Zha, Amit Khatri, Sandeep Dutta, Rajeev M Menon
Dasabuvir is a nonstructural (NS) 5B non-nucleoside inhibitor of the hepatitis C virus (HCV) used in combination with ombitasvir/paritaprevir/ritonavir for the treatment of chronic HCV infection. It is primarily metabolized by cytochrome P450 (CYP) 2C8, with a minor contribution from CYP3A. Biotransformation of dasabuvir forms the M1 metabolite, which retains antiviral activity. Dasabuvir exhibits linear pharmacokinetics with a terminal half-life of approximately 5-8 h, allowing for twice-daily dosing. The M1 metabolite of dasabuvir is the major metabolite in plasma and has a half-life similar to that of dasabuvir...
March 4, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28255850/clinical-pharmacokinetics-of-vemurafenib
#6
REVIEW
Weijiang Zhang, Dominik Heinzmann, Joseph F Grippo
Vemurafenib is an orally administered small-molecule inhibitor of the oncogenic BRAF kinase that is indicated for the treatment of patients with unresectable or metastatic melanoma harbouring BRAF (V600) mutations. Vemurafenib is absorbed rapidly after a single oral dose of 960 mg, reaching maximum drug concentration approximately 4 h after administration. Extensive accumulation occurs after multiple dosing at 960 mg twice daily. Steady state is achieved after approximately 15-21 days and exposure at steady state is relatively constant...
March 2, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28255849/population-pharmacokinetics-of-cladribine-in-patients-with-multiple-sclerosis
#7
Radojka M Savic, Ana M Novakovic, Marianne Ekblom, Alain Munafo, Mats O Karlsson
PURPOSE: The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA. METHODS: This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study...
March 2, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28247238/clinical-pharmacokinetic-monitoring-of-leflunomide-in-renal-transplant-recipients-with-bk-virus-reactivation-a-review-of-the-literature
#8
REVIEW
Joan C Y Ng, Marianna Leung, Alissa J Wright, Mary H H Ensom
Leflunomide is an immunosuppressive drug with in vitro and initial observational evidence of antiviral activity against BK virus (BKV), a pathogen that causes opportunistic infection upon reactivation in renal transplant recipients. Leflunomide is considered an ancillary option to immunosuppression reduction in the management of BKV reactivation. Plasma or blood concentrations of teriflunomide, the active metabolite of leflunomide, are commonly monitored because of high leflunomide doses being used, known inter-individual variability in pharmacokinetics, and hepatotoxicity risk...
February 28, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28238203/population-pharmacokinetic-modeling-of-jnj-53718678-a-novel-fusion-inhibitor-for-the-treatment-of-respiratory-syncytial-virus-results-from-a-phase-i-double-blind-randomized-placebo-controlled-first-in-human-study-in-healthy-adult-subjects
#9
Dymphy R H Huntjens, Sivi Ouwerkerk-Mahadevan, Anne Brochot, Sarah Rusch, Marita Stevens, Rene Verloes
BACKGROUND: JNJ-53718678 is a potent small-molecule inhibitor of the F-glycoprotein-mediated complex membrane fusion process of the respiratory syncytial virus. Here, we report the pharmacokinetics, the population pharmacokinetic modeling, and the safety and tolerability of JNJ-53718678 from the first-in-human, double-blind, randomized, placebo-controlled phase I study. METHODS: Healthy subjects were randomized (6:3) into five single-dose groups (25-1000 mg) or three multiple-dose groups [250 mg every 24 h (q24h), 500 mg q24h, 250 mg every 12 h; fed conditions for 8 days] to receive JNJ-53718678 or placebo...
February 25, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28236252/clinical-pharmacokinetics-of-paritaprevir
#10
REVIEW
Rajeev M Menon, Akshanth R Polepally, Amit Khatri, Walid M Awni, Sandeep Dutta
Paritaprevir is a potent hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with other direct-acting antivirals (DAAs) for the treatment of chronic HCV infection. Paritaprevir is primarily metabolized by cytochrome P450 (CYP) 3A4 and is administered with a low dose of ritonavir to achieve drug concentrations suitable for once-daily dosing. Coadministration of paritaprevir with ritonavir increases the half-life of single-dose paritaprevir from approximately 3 h to 5-8 h, doubles the time to maximum plasma concentration (T max) from 2...
February 25, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28236251/pharmacokinetics-of-rytary-%C3%A2-an-extended-release-capsule-formulation-of-carbidopa-levodopa
#11
REVIEW
Aravind Mittur, Suneel Gupta, Nishit B Modi
Parkinson's disease (PD) is a chronic progressive neurological disorder characterized by resting tremor, rigidity, bradykinesia, gait disturbance, and postural instability. Levodopa, the precursor to dopamine, coadministered with carbidopa or benserazide, aromatic amino acid decarboxylase inhibitors, is the most effective and widely used therapeutic agent in the treatment of PD. With continued levodopa treatment, a majority of patients develop motor complications such as dyskinesia and motor 'on-off' fluctuations, which are, in part, related to the fluctuations in plasma concentrations of levodopa...
February 24, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28229375/clinical-pharmacokinetics-of-ombitasvir
#12
REVIEW
Prajakta S Badri, Diana L Shuster, Sandeep Dutta, Rajeev M Menon
Ombitasvir is a potent, nonstructural protein 5A inhibitor of the hepatitis C virus (HCV) that is used in combination with other direct-acting antivirals for the treatment of chronic HCV infection. Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism and is a substrate of P-glycoprotein. Ombitasvir displays linear pharmacokinetics with minimal accumulation and is eliminated via metabolism and biliary excretion. A negligible amount of unchanged drug is excreted in urine...
February 22, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28229374/effect-of-short-term-fasting-on-systemic-cytochrome-p450-mediated-drug-metabolism-in-healthy-subjects-a-randomized-controlled-crossover-study-using-a-cocktail-approach
#13
Laureen A Lammers, Roos Achterbergh, Ron H N van Schaik, Johannes A Romijn, Ron A A Mathôt
BACKGROUND AND OBJECTIVE: Short-term fasting can alter drug exposure but it is unknown whether this is an effect of altered oral bioavailability and/or systemic clearance. Therefore, the aim of our study was to assess the effect of short-term fasting on oral bioavailability and systemic clearance of different drugs. METHODS: In a randomized, controlled, crossover trial, 12 healthy subjects received a single administration of a cytochrome P450 (CYP) probe cocktail, consisting of caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and warfarin (CYP2C9), on four occasions: an oral (1) and intravenous (2) administration after an overnight fast (control) and an oral (3) and intravenous (4) administration after 36 h of fasting...
February 22, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28210973/renal-drug-transporters-and-drug-interactions
#14
REVIEW
Anton Ivanyuk, Françoise Livio, Jérôme Biollaz, Thierry Buclin
Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side...
February 16, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28205039/a-pooled-analysis-of-clinical-pharmacology-trials-investigating-the-pharmacokinetic-and-pharmacodynamic-characteristics-of-fast-acting-insulin-aspart-in-adults-with-type-1-diabetes
#15
Tim Heise, Thomas R Pieber, Thomas Danne, Lars Erichsen, Hanne Haahr
BACKGROUND: Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation aiming to mimic the fast endogenous prandial insulin release more closely than currently available insulin products. In a post hoc analysis of pooled data from six clinical pharmacology trials, the pharmacological characteristics of faster aspart and IAsp were compared. METHODS: The analysis included 218 adult subjects with type 1 diabetes from six randomised, double-blind, crossover trials in the faster aspart clinical development programme...
February 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28205038/clinical-trial-simulations-and-pharmacometric-analysis-in-pediatrics-application-to-inhaled-loxapine-in-children-and-adolescents
#16
Min Dong, Tsuyoshi Fukuda, Sally Selim, Mark A Smith, Laura Rabinovich-Guilatt, James V Cassella, Alexander A Vinks
BACKGROUND AND OBJECTIVES: Loxapine for inhalation is a drug-device combination product approved in adults for the acute treatment of agitation associated with schizophrenia or bipolar I disorder. The primary objective of this study was to develop a clinical trial protocol to support a phase I pharmacokinetic study in children aged 10 years and older. In addition, this report details the results of the clinical study in relation to the predicted likelihood of achieving the target exposure associated with therapeutic effect in adults...
February 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28197931/pharmacokinetics-and-pharmacodynamics-of-lysergic-acid-diethylamide-in-healthy-subjects
#17
Patrick C Dolder, Yasmin Schmid, Andrea E Steuer, Thomas Kraemer, Katharina M Rentsch, Felix Hammann, Matthias E Liechti
BACKGROUND AND OBJECTIVE: Lysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure-response relationship of oral LSD. METHODS: We analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included...
February 14, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28185218/clinical-pharmacokinetics-and-pharmacodynamics-of-pazopanib-towards-optimized-dosing
#18
REVIEW
Remy B Verheijen, Jos H Beijnen, Jan H M Schellens, Alwin D R Huitema, Neeltje Steeghs
Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell receptor c-Kit, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib are complex and are characterized by pH-dependent solubility, large interpatient variability and low, non-linear and time-dependent bioavailability. Exposure to pazopanib is increased by both food and coadministration of ketoconazole, but drastically reduced by proton pump inhibitors...
February 10, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28185217/erratum-to-a-two-way-steady-state-pharmacokinetic-interaction-study-of-doravirine-mk-1439-and-dolutegravir
#19
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
No abstract text is available yet for this article.
February 10, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28155137/successful-use-of-14-c-paracetamol-microdosing-to-elucidate-developmental-changes-in-drug-metabolism
#20
Miriam G Mooij, Esther van Duijn, Catherijne A J Knibbe, Karel Allegaert, Albert D Windhorst, Joost van Rosmalen, N Harry Hendrikse, Dick Tibboel, Wouter H J Vaes, Saskia N de Wildt
BACKGROUND: We previously showed the practical and ethical feasibility of using [(14)C]-microdosing for pharmacokinetic studies in children. We now aimed to show that this approach can be used to elucidate developmental changes in drug metabolism, more specifically, glucuronidation and sulfation, using [(14)C]paracetamol (AAP). METHODS: Infants admitted to the intensive care unit received a single oral [(14)C]AAP microdose while receiving intravenous therapeutic AAP every 6 h...
February 2, 2017: Clinical Pharmacokinetics
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