A Two-Way Proposal for the Determination of Bioequivalence for Narrow Therapeutic Index Drugs in the European Union.

In the European Union, bioequivalence (BE) for narrow therapeutic index (NTI) drugs is currently demonstrated when the 90% confidence interval for the ratio of the population geometric means of the test and reference products for AUC, and in some cases for Cmax, falls within the acceptance range of 90.00% to 111.11%. However, meeting this requirement results in an increased difficulty of demonstrating BE and a need for clinical trials with larger subject sample sizes, especially for medium-to-high variability drugs. To address this challenge, a scaled average BE based on the reference product within-subject variability for narrowing the acceptance range of NTI drugs was recently proposed. However, this approach showed increased type I error (T1E), especially close to the cut-off point between the unscaled and scaled portions of the method. Based on simulations, this limitation can be overcome by predefining the protocol the path to be followed: either the fixed 90.00-111.11% acceptance range approach or the previously proposed scaled average BE approach with a slight adjustment of the one-sided significance level α to 0.042 for a 2 × 3 × 3 partial replicate design and without a lower cut-off point. This results in a mixed approach allowing to reduce the sample size whilst not inflating the T1E.

Clinical Pharmacology of Vinpocetine: Properties Revisited and Introduction of a Population Pharmacokinetic Model for Its Metabolite, Apovincaminic Acid (AVA).

This paper examines the use of vinpocetine in the context of clinical pharmacology. The main and active metabolite of vinpocetine is apovincaminic acid (AVA). Due to the scarce information in the literature on AVA pharmacokinetics, we propose a population pharmacokinetic (PopPK) model for AVA based on a study in healthy volunteers with three different formulations of vinpocetine. The suggested PopPK model (and simulations) could be helpful in ensuring the more effective and safer use of the vinpocetine in the future given the increasing range of suggested indications for its use.

Under the Umbrella of Clinical Pharmacology: Inflammatory Bowel Disease, Infliximab and Adalimumab, and a Bridge to an Era of Biosimilars.

Monoclonal antibodies (MAbs) have revolutionized the treatment of many chronic inflammatory diseases, including inflammatory bowel disease (IBD). IBD is a term that comprises two quite similar, yet distinctive, disorders-Crohn's disease (CD) and ulcerative colitis (UC). Two blockbuster MAbs, infliximab (IFX) and adalimumab (ADL), transformed the pharmacological approach of treating CD and UC. However, due to the complex interplay of pharmacology and immunology, MAbs face challenges related to their immunogenicity, effectiveness, and safety. To ease the burden of IBD and other severe diseases, biosimilars have emerged as a cost-effective alternative to an originator product. According to the current knowledge, biosimilars of IFX and ADL in IBD patients are shown to be as safe and effective as their originators. The future of biosimilars, in general, is promising due to the potential of making the health care system more sustainable. However, their use is accompanied by misconceptions regarding their effectiveness and safety, as well as by controversy regarding their interchangeability. Hence, until a scientific consensus is achieved, scientific data on the long-term effectiveness and safety of biosimilars are needed.

The controversies of parabens - an overview nowadays.

Effects of paraben toxicity, i.e., endocrine-disruption properties, are in the focus of researchers for decades, but still - they are a hot subject of debate. Parabens are aliphatic esters of p-hydroxybenzoic acid, which are widely used as antimicrobial agents for the preservation of cosmetics, pharmaceuticals and foods. Mostly used parabens are methyl-, ethyl-, propyl- and butylparaben. Although the toxicity of parabens is reported in animals and in in vitro studies, it cannot be taken for granted when discussing hazards for human health due to an unrealistic exposure -safety profile. Many studies have demonstrated that parabens are non-teratogenic, non-mutagenic, non-carcinogenic and the real evidence for their toxicity in humans has not been established. For now, methyl-, ethyl- and propylparaben are considered safe for use in cosmetics and pharmaceuticals within the recommended range of doses. Regarding alternatives for parabens, a variety of approaches have been proposed, but every substitute would need to be tested rigorously for toxicity and safety.

Food-Drug Interactions with Fruit Juices.

Fruit juices contain a large number of phytochemicals that, in combination with certain drugs, can cause food-drug interactions that can be clinically significant and lead to adverse events. The mechanisms behind such interactions are in most cases related to phytochemical interference with the activity of cytochrome P450 metabolizing enzymes (CYPs) or drug transporters. Moreover, alterations in their activity can have a clinical relevance if systemic exposure to the drug is decreased or increased, meaning that the pharmacological drug effects are suboptimal, or the drug will cause toxicity. In general, the common pharmacokinetic parameters found to be altered in food-drug interactions regarding fruit juices are the area under the concentration-time curve, bioavailability, and maximum plasma concentration. In most cases, the results from the drug interaction studies with fruit juices provide only limited information due to the small number of subjects, which are also healthy volunteers. Moreover, drug interactions with fruit juices are challenging to predict due to the unknown amounts of the specific phytochemicals responsible for the interaction, as well as due to the inter-individual variability of drug metabolism, among others. Therefore, this work aims to raise awareness about possible pharmacological interactions with fruit juices.

Safety of Probiotics: Functional Fruit Beverages and Nutraceuticals.

Over the last decade, fruit juice consumption has increased. Their rise in popularity can be attributed to the belief that they are a quick way to consuming a dietary portion of fruit. Probiotics added to fruit juices produce various bioactive compounds, thus probiotic fruit juices can be considered as a new type of functional foods. Such combinations could improve nutritional properties and provide health benefits of fruit juices, due to delivering positive health attributes from both sources (fruit juices and probiotics). However, this review discusses the other side of the same coin, i.e., the one that challenges general beliefs that probiotics are undoubtedly safe. This topic deserves more acknowledgments from the medical and nutritional literature, as it is highly important for health care professionals and nutritionists who must be aware of potential probiotic issues. Still, clinical trials have not adequately questioned the safety of probiotics, as they are generally considered safe. Therefore, this reviews aims to give an evidence-based perspective of probiotic safety, focusing on probiotic fruit beverages and nutraceuticals, by providing documented clinical case reports and studies. Finally, the paper deals with some additional insights from the pharmacological and toxicological point of views, such as pharmacological repercussions of probiotics on health.