Application Of A Physiologically-Based Pharmacokinetic (PBPK) Model In Predicting Drug Interactions

Physiologically-based pharmacokinetic (PBPK) modeling and simulation have become an integral part of the drug development process. This approach is a mathematical technique using a series of differential equations to predict the pharmacokinetic behavior of drug molecules in humans and animals. The main application of the model to date is its use to translate in vitro data to predict and assess possible drug interactions at the level of biotransformation arising from inhibition or induction of metabolizing enzymes. These models provide numerous advantages over static models, as they include both drug-specific physico-chemical properties and system-specific physiologic factors, thus being able to predict pharmacokinetic behavior as much as possible and to predict possible drug interactions with high probability. That is why these models have already received regulatory approval and are routinely used to predict cytochrome P450-mediated drug interactions

In vitro inhibitions of CYP2C9 and CYP3A4 by fractions isolated from Goji berry (Lycium barbarum) fruits

IntroductionLycium barbarum L., known as Goji, is widely used as a medicinal and functional food. Besides the positive therapeutic properties it possesses, it can inhibit enzymes involved in the metabolism of drugs and it can cause herb-drug interactions (HDIs).AimThe aim of the study is evaluation of the potential of polysaccharide and polyphenolic fractions isolated from L. barbarum fruits to inhibit the activity of CYP3A4 and CYP2C9Materials and MethodsThe inhibitory effects of polysaccharide and polyphenolic fractions isolated from L. barbarum on CYP3A4 and CYP2C9 activity were determined using Vivid® CYP3A4 and CYP2C9 Green Screening Kits.ResultsThe both fractions inhibit the activity of investigated CYP isoenzymes. The polyphenolic fraction was more potent with IC50 values of 0.119 mg/ml and 0.048 mg/ml against CYP3A4 and CYP2C9 respectively. The polysaccharide fraction has inhibited CYP3A4 and CYP2C9 with IC50 values of 2.244 mg/ml and 4.094 mg/ml respectively.ConclusionThe usage of beverages based on L.barbarum can lead to herb-drug interactions (HDIs). Further research in this direction will assess the significance of these interactions

Role of the hospital pharmacist in preventing drug interactions in clinical practice

Drug-drug interactions (DDIs) represent a serious problem for current pharmacotherapy worldwide, as they may influence drug safety and/or therapeutic effect. In addition, they are often observed in hospitalized patients, who usually have to take several drugs simultaneously. Therefore, different strategies have been sought to detect and prevent dangerous interactions. The aim of the present work is to summarize the main mechanisms of DDIs and evaluate the role of hospital pharmacists in identifying and preventing potentially dangerous DDIs. According to the literature review, the most frequently reported clinically significant interactions are due to modulation of drug-metabolizing enzymes or transmembrane transporter activity. A deep understanding of drug pharmacology and toxicity is necessary to identify and prevent certain potential interactions. Hospital pharmacists can enhance patient safety through interventions such as medication reconciliation and patient education at discharge, reducing hospital readmissions and the risk of drug-related problems

Potential Drug-Drug Interactions With Tyrosine Kinase Inhibitors

През последните години се наблюдава голям напредък при лечението на туморните заболявания поради въвеждането на нови фармакологични подходи като таргетната терапия и имунотерапията. Таргетната терапия се състои в потискане активността на специфични таргетни молекули в туморните клетки, необходими за клетъчния им растеж, диференциация и оцеляване. Особен интерес представляват инхибиторите на тирозин киназите, протеини, които играят основна роля в клетъчната сигнализация, тъй като свръхекспресия или мутантни форми на голям брой тирозин кинази са открити при множество тумори. Тирозин киназните инхибитори блокират активността на тирозин киназите и нарушават вътреклетъчната сигнална трансдукция, като по този начин потискат растежа и развитието на раковите клетки. Лечението с тирозин киназни инхибитори се понася добре, като един от основните проблеми при приложението им е повишеният риск от възникване на лекарствени взаимодействия при едновременен прием с други лекарства.В настоящия обзор са описани потенциалните лекарствени взаимодействия, които биха могли да възникнат при лечение с някои тирозин киназни инхибитори (ALK инхибитори, TRK инхибитори, EGFR инхибитори, FGFR инхибитори), използвани за лечение на редки и агресивни форми на рак. Необходимо е внимателно подбиране на лекарствата, които се приемат едновременно с тирозин киназните инхибитори с цел да се избегнат промени в плазмените им концентрации, които могат да рефлектират върху терапевтичните и токсичните им ефекти.There has been great progress in the treatment of tumors in recent years due to the introduction of new pharmacological approaches such as targeted therapy and immunotherapy. Targeted therapy is associated with suppressing the activity of specific targeting molecules in the cancer cells necessary for their growth, differentiation and survival. Of particular interest are tyrosine kinase inhibitors, proteins that play a major role in cell signaling, since overexpression or mutant forms of a large number of tyrosine kinases have been found in multiple tumors. Tyrosine kinase inhibitors block the activity of tyrosine kinases and disrupt intracellular signal transduction, thereby inhibiting the growth and development of cancer cells. Treatment with tyrosine kinase inhibitors is well tolerated and one of the main problems with their administration is the increased risk of drug interactions when co-administered with other drugs.This review describes the potential drug-drug interactions that may occur during the treatment with certain tyrosine kinase inhibitors (ALK inhibitors, TRK inhibitors, EGFR inhibitors, FGFR inhibitors) used to treat rare and aggressive tumors. Careful selection of drugs that are co-administered with tyrosine kinase inhibitors is needed in order to avoid changes in their plasma concentrations that may lead to changes in their therapeutic and toxic effects

A review of clinically significant interactions between medicines and green tea

Green tea intake for prevention and/or treatment of diseases is widespread worldwide. Green tea is known for its antioxidant, anti-inflammatory, anti-tumor effects, and others. Tea leaves contain various biologically active substances and their concomitant use with medicinal products carries the risk of potentially dangerous interactions. The aim of the present study was to assess the clinical significance of interactions that may occur after co-administration of drugs with green tea. A thorough review of the scientific literature was conducted and a number of studies, both in experimental animals and in humans that reported pharmacokinetic interactions with certain drugs were identified. Most authors suggest that the observed interactions are due to the ability of the green tea extract, as well as the contained catechins, mainly epigallocatechin-3-gallate (EGCG), to modulate the activity of some drug-metabolizing enzymes and transmembrane transporters. As a result, changes in plasma drug concentrations leading to an increased risk of toxic effects or reduced therapy effectiveness are observed. Drug interactions have also been observed after simultaneous intake of certain medications and caffeine, which is also present in tea leaves. In conclusion, concomitant use of drugs with green tea, EGCG or caffeine, in any form, may lead to clinically significant drug interactions and adverse patient outcomes

A review of cancer immunotherapy: immune checkpoint inhibitors

Immunotherapy is a method of treating malignant diseases that aims to stimulate the immune system to destroy tumor cells. For this purpose, immune checkpoint inhibitors are mainly used. These drugs block coin-hibitory signaling pathways in T-cells and thus induce antitumor immune responses. The most common targets for immune checkpoint inhibitors are programmed cell death receptor-1 (PD-1), programmed death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). PD-1/PD-L1 inhibitors and CTLA-4 inhibitors are widely used in the treatment of various types of cancer, for instance, melanoma, non-small cell lung cancer, colorectal carcinoma, esophageal carcinoma, urothelial carcinoma, and others. In comparison to other approaches to cancer treatment such as chemotherapy and radiotherapy, immunotherapy has been shown to improve patients' quality of life and survival and is generally better tolerated. In conclusion, while immunotherapy with immune checkpoint inhibitors has seen rapid development in recent years, further clinical studies are necessary to enhance the safety and efficacy of PD-1/PD-L1 and CTLA-4 inhibitors, whether administered alone or in combination

INNs granted with specific storage requirements in Bulgarian pharmacies. Part 2: Antineoplastic and immunomodulating agents

There are drugs that require special storage in Bulgarian pharmacies as well as extra caution during the dispensing process. This is due to serious adverse reactions that may be even fatal. These medicines are included in Appendix № 9 to Art. 17, para. 1 of Ordinance № 28/9.12.2008, issued by the Minister of Health. The performed study of the anticancer drugs listed in the Appendix showed that a major part of these medicines that have a marketing authorization for use in Bulgaria are not included in the Appendix № 9. In addition, there are antitumor drugs that are listed in the appendix but are not authorized in Bulgaria to date. In conclusion, it is necessary to periodically update the drugs in Appendix № 9 as well as to develop clear and precise criteria for the inclusion of medicines in it

The Sea – A Source Of Bioactive Substances

Seventy-five percent of the Earth's surface is covered in water. The marine environment provides a huge ecological resource, including a variety of marine plants and animals, and is an exclusive reservoir for bioactive substances many of which have structural and chemical characteristics that are absent in natural terrestrial products. These marine organisms are researched as antibacterial, immunomodulating, antifungal, anti-inflammatory, anti-carcinogenic, antimicrobial, neuroprotective, analgesic and antimalarial agents with some of them having proven themselves as homeopathic monoremedies.At present, there are ten drugs of marine origin approved in different parts of the world, and thirteen compounds are at different stages of clinical trials. There are many marine compounds/molecules that are in the pre-clinical stage of testing. Substances of marine origin are also used in homeopathy, 6 monoremedies extracted from marine organisms are registered in Bulgaria.  Marine pharmacology presents a huge field for research of medicines of marine origin, but nevertheless the available registered drugs derived from marine organisms are relatively limited. Interest in marine species is on the rise. The explanation for this is more than four billion years of evolution invested in the combined chemistry of marine organisms’ bioactive substances, aimed at appropriate and effective biological activity.