Recommendations for the content and management of Certificates of Analysis for reference standards from the GCC for bioanalysis.

The 13th Global CRO Council (GCC) closed forum for bioanalysis was held in New Orleans, LA, USA on 5 April 2019. This GCC meeting was organized to discuss the contents of the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline published in February 2019 and consolidate the feedback of the GCC members. While ICH M10 will cover requirements for reference standards, one of the biggest challenges facing the CRO community is the lack of consistency and completeness of Certificates of Analysis for reference standards used in regulated bioanalysis.

Epithelial Lining Fluid and Plasma Concentrations of Dalbavancin in Healthy Adults after a Single 1,500-Milligram Infusion.

Dalbavancin is a lipoglycopeptide antibiotic with a prolonged half-life. A phase 1 study assessed dalbavancin levels in epithelial lining fluid (ELF) in 35 healthy adults using ELF bronchial microsampling up to 168 h after administration of 1,500 mg dalbavancin. The penetration of dalbavancin into ELF was 36%.

A Single-Center, Open-Label, 3-Way Crossover Trial to Determine the Pharmacokinetic and Pharmacodynamic Interaction Between Nebivolol and Valsartan in Healthy Volunteers at Steady State.

Combining different classes of antihypertensives is more effective for reducing blood pressure (BP) than increasing the dose of monotherapies. The aims of this phase I study were to investigate pharmacokinetic and pharmacodynamic interactions between nebivolol, a vasodilatory β1-selective blocker, and valsartan, an angiotensin II receptor blocker, and to assess safety and tolerability of the combination. This was a single-center, randomized, open-label, multiple-dose, 3-way crossover trial in 30 healthy adults aged 18-45 years.

2014 White Paper on recent issues in bioanalysis: a full immersion in bioanalysis (Part 1--small molecules by LCMS).

The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity.

Assessment of the genotoxic and carcinogenic risks of p-nitrophenol when it is present as an impurity in a drug product.

According to the 2008 US FDA (draft) and 2006 EMEA guidance documents for genotoxic impurities, an impurity that is positive in an in vitro genotoxicity study, in the absence of in vivo genotoxicity or carcinogenicity data, should be treated as genotoxic and typically controlled to 1.5 microg/day for chronic use. For p-nitrophenol (PNP), existing study results (i.

Disposition, metabolism, and excretion of [14C]doripenem after a single 500-milligram intravenous infusion in healthy men.

In this open-label, single-center study, eight healthy men each received a single 500-mg dose of [(14)C]doripenem, containing 50 microCi of [(14)C]doripenem, administered as a 1-h intravenous infusion. The concentrations of unchanged doripenem and its primary metabolite (doripenem-M-1) resulting from beta-lactam ring opening were measured in plasma and urine by a validated liquid chromatography method coupled to a tandem mass spectrometry assay. Total radioactivity was measured in blood, plasma, urine, and feces by liquid scintillation counting.

The novel, orally active, delta opioid RWJ-394674 is biotransformed to the potent mu opioid RWJ-413216.

Although the mu opioid receptor is the primary target of marketed opioid analgesics, several studies suggest the advantageous effect of combinations of mu and delta opioids. The novel compound RWJ-394674 [N,N-diethyl-4-[(8-phenethyl-8-azabicyclo]3.2.

Simultaneous determination of glipizide and rosiglitazone unbound drug concentrations in plasma by equilibrium dialysis and liquid chromatography-tandem mass spectrometry.

Glipizide and rosiglitazone are widely used to treat Type 2 diabetes. In order to investigate drug-drug protein binding interaction between glipizide and rosiglitazone, a method was developed and validated for simultaneously determining the free (unbound) fraction of glipizide and rosiglitazone in plasma employing equilibrium dialysis for the separation of free drug and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for quantitation. Post-dialysis human plasma or buffer samples of 0.

Simultaneous determination of pioglitazone and its two active metabolites in human plasma by LC-MS/MS.

A liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of pioglitazone (PIO) and its two metabolites: M-III (keto-derivative) and M-IV (hydroxy-derivative) in human plasma. Human plasma samples of 0.2 ml were extracted by a single step liquid-liquid extraction procedure and analyzed using a high performance liquid chromatography (HPLC) electrospray tandem mass spectrometer system.

Single-dose pharmacokinetics and pharmacodynamics of RWJ 67657, a specific p38 mitogen-activated protein kinase inhibitor: a first-in-human study.

The objective of this study was to investigate the pharmacokinetics and ex vivo pharmacodynamics of increasing doses of RWJ 67657, along with the effect of food at one dose level in a first-in-human (FIH) study. This was a placebo-controlled, double-blind, randomized trial in healthy male subjects. Subjects received increasing doses of RWJ 67657 or placebo as a single oral dose (0.

Differential tramadol and O-desmethyl metabolite levels in brain vs. plasma of mice and rats administered tramadol hydrochloride orally.

Objective: To investigate a possible differential brain uptake of tramadol vs. its major metabolite (O-desmethyl tramadol; M1) in mice and rats.

Methods: An extraction and measurement technique (gas chromatograph equipped with a nitrogen phosphorus detector) was used to measure plasma and brain levels of tramadol and M1 at intervals 10-300 min after oral dosing of tramadol hydrochloride to mice and rats.

Oral administration of cyclopentane neuraminidase inhibitors protects ferrets against influenza virus infection.

Several cyclopentane inhibitors of influenza virus neuraminidase that have inhibitory activities in tissue culture similar to those of zanamivir and oseltamivir have recently been described. These new inhibitors have been examined for efficacy against a virulent H3N2 influenza virus when administered orally to infected ferrets. Preliminary studies indicated that oral administration of BCX-1923, BCX-1827, or BCX-1812 (RWJ-270201) at a dose of 5 or 25 mg/kg of body weight was active in ferrets in reducing respiratory and constitutional signs and symptoms, but these antivirals affected virus titers in the upper and lower respiratory tracts only marginally.

Gas chromatographic method using nitrogen-phosphorus detection for the measurement of tramadol and its O-desmethyl metabolite in plasma and brain tissue of mice and rats.

A method that allows the measurement of plasma and brain levels of the centrally-acting analgesic tramadol and its major metabolite (O-desmethyl tramadol) in mice and rats was developed using gas chromatography equipped with nitrogen-phosphorus detection (GC-NPD). Plasma samples were extracted with methyl tert.-butyl ether (MTBE) and were injected directly into the GC system.