First-in-human study of CPL207280, a novel G-protein-coupled receptor 40/free fatty acid receptor 1 agonist, in healthy volunteers after single and multiple administration.

Aim: To assess the safety, tolerability and pharmacokinetic (PK) profile of single and multiple doses of CPL207280, a new G-protein-coupled receptor 40 agonist developed to treat type 2 diabetes (T2D).

Methods: The phase 1 study in healthy volunteers (White, age 18-55 years, body mass index 18.5-29.

How does the order of sample analysis influence the matrix effect during LC-MS bioanalysis?

Mass spectrometry coupled with liquid chromatography is a valuable tool for drug development and personalised drug therapy. The matrix effect is caused by enhancing or suppressing the analyte signal intensity by the interfering compounds of biological fluids. The matrix effect may influence the reliability of the quantitative results.

Replicates Number for Drug Stability Testing during Bioanalytical Method Validation-An Experimental and Retrospective Approach.

Background: The stability of a drug or metabolites in biological matrices is an essential part of bioanalytical method validation, but the justification of its sample size (replicates number) is insufficient. The international guidelines differ in recommended sample size to study stability from no recommendation to at least three quality control samples. Testing of three samples may lead to results biased by a single outlier.

Combined Protein and Alkaloid Research of Latex Reveals CmMLP1 Accompanied by Alkaloids with Cytotoxic Potential to Human Cervical Carcinoma Cells.

L. is a latex-bearing plant used in traditional folk medicine to treat human papillomavirus (HPV)-caused warts, papillae, and condylomas. Its latex and extracts are rich in many low-molecular compounds and proteins, but there is little or no information on their potential interaction.

Evaluation of tramadol human pharmacokinetics and safety after co-administration of magnesium ions in randomized, single- and multiple-dose studies.

Background: Magnesium ions (Mg) increase and prolong opioid analgesia in chronic and acute pain. The nature of this synergistic analgesic interaction has not yet been explained. Our aim was to investigate whether Mg alter tramadol pharmacokinetics.

Low-oxidation-potential thiophene-carbazole monomers for electro-oxidative molecular imprinting: Selective chemosensing of aripiprazole.

New thiophene-carbazole functional and cross-linking monomers electropolymerizing at potentials sufficiently low for molecular imprinting of an electroactive aripiprazole antipsychotic drug were herein designed and synthesized. Numerous conducting molecularly imprinted polymer (MIP) films are deposited by electropolymerization at relatively low potentials by electro-oxidation of pyrrole, aniline, phenol, or 3,4-ethylenedioxythiophene (EDOT). However, their interactions with templates are not sufficiently strong.

10th Anniversary of a Two-Stage Design in Bioequivalence. Why Has it Still Not Been Implemented?

Purpose: In 2010 the European Medicines Agency allowed a two-stage design in bioequivalence studies. However, in the public domain there are mainly articles describing the theoretical and statistical base for the application of the two-stage design. One of the reasons seems to be the lack of practical guidance for the Sponsors on when and how the two-stage design can be beneficial in bioequivalence studies.

Incurred Sample Reanalysis: Time to Change the Sample Size Calculation?

Reliable results of pharmacokinetic and toxicokinetic studies are vital for correct decision making during drug discovery and development. Thus, ensuring high quality of bioanalytical methods is of critical importance. Incurred sample reanalysis (ISR)-one of the tools used to validate a method-is included in the bioanalytical regulatory recommendations.

Matrix effect screening for cloud-point extraction combined with liquid chromatography coupled to mass spectrometry: Bioanalysis of pharmaceuticals.

Matrix effects are one of the most challenging issues in the analysis of complex samples using liquid chromatography coupled to mass spectrometry (LC-MS). Apart from the instrumental origin, these effects are also related to sample preparation. Cloud-point extraction (CPE) is rarely combined with LC-MS as it requires the use of surfactants which might interfere with droplet evaporation.

Bioanalytical method validation: new FDA guidance vs. EMA guideline. Better or worse?

Bioanalysis concerns the identification and quantification of analytes in various biological matrices. Validation of any analytical method helps to achieve reliable results that are necessary for proper decisions on drug dosing and patient safety. In the case of bioanalytical methods, validation additionally covers steps of pharmacokinetic and toxicological studies - such as sample collection, handling, shipment, storage, and preparation.

Quantitative evaluation of the matrix effect in bioanalytical methods based on LC-MS: A comparison of two approaches.

Liquid chromatography coupled to mass spectrometry (LC-MS) is a powerful tool for studying pharmacokinetics and toxicokinetics. Reliable bioanalysis requires the characterization of the matrix effect, i.e.

Extended 3D and 4D cumulative plots for evaluation of unmatched incurred sample reanalysis.

Aim: Incurred sample reanalysis (ISR) helps ensure the reliability of pharmacokinetic studies. An appropriate graph may facilitate the evaluation of an unmatched reanalyses or a failed ISR test.

Methods: We evaluated different ways of visualizing multidimensional ISR data using an extended cumulative ISR plot.

Incurred sample reanalysis: adjusted procedure for sample size calculation.

Aim: The incurred sample reanalysis (ISR) helps to assure bioanalysis reliability. The regulatory guidelines recommend the reanalysis of up to 10% of the study samples for this test, but not all reanalyses are necessary to evaluate the test result.

Materials & Methods: We have optimized ISR sample size calculation to eliminate negligible reanalyses.

Comprehensive graphical presentation of data from incurred sample reanalysis.

Aim: Incurred sample reanalysis (ISR) contributes to the reliability of pharmacokinetic studies. Despite regulatory guidelines having adopted ISR methodology, graphical presentation of data has been overlooked.

Materials & Methods: Different graphs were tested for datasets including limited, standard and large numbers of ISR pairs.

Is a deuterated internal standard appropriate for the reliable determination of olmesartan in human plasma?

A right choice of the internal standard is one of the most challenging tasks during bioanalytical method development. Surprisingly, among the HPLC-MS methods for the determination of a cardiovascular drug olmesartan in plasma only structural analogues or similar compounds were used as internal standards. We have tried to answer the question whether the stable isotope labelled (deuterated) internal standard, as recommended by regulatory agencies, can be used for the reliable determination of olmesartan in human plasma.

HPLC-UV ASSAY OF IMATINIB IN HUMAN PLASMA OPTIMIZED FOR BIOEQUIVALENCE STUDIES.

lmatimb is an anticancer drug approved for the treatment of a number of cancers, mostly used in chronic myeloid leukemia. Numerous bioanalytical methods using high performance liquid chromatography coupled to ultraviolet detection point at the importance and necessity of the therapeutic drug monitoring of imatinib. Unfortunately, these methods are not optimized for single dose pharmacokinetic studies such as bioe- quivalence.

ENVIRONMENTALLY FRIENDLY LC/MS DETERMINATION OF EPLERENONE IN HUMAN PLASMA.

Eplerenone (EPL), a selective aldosterone receptor antagonist, is indicated in the treatment of chronic heart failure and hypertension. It is hard to find a green assay among a few published methods for its determination in human plasma or serum. Following a liquid-liquid extraction with methyl t-butyl ether, eplerenone and isotope labelled eplerenone - used as an internal standard - were separated from the endogenous compounds on an Atlantis dCl8 column (150 x 3 mm, 3.

Bioequivalence study of 2.5 mg film-coated bisoprolol tablets in healthy volunteers.

Background: Bisoprolol is one of the most widely used beta-blockers characterised by cardioselectivity, and it has no intrinsic sympathomimetic activity. It is commonly used in the treatment of coronary heart disease and heart failure.

Aim: The aim of study was to assess the bioequivalence of the film-coated tablets containing 2.

Cloud-point extraction is compatible with liquid chromatography coupled to electrospray ionization mass spectrometry for the determination of bisoprolol in human plasma.

Cloud-point extraction (CPE) draws increasing interest in a number of analytical fields including bioanalysis, but combining CPE and LC-MS with electrospray ionization (ESI) in the determination of drugs in biological fluids such as plasma, serum or blood has not been reported so far. Bisoprolol was determined in human plasma by CPE using Trition X-114 as a surfactant and metoprolol as the internal standard. NaOH concentration, temperature and Trition X-114 concentration were optimized.

Sensitive single quadrupole LC/MS method for determination of lapatinib in human plasma.

A sensitive liquid chromatographic-single quadrupole mass spectrometric method was developed and validated for the determination of lapatinib in human plasma. Following a liquid-liquid extraction with methyl t-butyl ether, lapatinib and isotope labelled lapatinib, used as an internal standard (IS), were separated from the endogenous compounds on a Zorbax SB-C18 (150 x 3 mm, 3.5 μm) column.

Simplified LC-MS/MS method enabling the determination of azithromycin in human plasma after a low 100mg dose administration.

A sensitive liquid chromatographic-tandem mass spectrometric method was developed and validated to study the pharmacokinetics of a low dose of azithromycin in human plasma. The sample preparation was based on liquid-liquid extraction with the low volume of methyl t-butyl ether. The chromatographic separation was performed on a Symmetry C18 column (50×2.

Determination of sunitinib in human plasma using liquid chromatography coupled with mass spectrometry.

An original method based on liquid chromatography with single quadrupole electrospray ionization mass spectrometry was developed for the determination of sunitinib in human plasma. The quantitation limit of the method at 0.10 ng/mL is comparable to that of tandem mass spectrometry assays.

Determination of duloxetine in human plasma with proven lack of influence of the major metabolite 4-hydroxyduloxetine.

Objectives: Minimizing the impact of major or unstable metabolites on the determination of a drug substance represents a leading task in the development and validation of bioanalytical methods. "Incurred samples reanalysis" provides relevant information too late; therefore, carefully selected tests on known metabolites should precede the pharmacokinetic studies.

Design And Methods: This paper describes a simple and rapid HPLC-UV method for the determination of duloxetine, a potent serotonin and norepinephrine reuptake inhibitor, in the presence of its major metabolite, i.

Bioequivalence study of 500 mg cefuroxime axetil film-coated tablets in healthy volunteers.

The aim of the study was to investigate the bioavailability of a generic product of 500 mg cefuroxime axetil film-coated tablets (test) as compared to that of a branded product (reference) at the same strength to determine bioequivalence and to apply for regulatory approval. The secondary objective of the study was to evaluate tolerability of both products. A double blinded, randomized, crossover, two-period, single-dose, comparative study was conducted in Caucasian healthy volunteers in fasting conditions.