A highly sensitive simultaneous quantitative method for a cassette cold-microdosing study on celiprolol and atenolol was developed with liquid chromatography-tandem mass spectrometry. The method utilizes a combination of solid-phase extraction (SPE) with strong cation exchange (SCX) cartridge columns and reversed-phase chromatography with an ODS analytical column. SCX-SPE cartridge columns (100 mg sorbent) were used for a selective extraction of celiprolol, atenolol and metoprolol (internal standard) from 500 μL of human plasma samples. Turbo-ion spray at positive mode was employed for the ionization of the drug compounds. Quantitation was performed on a triple quadrupole mass spectrometer by selected reaction monitoring with the transitions of m/z 380 to m/z 251 for celiprolol and m/z 267 to m/z 145 for atenolol. Separation of analytes was achieved on an ODS column (100 mm length × 2.1 mm id, 3 μm) by a gradient elution with 10 mM formic acid and methanol by varying their proportion at a flow rate of 0.2 mL/min. The method was validated in the range of 1-250 pg/mL for celiprolol and 2.5-250 pg/mL for atenolol and was successfully applied to the elucidation of pharmacokinetic profiling in a cold cassette microdosing study of the β-blockers.
This phase 1 study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of losmapimod and its metabolite GSK198602 following single and repeat doses of oral losmapimod in healthy Japanese volunteers. Subjects (n = 41) received single oral doses of losmapimod (2.5, 7.5, 20 mg) or matching placebo on 3 separate days (n = 20) or losmapimod 7.5 mg or matching placebo twice daily for 14 days (n = 21). Assessments included maximum observed plasma concentration (Cmax ), time to Cmax (Tmax ), apparent terminal-phase half-life (t1/ )2 , area under the curve (AUC), and change in C-reactive protein and phosphorylated heat shock protein 27 levels. No serious adverse events occurred during the study, and there were no safety concerns regarding clinical laboratory parameters, 12-lead electrocardiogram, or vital signs. The losmapimod Tmax was 3-4 hours, and the mean t1/2 was approximately 7.9-9.0 hours, with no appreciable difference in Tmax and apparent clearance following oral dosing between dosing regimens. Single and repeat oral doses of losmapimod were well tolerated in healthy Japanese volunteers. The Tmax of GSK198602 was similar to and t1/2 was slightly longer than those of losmapimod. Approximate dose-proportional increases in exposure to losmapimod and GSK198602 were observed in AUC with single-dose administration. Repeat-dose trough concentrations reached steady state within 2 days, with an observed accumulation ratio of 1.56 and 1.91 for losmapimod and GSK198602, respectively.
Lamivudine (LMV)-adefovir pivoxil (ADV) combination therapy suppresses the replication of LMVresistant hepatitis B virus (HBV), although its efficacy in suppressing HBV varies among patients. This study analyzed the clinical, virological, and pharmaceutical factors that influence the effect of the combination therapy. Patients negative for hepatitis B virus e antigen (HBeAg) and with low HBV DNA titers immediately prior to the combination therapy effectively cleared serum HBV DNA (P ؍ 0.0348 and P ؍ 0.0310, respectively). The maximum concentration of ADV in serum (ADV C max ) was higher in patients who showed HBV DNA clearance (P ؍ 0.0392), and the cumulative clearance rates of HBV DNA were significantly higher in patients with ADV C max equal to or greater than 24 ng/ml (P ؍ 0.0284). HBeAg negativity and lower HBV DNA at the start of the combination therapy and higher ADV C max were found to be independent factors for serum HBV DNA clearance. Serum creatinine increased significantly during the combination therapy, and the ADV C max was higher in patients with low creatinine clearance rates. In conclusion, higher serum concentrations of ADV are associated with a good response to therapy based on clearance of HBV DNA in serum. However, care should be taken to prevent worsening of renal function due to high ADV serum concentrations.Hepatitis B virus (HBV) infection is a serious global health problem. The risk of chronic HBV infection in immunocompetent adults is generally less than 5% but increases significantly in young children and immunocompromised adults (15,36). Chronically infected individuals often develop chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, and more than 500,000 people die every year from advanced liver diseases (6). Complete elimination of the virus is difficult, and patients are generally treated with interferon and nucleoside/ nucleotide analogues, which suppress viral replication and prevent the progression of liver disease by combating inflammation (11,23,33). However, the emergence of drug-resistant viral mutants and hepatitis flare-up (breakthrough hepatitis) is a serious concern for such suppressive therapies (7,9,20,32).Lamivudine (LMV) is the first approved nucleoside analogue that terminates viral DNA synthesis by inhibiting chain elongation (31). Serum HBV DNA levels decrease soon after commencement of LMV therapy. However, long-term therapy frequently results in the emergence of drug-resistant HBV mutants (8,24). In one study, the rate of LMV resistance increased from 24% in patients treated for 1 year to 70% after 4 years of treatment (21). LMV resistance is usually associated with amino acid substitutions in the YMDD motif of the viral reverse transcriptase (RT) (rtM204V/I/S) (4,5,19,26). Additional substitutions, rtL180M and rtV173L, then further enhance the mutated transcriptase activity (1,12,26). The emergence of resistant mutants also often results in viral breakthrough and subsequent breakthrough hepatitis (21). The nucleotide analogue adefovir dip...
Abstract. The importance of appropriate sample management in regulated bioanalysis is undeniable for clinical and non-clinical study support due to the fact that if the samples are compromised at any stage prior to analysis, the study results may be affected. Health authority regulations do not contain specific guidance on sample management; therefore, as part of the Global Bioanalysis Consortium (GBC), the A5 team was established to discuss sample management requirements and to put forward recommendations.The recommendations from the team concern the entire life span of the sample and include the following:1. Sampling procedures should be described in the protocol or within the laboratory manual. This information should include the volume of the sample to be collected, the required anticoagulant, light sensitivity, collection and storage containers, and labeling with a unique identifier. 2. The correct procedures for processing and then storing the samples after collection at the clinical/non-clinical testing site and during shipment are also very important to ensure the analyte(s) stability and should be documented. 3. Chain of custody for the samples must be maintained throughout the complete life span of each sample. This is typically maintained via paper and electronic data systems, including Laboratory Information Management Systems (LIMS) where available.4. Pre-and post-analysis storage location and conditions must also be clearly defined at the analytical laboratory. The storage temperature of the samples must be traceable and controlled by monitoring and warning alerts. The team suggests moving away from using temperatures and to adopt standard terminology of Broom temperature,^Brefrigerator,^Bfreezer,^and Bultrafreezer^that have defined and industry-wide accepted temperature ranges. 5. At the end of the study, documentation of the samples' disposal is required.
Background and Objectives GSK2982772 is an oral small-molecule RIPK1 inhibitor with potential therapeutic efficacy in immune-mediated inflammatory diseases (IMIDs). An inter-ethnic comparison of GSK2982772 pharmacokinetics was conducted based on data from Western (Study 1) and Japanese subjects (Study 2). Methods Both studies were single-centre, randomised, double-blind, placebo-controlled studies with objectives to assess the safety and characterise the pharmacokinetics of GSK2982772. Western subjects in Study 1 (NCT03305419), Part A ( N = 15), were randomly assigned to receive 120 mg three times daily (TID), 240 mg TID, or 360 mg twice daily (BID) doses of GSK2982772, or placebo (TID or BID) for 1 day. Part B subjects ( N = 47) received GSK2982772 120 mg TID, 240 mg TID, or placebo TID for 14 days. Japanese subjects in Study 2 ( N = 13) (NCT03590613) were randomly assigned to receive TID doses of GSK2982772 60, 120, 240 mg TID or placebo TID for 1 day. Results GSK2982772 was well tolerated and adverse events were generally mild. Maximum observed plasma drug concentration ( C max ), time to reach C max ( T max ), area under the plasma drug concentration versus time curve after the first GSK2982772 dose (AUC (0–7) ) of 120 and 240 mg, and (AUC (0–24) ) values for the 120 and 240 mg TID doses over a single day were similar in Japanese and Western subjects. Conclusions The pharmacokinetics and tolerability of GSK2982772 were similar between Western and Japanese subjects, justifying inclusion of Japanese subjects in future global clinical studies to assess the therapeutic potential of RIPK1 inhibition for the treatment of IMIDs. Clinical Trials: NCT03305419 and NCT03590613 available from http://www.clinicaltrials.gov . Electronic supplementary material The online version of this article (10.1007/s13318-020-00652-2) contains supplementary material, which is available to authorized users.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.