Pharmacokinetics and Bioequivalence of a Generic Ticagrelor 90-mg Formulation Versus the Innovator Product in Healthy White Subjects Under Fasting Conditions.

Ticagrelor is a key antiplatelet agent used to prevent thrombotic events in patients with acute coronary syndrome. This open-label, 2-period, crossover Phase I study assessed the pharmacokinetics and bioequivalence of a generic ticagrelor 90-mg formulation compared to the innovator product under fasting conditions. Twenty-eight healthy White adults participated in the study.

Single Dose Comparative Bioavailability Study of Lisdexamfetamine Dimesylate as Oral Solution Versus Reference Hard Capsules in Healthy Volunteers.

Lisdexamfetamine is an inactive prodrug of dexamfetamine that is used for the second-line treatment of attention-deficit/hyperactivity disorder (ADHD) and moderate to severe binge eating disorder (BED). Once in the blood, the prodrug is hydrolyzed in erythrocyte cytosol, thus releasing the active dexamfetamine. We here present a fully validated HPLC-MS/MS analytical method for simultaneous determination of lisdexamfetamine and dexamfetamine in human plasma and the first published comparative bioavailability study of lisdexamfetamine including a GMP finished product formulated as oral solution.

Single Dose Study Assessing the Pharmacokinetic and Metabolic Profile of Alverine Citrate in Healthy Volunteers.

Alverine citrate is a spasmolytic commonly prescribed in conditions such as irritable bowel syndrome, painful diverticular disease of the colon, and primary dysmenorrhea. While clinical efficacy data on alverine alone or in combination with simethicone is freely available, surprisingly little information regarding the pharmacokinetics and metabolism of alverine can be found in literature. The first HPLC-MS/MS analytical protocol for determination of alverine parent, 4-hydroxy alverine, N-desethyl alverine and 4-hydroxy alverine glucuronide in human plasma was developed and validated.

The Effect of Food on the Single-Dose Bioavailability and Tolerability of the Highest Marketed Strength of Duloxetine.

Duloxetine is a combined serotonin and norepinephrine reuptake inhibitor indicated in adults for the treatment of major depressive disorder, diabetic peripheral neuropathic pain, and generalized anxiety disorder. The aim of these studies was to evaluate the effect of food on the pharmacokinetics and safety of duloxetine 60-mg gastroresistant hard capsules following single-dose administration. The data were obtained from 2 phase 1 bioequivalence studies, 1 in a fasting state and the other under fed conditions.

12th GCC Closed Forum: critical reagents; oligonucleotides; CoA; method transfer; HRMS; flow cytometry; regulatory findings; stability and immunogenicity.

The 12th GCC Closed Forum was held in Philadelphia, PA, USA, on 9 April 2018. Representatives from international bioanalytical Contract Research Organizations were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The issues discussed at the meeting included: critical reagents; oligonucleotides; certificates of analysis; method transfer; high resolution mass spectrometry; flow cytometry; recent regulatory findings and case studies involving stability and nonclinical immunogenicity.

Recommendations for classification of commercial LBA kits for biomarkers in drug development from the GCC for bioanalysis.

Over the last decade, the use of biomarker data has become integral to drug development. Biomarkers are not only utilized for internal decision-making by sponsors; they are increasingly utilized to make critical decisions for drug safety and efficacy. As the regulatory agencies are routinely making decisions based on biomarker data, there has been significant scrutiny on the validation of biomarker methods.

Single-Dose Pharmacokinetic Properties and Relative Bioavailability of Different Formulations of Posaconazole Oral Suspension in Healthy Volunteers.

The rate and extent of absorption of drugs belonging to Biopharmaceutics Classification System class II are rate-limited by dissolution and highly dependent on the performance of the formulated product. The purpose of the present study was to investigate the potential impact of a surfactant and the particle size of the active substance on the in vitro drug dissolution profiles and in vivo pharmacokinetics of the poorly soluble drug posaconazole. A comparative physicochemical evaluation was conducted, and 3 formulations of posaconazole oral suspension were tested in various dissolution media compared with the reference product.

The 10th GCC Closed Forum: rejected data, GCP in bioanalysis, extract stability, BAV, processed batch acceptance, matrix stability, critical reagents, ELN and data integrity and counteracting fraud.

The 10th Global CRO Council (GCC) Closed Forum was held in Orlando, FL, USA on 18 April 2016. In attendance were decision makers from international CRO member companies offering bioanalytical services. The objective of this meeting was for GCC members to meet and discuss scientific and regulatory issues specific to bioanalysis.

Evaluation of Clopidogrel Conjugation Metabolism: PK Studies in Man and Mice of Clopidogrel Acyl Glucuronide.

The existence of a glucuronide conjugate of the major circulating clopidogrel metabolites, called clopidogrel acyl glucuronide (CAG), is already known. However, information regarding its pharmacokinetics (PK), metabolism, and clearance are modest. We investigated in vivo the potential CAG trans-esterification to clopidogrel (reaction occurring in vitro in particular conditions) by administering the metabolite to mice.

An update on solid phase-supported liquid extraction.

Solid phase-supported liquid extraction (SLE) is a technique almost 40 years old being rediscovered in the last few years due to its simplicity, optimal for automation and giving very clean extracts with minimal matrix effects when analyzed by techniques like HPLC-MS/MS, GC-MS/MS, CE-MS/MS. In the next paragraphs the evolution of SLE, according to literature, will be presented first, followed by some considerations on the SLE material now available and a typical protocol of work. To conclude, considerations based on the author's practical experiences with SLE will be done, as well as few remarks on potential future areas of SLE development.

Pharmacokinetic study for the establishment of bioequivalence of two inhalation treatments containing budesonide plus formoterol.

Objectives: The aim of this study was to compare lung deposition and assess the bioequivalence of two formulations containing budesonide and formoterol and being delivered via Elpenhaler and Turbuhaler, respectively. A pharmacokinetic (PK) study was conducted.

Methods: An open, randomized, two-sequence, two-period, crossover, single-dose study in 100 asthmatic patients under fasting conditions was performed.

Confirmation of diosmetin 3-O-glucuronide as major metabolite of diosmin in humans, using micro-liquid-chromatography-mass spectrometry and ion mobility mass spectrometry.

Diosmin is a flavonoid often administered in the treatment of chronic venous insufficiency, hemorrhoids, and related affections. Diosmin is rapidly hydrolized in the intestine to its aglicone, diosmetin, which is further metabolized to conjugates. In this study, the development and validations of three new methods for the determination of diosmetin, free and after enzymatic deconjugation, and of its potential glucuronide metabolites, diosmetin-3-O-glucuronide, diosmetin-7-O-glucuronide, and diosmetin-3,7-O-glucuronide from human plasma and urine are presented.

Development of a sensitive method for simultaneous determination of fluticasone propionate and salmeterol in plasma samples by liquid chromatography-tandem mass spectrometry.

A new method for the fast simultaneous quantification of fluticasone propionate and salmeterol from plasma samples by liquid chromatography-tandem mass spectrometry, with adequate sensitivity for pharmacokinetic applications, was developed and validated. The chromatographic separation and mass-spectrometric parameters were optimized for the retention and detection of the two compounds, despite quite different structures and properties. Two columns connected in series were used, cation-exchange (Zorbax 300-SCX, 5 cm x 2.

Development and validation of an HPLC-MS/MS method to quantify clopidogrel acyl glucuronide, clopidogrel acid metabolite, and clopidogrel in plasma samples avoiding analyte back-conversion.

A new sensitive and fast quantitative analytical method for the simultaneous determination of clopidogrel, its main metabolite clopidogrel carboxylic acid, and the newly described acyl glucuronide metabolite, in human plasma samples, is presented. The analytical procedures (plasma storage, handling, and extract storage in the autosampler) were optimized in order to avoid back-conversion; a known drawback in measurements of clopidogrel. Clopidogrel acyl glucuronide was confirmed as a major source of back-conversion to the parent drug in the presence of methanol, and thorough stability experiments were carried out to find the most appropriate conditions for an accurate analysis of clopidogrel and the two metabolites.

Development and validation of an HPLC-MS/MS method to determine clopidogrel in human plasma. Use of incurred samples to test back-conversion.

Quantitative methods using LC-MS/MS allow achievement of adequate sensitivity for pharmacokinetic studies with clopidogrel; three such methods, with LLOQs as low as 5 pg/mL, were developed and fully validated according to the well established FDA 2001 guidelines. The chromatographic separations were performed on reversed phase columns Ascentis RP-Amide (15 cm x 2.1 mm, 5 μm), Ascentis Express C8 (10 cm x 2.

High-throughput HPLC-MS/MS method to determine ibandronate in human plasma for pharmacokinetic applications.

A sensitive high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of ibandronate in human plasma. In a previous study, we have analyzed alendronate in urine samples of subjects treated at therapeutic dosages, using a derivatization approach; a similar derivatization was adapted and improved to determine ibandronate in plasma. The bisphosphonate was isolated from the biological matrix by liquid-liquid extraction, and derivatized with trimethylsilyldiazomethane prior to separation on a reversed-phase column (Supelco Discovery HSC18) and detection on a quadrupole-linear ion trap mass spectrometer (API 4000 QTrap).

Development and application of a high-performance liquid chromatography-mass spectrometry method to determine alendronate in human urine.

Despite the high potential offered by electrospray ionization on highly polar compounds like biphosphonates, few applications have been developed. High-performance liquid chromatography (HPLC) separation methods suitable for such molecules cannot be used in tandem with mass spectrometry (MS) due to high non-volatile salt content; at the same time the sample preparation, in biological fluids, is also a challenging problem. In the past ion-pair chromatography was mainly used in the case of HPLC-MS of biphosphonates, but no application to quantitative pharmacokinetic (PK) studies has been presented.

Adhesion inhibition "in vitro" by heparin derivatives correlates with their activity on angiogenesis in mice.

Heparin (HEP) play an important role in angiogenesis. Inhibition of matrix degrading enzymes and binding to adhesion molecules are some of the interaction mechanism. The bleeding risk and the need of parenteral administration, restrict the therapeutic use of HEP as angiogenesis modulator; presently derivatives, with different pharmacokinetic and anticoagulant properties, are available.

Intra-plaque production of platelet-activating factor correlates with neoangiogenesis in human carotid atherosclerotic lesions.

Platelet-activating factor (PAF) is a phospholipid mediator synthesized by activated inflammatory and endothelial cells. Recently PAF has been shown to contribute to neoangiogenesis in several experimental models. Here we evaluated the presence of PAF and its potential role in neovascularization within human atherosclerotic plaques.