Effects of Food, Gastric Acid Reduction, and Strong CYP3A Induction on the Pharmacokinetics of Tasurgratinib, a Novel Selective Fibroblast Growth Factor Receptor Inhibitor.

We conducted this three-part study in healthy subjects to investigate the pharmacokinetics of tasurgratinib (orally available selective inhibitor of fibroblast growth factor receptor 1-3) and M2 (its major metabolite) under different conditions. In Part A, subjects received tasurgratinib 35 mg either fed with a high-fat meal or fasted. In Parts B and C, subjects received tasurgratinib 35 mg alone or with either rabeprazole (acid-reducing agent) 20 mg (Part B) or rifampin (strong CYP3A inducer) 600 mg (Part C). Primary endpoints were maximum concentration (Cmax), and areas under the plasma concentration-time curve to time of last quantifiable concentration (AUC(0-t)) and extrapolated to infinite time (AUC(0-inf)). Forty-two subjects were enrolled, 14 each into Parts A, B, and C. In Part A, administration of tasurgratinib with a high-fat meal resulted in 33% reduction in Cmax and ∼23% reduction in AUC(0-t) and AUC(0-inf) of tasurgratinib, and 47% reduction in Cmax with ∼30% reduction in AUC(0-t) and AUC(0-inf) of M2. In Part B, co-administration of rabeprazole at steady state resulted in no/weak interaction with tasurgratinib (∼8% increase in AUC(0-t) and AUC(0-inf) without an effect on Cmax) and M2 (∼18% increase in AUC(0-t) and AUC(0-inf) without an effect on Cmax). In Part C, co-administration of rifampin at steady state resulted in a weak interaction with tasurgratinib (∼16% reduction in AUC(0-t) and AUC(0-inf)) and M2 (∼12% reduction in AUC(0-t) and AUC(0-inf)). Administration of tasurgratinib with a high-fat meal appeared to reduce systemic exposure of tasurgratinib, however co-administration with an acid-reducing agent or a CYP3A inducer had a minimal impact on pharmacokinetics.

Unexpected Sudden Deaths Following the Co-administration of Ceftriaxone and Lansoprazole: A Case Series.

Ceftriaxone and lansoprazole are commonly used in clinical settings, but recent analyses indicate a potential risk for QTc prolongation and cardiac events when used together. This case series examines three patients from a cohort of sudden death cases at a single institution over a decade, who received both medications within 24 hours before death. Three cases were identified, each with contributing factors for cardiac arrhythmias. The results underscore the importance of monitoring and possibly avoiding this drug combination in patients at risk of QT prolongation, pending further investigation into the underlying mechanisms.

Anaphylaxis to Patent Blue V Dye With Clinical Deterioration Following Administration of Suxamethonium and Sensitisation on Skin Testing to Methylene Blue, Patent Blue V Dye and Suxamethonium.

Neuromuscular blocking drugs (NMBAs) and Patent Blue V dye sodium salt 2.5% (Guerbet, Roissy, France) are frequently implicated in perioperative allergic immunoglobulin E (IgE) mediated anaphylaxis. Most cases of anaphylaxis during surgery occur at induction of anaesthesia, although reactions to vital dyes injected into soft tissues often show a delayed onset. We present the case of a female in her 60s who suffered perioperative anaphylaxis to Patent Blue V dye and possibly suxamethonium during oncological breast surgery. Allergy clinic follow-up confirmed sensitivity to both drugs which may explain the unusual bi-phasic nature of the reaction. Intradermal testing also found cross-sensitivity to methylene blue, but not to other common allergens or NMBAs. This case demonstrates the importance of thorough post-anaphylaxis follow-up and raises the possibility of cross-sensitivity between unrelated compounds.

Treating cancer-associated venous thromboembolism: A practical approach.

Venous thromboembolism (VTE) is a common and potentially life-threatening complication in patients with cancer. Both cancer and its treatments increase the risk of developing VTE. Specific cancer types and individual patient comorbidities increase the risk of developing cancer-associated VTE, and the risk of bleeding is increased with anticoagulation therapies. The aims of this article are to summarize the latest evidence for treating cancer-associated VTE, discuss the practical considerations involved, and share best practices for VTE treatment in patients with cancer. The article pays particular attention to challenging contexts including patients with brain, lung, gastrointestinal, and genitourinary tumors and those with hematological malignancies. Furthermore, the article summarizes specific clinical scenarios that require additional treatment considerations, including extremes of body weight, nausea and gastrointestinal disturbances, compromised renal function, and anemia, and touches upon the relevance of drug-drug interactions. Historically, vitamin K antagonists and low-molecular-weight heparins (LMWHs) have been used as therapy for cancer-associated VTE. The development of direct oral anticoagulants has provided additional treatment options, which, in certain instances, offer advantages over LMWHs. There are numerous factors that need to be considered when treating cancer-associated VTE, and although various treatment guidelines are helpful, they do not reflect each unique scenario that may arise in clinical practice. This article provides a summary of the latest evidence and a practical approach for treating cancer-associated VTE.

Physiologically based pharmacokinetic modeling in obesity: applications and challenges.

INTRODUCTION: Rising global obesity rates pose a threat to people's health. Obesity causes a series of pathophysiologic changes, making the response of patients with obesity to drugs different from that of nonobese, thus affecting the treatment efficacy and even leading to adverse events. Therefore, understanding obesity's effects on pharmacokinetics is essential for the rational use of drugs in patients with obesity. AREAS COVERED: Articles related to physiologically based pharmacokinetic (PBPK) modeling in patients with obesity from inception to October 2023 were searched in PubMed, Embase, Web of Science and the Cochrane Library. This review outlines PBPK modeling applications in exploring factors influencing obesity's effects on pharmacokinetics, guiding clinical drug development and evaluating and optimizing clinical use of drugs in patients with obesity. EXPERT OPINION: Obesity-induced pathophysiologic alterations impact drug pharmacokinetics and drug-drug interactions (DDIs), altering drug exposure. However, there is a lack of universal body size indices or quantitative pharmacology models to predict the optimal for the patients with obesity. Therefore, dosage regimens for patients with obesity must consider individual physiological and biochemical information, and clinically individualize therapeutic drug monitoring for highly variable drugs to ensure effective drug dosing and avoid adverse effects.

Knowledge of Food-Drug Interactions among Medical University Students.

BACKGROUND: Food-drug interactions (FDIs) may alter drug pharmacokinetics and pharmacodynamics, modifying the whole therapy's effectiveness. Some of them cause the attenuation of drug effects, while others inhibit the medicines' metabolism resulting, in too high concentrations of the medicine in the body. Thus, some healthcare professionals-doctors, pharmacists or dieticians-should be aware of the possibility of food-drug interactions. This study aimed to assess knowledge of food-drug interactions among students of pharmacy, medicine, stomatology, medical analysis and dietetics and students of the college of further medical education for pharmacy technicians. METHODS: Students (n = 820) completed a custom-made questionnaire. The relationships between the continuous variables were analysed on the basis of Pearson's correlation coefficient. To verify the predictors of objective students' knowledge about food-drug interactions, a multiple linear regression model with analysis of covariance (ANCOVA) was used. The Kruskal-Wallis test was performed to compare the total scores the respondents received for questions assessing their objective knowledge of FDI. RESULTS: Students' objective knowledge of FDIs correlated positively with their year of study and their self-evaluation of it. It was also significantly influenced by the field and mode of studies and by the fact that the issue had been discussed during the courses. CONCLUSIONS: Most students of the medical university had serious deficiencies in their knowledge of food-drug interactions. This is of particular concern for future doctors and dentists. Among the respondents, pharmacy students stood out, as their FDI knowledge was greater. The issue of food-drug interactions should be more widely taught at medical universities, which was emphasised by the respondents themselves.

Impact of protein and small molecule interactions on kinase conformations.

Protein kinases act as central molecular switches in the control of cellular functions. Alterations in the regulation and function of protein kinases may provoke diseases including cancer. In this study we investigate the conformational states of such disease-associated kinases using the high sensitivity of the kinase conformation (KinCon) reporter system. We first track BRAF kinase activity conformational changes upon melanoma drug binding. Second, we also use the KinCon reporter technology to examine the impact of regulatory protein interactions on LKB1 kinase tumor suppressor functions. Third, we explore the conformational dynamics of RIP kinases in response to TNF pathway activation and small molecule interactions. Finally, we show that CDK4/6 interactions with regulatory proteins alter conformations which remain unaffected in the presence of clinically applied inhibitors. Apart from its predictive value, the KinCon technology helps to identify cellular factors that impact drug efficacies. The understanding of the structural dynamics of full-length protein kinases when interacting with small molecule inhibitors or regulatory proteins is crucial for designing more effective therapeutic strategies.

A Review of Concordance and Quality in Clinical Guidelines for Hormonal Contraceptives to Mitigate Drug-Drug Interactions in Women With Epilepsy.

PURPOSE: Concomitant use of hormonal contraceptive agents (HCAs) and enzyme-inducting antiepileptic drugs (EIAEDs) may lead to contraceptive failure and unintended pregnancy. This review identified and evaluated concordance and quality of clinical treatment guidelines related to the use of HCAs in women with epilepsy (WWE) receiving EIAEDs. METHODS: Relevant clinical guidelines were identified across four databases and were independently evaluated for quality utilizing the AGREE-II protocol instrument. Quality in this context is defined as the rigor and transparency of the methodologies used to develop the guideline. Guidelines were further assessed in terms of concordance and discordance with the latest body of knowledge concerning the use of hormonal contraception in the presence of EIAEDs. RESULTS: A total of n = 5 guidelines were retrieved and evaluated. Overall guideline scores ranged from 17% to 92%, while individual domain scores ranged from 0% to 100%. Contraceptive guidelines consistently recommended the use of intrauterine systems and long-acting injectables in the presence of EIAEDs, recommended against the use of oral, transdermal, and vaginal ring contraceptives, and differed regarding recommendations related to implants. Guidelines agreed regarding recommendations that women treated with EIAEDs should receive intrauterine systems and long-acting injectables; however, the suggested frequency of administration of injectable contraceptives differed. The use of intrauterine systems in this population is supported by evidence, but there is uncertainty surrounding the use of long-acting injectables and contraceptive implants. CONCLUSIONS: To mitigate the risk of unintended pregnancy and its consequences, recommendations related to implants and long-acting injectable contraceptives should be evidence-based.

Carboxylesterase 1-Based Drug-Drug Interaction Potential of Remimazolam: In-Vitro Studies and Literature Review.

BACKGROUND: The ultra-short-acting benzodiazepine remimazolam, approved for procedural sedation and general anesthesia, is inactivated by carboxylesterase 1 (CES1). OBJECTIVE: Remimazolam´s involvement in CES1-mediated drug-drug interactions (DDIs) was investigated. METHODS: Possible interactions of remimazolam were studied in co-exposure experiments with eleven different drugs. Further, substrates and inhibitors of CES1, identified in the literature, were evaluated for possible in-vivo inhibition using pharmacokinetic and Ki or IC50 values. Compounds with only one published inhibitory concentration and CES1 substrates lacking inhibition data were assigned conservative Ki values. RESULTS: In human liver homogenates and/or blood cells, remimazolam showed no significant inhibition of esmolol and landiolol metabolism, which, in turn, at up to 98 and 169 µM, respectively, did not inhibit remimazolam hydrolysis by human liver homogenates. In human liver S9 fractions, IC50 values ranged from 0.69 µM (simvastatin) and 57 µM (diltiazem) to > 100 µM (atorvastatin) and, for the remaining test items (bupropion, carvedilol, nelfinavir, nitrendipine, and telmisartan), they ranged from 126 to 658 µM. Remifentanil was ineffective even at 1250 µM. Guidance-conforming evaluation revealed no relevant drug-drug interactions with remimazolam via CES1. The algorithm-based predictions were consistent with human study data. Among CES1 inhibitors and substrates identified in the literature, only dapsone and rufinamide were found to be possible in-vivo inhibitors of remimazolam metabolism. CONCLUSION: Data and analyses suggest a very low potential of remimazolam for pharmacokinetic DDIs mediated by CES1. The theoretical approach and compiled data are not specific to remimazolam and, hence, applicable in the evaluation of other CES1 substrates.

Nirmatrelvir/ritonavir: real world drug-drug interaction management experience.

BACKGROUND: In the UK, a regional vertical system for delivery of COVID-19 medicines has been in place. This enabled centralization of expertise in risk stratification of patients, and in understanding and mitigating drug-drug interactions. RESEARCH DESIGN AND METHODS: We analyzed real world drug-drug interactions in adult patients referred for nirmatrelvir/ritonavir therapy across one such geographic area covering 2.2 million London citizens. RESULTS: Among 208 who received NMV/r therapy, we identified 184 potential DDIs, 8% precluded nirmatrelvir/ritonavir use, 53% required management, but 56% of these did not have documented advice to hold therapy. CONCLUSIONS: This highlights the need to maintain and develop pathways for clinical pharmacology expertise in COVID-19 management.

Advancements in physiologically based pharmacokinetic modeling for fedratinib: updating dose guidance in the presence of a dual inhibitor of CYP3A4 and CYP2C19.

PURPOSE: A physiologically based pharmacokinetic (PBPK) model for fedratinib was updated and revalidated to bridge a gap between the observed drug-drug interaction (DDI) of a single sub-efficacious dose in healthy participants and the potential DDI in patients with cancer at steady state. The study aimed to establish an appropriate dose for fedratinib in patients coadministered with dual CYP3A4 and CYP2C19 inhibitors, providing quantitative evidence to inform dosing guidance. METHODS: The original minimal PBPK model was developed using Simcyp® Simulator v17. The model was updated by substituting a single distribution rate (Qsac) with 2 separate rates (CLin/CLout) and transitioning to v20. Model parameter updates were further informed with 3 clinical studies, and 3 more studies served as independent validation data. The validated model was applied to simulate potential DDIs between fedratinib and a known dual inhibitor of CYP3A4 and CYP2C19 (fluconazole). RESULTS: Coadministration of fedratinib with fluconazole in patients was predicted to increase fedratinib exposure by < 2-fold in all simulated scenarios. For patients with cancer receiving the approved dose of fedratinib 400 mg once daily along with fluconazole 200 mg daily, the model predicted an approximate 50% increase in fedratinib exposure at steady state. CONCLUSIONS: The updated PBPK model improved description of the observed pharmacokinetics and predicted a low risk of clinically significant DDIs between fedratinib and fluconazole. The quantitative evidence serves as a primary foundation for providing dose guidance in clinical practice for the coadministration of fedratinib with dual CYP3A4 and CYP2C19 inhibitors.

Utility of Chimeric Mice with Humanized Livers for Predicting Hepatic Organic Anion - Transporting Polypeptide 1B (OATP1B) - Mediated Clinical Drug-Drug Interactions.

The influence of transporters on the pharmacokinetics of drugs is being increasingly recognized, and drug-drug interactions (DDIs) via modulation of transporters could lead to clinical adverse events. Organic anion-transporting polypeptide 1B (OATP1B) are liver specific uptake transporters in humans that can transport a broad range of substrates, including statins. It is a challenge to predict OATP1B-mediated DDIs using preclinical animal models because of species differences in substrate specificity and abundance levels of transporters. PXB-mice are chimeric mice with humanized livers that are highly repopulated with human hepatocytes and have been widely used for drug metabolism and pharmacokinetics studies in drug discovery. In the present study, we measured the exposure increases (blood AUC and Cmax) of ten OATP1B substrates in PXB-mice upon co-administration with rifampin, a potent OATP1B specific inhibitor. These data in PXB-mice were then compared with the observed DDIs between OATP1B substrates and single-dose rifampin in humans. Our findings suggest that the DDIs between OATP1B substrates and rifampin in PXB-mouse are comparable with the observed DDIs in the clinic. Since most OATP1B substrates are metabolized by CYPs and/or are substrates of P-glycoprotein (P-gp), we further validated the utility of PXB-mice to predict complex DDIs involving inhibition of OATP1B, CYPs and P-gp using CsA and gemfibrozil as perpetrators. Overall, the data support that the chimeric mice with humanized livers could be a useful tool for the prediction of hepatic OATP1B-mediated DDIs in humans. Significance Statement The ability of PXB-mouse with humanized liver to predict OATP1B-mediated drug-drug interactions (DDIs) in humans was evaluated. The plasma exposure increases of ten OATP1B substrates with rifampin, an OATP1B inhibitor, in PXB-mice have a good correlation with those observed in humans. More importantly, PXB-mice can predict complex DDIs including inhibition of OATP1B, CYPs and P-gp in humans. PXB-mice are a promising useful tool to assess OATP1B-mediated clinical DDIs.

Proton pump inhibitors decrease efficacy of palbociclib in patients with metastatic breast.

OBJECTIVES: The objective of this investigation was to assess the impact of concurrent proton pump inhibitors (PPIs) on progression-free survival (PFS) in patients with hormone receptor-positive and HER2-negative metastatic breast cancer (mBC) who received palbociclib as first-line or successives therapy. MATERIALS AND METHODS: A retrospective observational study was conducted, enrolling patients diagnosed with estrogen receptor-positive, human epidermal growth factor receptor 2-negative mBC, and eligible for palbociclib treatment. Patients were categorized as "concurrent PPIs" if they received PPIs for at least two-thirds of the palbociclib therapy duration, and as "no concurrent PPIs" if they did not receive PPIs during the course of palbociclib treatment. RESULTS: A total of 165 patients were included in the study. Among first-line patients treated with palbociclib, those using concurrent PPIs exhibited a PFS of 8.88 months, while patients using palbociclib without concurrent PPIs had a PFS of 67.81 months (p < 0.0001). In second-line or subsequent treatments, patients on palbociclib with concurrent PPIs had a PFS of 7.46 months, whereas those using palbociclib without concurrent PPIs had a PFS of 17.29 months (p = 0.122). CONCLUSION: This study demonstrates that the concurrent use of PPIs in mBC patients receiving palbociclib negatively affects PFS, particularly in the first-line setting. Nevertheless, further investigation is warranted to explore the impact of PPIs on cycle-dependent kinase 4/6 inhibitors.