Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: Development and application of the Carcinogenic Potency Categorization Approach (CPCA).

N-Nitrosamine impurities, including nitrosamine drug substance-related impurities (NDSRIs), have challenged pharmaceutical industry and regulators alike and affected the global drug supply over the past 5 years. Nitrosamines are a class of known carcinogens, but NDSRIs have posed additional challenges as many lack empirical data to establish acceptable intake (AI) limits. Read-across analysis from surrogates has been used to identify AI limits in some cases; however, this approach is limited by the availability of robustly-tested surrogates matching the structural features of NDSRIs, which usually contain a diverse array of functional groups.

The EU Response to the Presence of Nitrosamine Impurities in Medicines.

The unexpected detection of nitrosamine impurities in human medicines has recently seen global regulators act to understand the risks of these contaminations to patients and to limit their presence. Over 300 nitrosamines are known, many of which are highly potent mutagenic carcinogens. Regulators first became aware of the presence of nitrosamines in EU medicines in 2018, with reports of detection of -nitroso-dimethylamine (NDMA) in valsartan from one manufacturer.

Environmental risk assessment of advanced therapies containing genetically modified organisms in the EU.

Gene therapy medicinal products have the potential to provide curative treatment for many diseases with current limited therapeutic options. As advanced therapy medicinal products (ATMPs), these therapies undergo a centralised, single European Union authorisation by the European Medicines Agency (EMA), but the risks and potential harm to the environment and population at large are weighted in each application, and different interpretations at national level exist. A streamlined procedure is now in place to facilitate a consistent approach for the assessment of the environmental risks of medicines containing genetically modified organisms for both clinical trial applications and marketing authorisation applications.

Vandetanib-eluting Radiopaque Beads: Pharmacokinetics, Safety, and Efficacy in a Rabbit Model of Liver Cancer.

Background Transarterial chemoembolization with cytotoxic drugs is standard treatment for unresectable intermediate-stage hepatocellular carcinoma but achieves suboptimal outcomes because of hypoxic stress and the production of detrimental proangiogenic factors. An alternative approach using radiopaque embolization beads loaded with the antiangiogenic drug vandetanib may provide improved anticancer efficacy. Purpose To evaluate the pharmacokinetics, safety, and efficacy of vandetanib-eluting radiopaque bead (VERB) chemoembolization of rabbit liver tumors.

Vandetanib-eluting Radiopaque Beads: Pharmacokinetics, Safety and Toxicity Evaluation following Swine Liver Embolization.

Purpose: To evaluate the plasma and tissue pharmacokinetics, safety and toxicity following intra-arterial hepatic artery administration of Vandetanib (VTB)-eluting Radiopaque Beads (VERB) in healthy swine.

Materials And Methods: In a first phase, healthy swine were treated with hepatic intra-arterial administration of VERB at target dose loading strengths of 36 mg/mL (VERB36), 72 mg/mL (VERB72) and 120 mg/mL (VERB120). Blood and tissue samples were taken and analysed for VTB and metabolites to determine pharmacokinetic parameters for the different dose forms over 30 days.

Drug interactions.

Drugs for allergy are often taken in combination with other drugs, either to treat allergy or other conditions. In common with many pharmaceuticals, most such drugs are subject to metabolism by P450 enzymes and to transmembrane transport. This gives rise to considerable potential for drug-drug interactions, to which must be added consideration of drug-diet interactions.

Pharmacokinetics in special populations.

Pharmacokinetics are typically dependent on a variety of physiological variables (e.g., age, ethnicity, or pregnancy) or pathological conditions (e.

Drug metabolism and pharmacokinetics.

In this article, aspects of absorption, distribution, metabolism, and excretion have been described bearing in mind the pathogenesis of allergic diseases and their possible therapeutic opportunities. The importance of the routes of administration of the different therapeutic groups has been emphasized. The classical aspects of drug metabolism and disposition related to oral administration have been reviewed, but special emphasis has been given to intranasal, cutaneous, transdermal, and ocular administration as well as to the absorption and the subsequent bioavailability of drugs.

Amine oxidases and monooxygenases in the in vivo metabolism of xenobiotic amines in humans: has the involvement of amine oxidases been neglected?

In this review, the major enzyme systems involved in vivo in the oxidative metabolism of xenobiotic amines in humans are discussed, i.e. the monooxygenases [cytochrome P450 system (CYPs) and flavin-containing monooxygenases (FMOs)] and the amine oxidases (AOs).

Drug metabolism in the paediatric population and in the elderly.

This review focuses on one of the key factors accounting for differences in drug/metabolite exposure in paediatric and elderly subjects compared with that of the adult population, that is, differences in drug metabolism (both qualitative and quantitative) and in particular differences due to changes in the activity and/or concentration of drug metabolizing enzymes. Important differences have been found in the paediatric population compared with adults for both phase I (e.g.

Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics.

Although the majority of oxidative metabolic reactions are mediated by the CYP superfamily of enzymes, non-CYP-mediated oxidative reactions can play an important role in the metabolism of xenobiotics. The (major) oxidative enzymes, other than CYPs, involved in the metabolism of drugs and other xenobiotics are: the flavin-containing monooxygenases, the molybdenum hydroxylases (aldehyde oxidase and xanthine oxidase), the prostaglandin H synthase, the lipoxygenases, the amine oxidases (monoamine, polyamine, diamine and semicarbazide-sensitive amine oxidases) and the alcohol and aldehyde dehydrogenases. In a similar manner to CYPs, these oxidative enzymes can also produce therapeutically active metabolites and reactive/toxic metabolites, modulate the efficacy of therapeutically active drugs or contribute to detoxification.

Pharmacokinetics and metabolism of 14C-levetiracetam, a new antiepileptic agent, in healthy volunteers.

The absorption, disposition and metabolism of levetiracetam, a new antiepileptic drug, have been investigated after a single oral dose of the (14)C-labelled molecule administered to male healthy volunteers. As chiral inversion can occur during drug metabolism, the chiral inversion of levetiracetam and/or of its major metabolite produced by hydrolysis (the corresponding acid) was also investigated. Finally, the in vitro hydrolysis of levetiracetam to its major metabolite and the inhibition of this reaction in human blood have been studied.

Use of a low-density microarray for studying gene expression patterns induced by hepatotoxicants on primary cultures of rat hepatocytes.

In the field of gene expression analysis, DNA microarray technology is having a major impact on many different areas including toxicology. For instance, a number of studies have shown that transcription profiling can generate the information needed to assign a compound to a mode-of-action class. In this study, we investigated whether compounds inducing similar toxicological endpoints produce similar changes in gene expression.