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.

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.

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.

A descriptive analysis of drug-drug interactions and corresponding adverse drug reactions in multimorbid older inpatients: findings from the SENATOR trial.

PURPOSE: Drug-drug interactions (DDIs) are prevalent among multimorbid and polymedicated older adults and can increase the risk of adverse drug reactions (ADRs), hospital admissions, and mortality. This study describes the incidence and prevalence of 66 clinically relevant DDIs and analyses the occurrence of 12 corresponding predefined ADRs in older inpatients enrolled in the SENATOR trial. METHODS: The sub-study of the SENATOR trial that involved 1537 multimorbid older inpatients, recruited from 2016 to 2018 in six academic teaching hospitals in Belgium, Iceland, Ireland, Italy, Scotland, and Spain respectively, and analysed 66 potentially clinically significant DDIs. Descriptive analysis determined DDI and corresponding ADR prevalence/incidence. RESULTS: At baseline (median age: 78 [72, 84], 52.8% male), the prevalence of patients with DDIs was high (50.9%), increased during hospitalisation (55.2%) and reduced to 49.7% after 12 weeks. The most common DDIs were: ≥ 2 potassium reducing drugs (17.1%), ≥ 3 centrally acting drugs (9.0%), and SSRI + loop/thiazide diuretic (7.2%). Of all participants, one-third experienced a prevalent (36.6%)/incident (35.8%) ADR. Major serum electrolyte disturbance had the highest incidence (10.7%)/prevalence (11.5%). Incident ADRs were more common in patients with DDIs (p = 0.013). A higher prevalence of new onset falls (p = 0.013), major constipation (p = 0.004), and major serum electrolyte disturbances (p = 0.006) was observed in patients with related and thus potentially causal DDIs. CONCLUSIONS: Clinicians should, be aware of DDIs and the involved drug classes that can lead to an increased rate of ADRs in older multimorbid inpatients. Regularly reevaluating the appropriateness of the frequently prescribed drug classes and initiating judicious deprescribing is recommended.

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.

Exploring Synthesis Strategies and Interactions between MOFs and Drugs for Controlled Drug Loading and Release, Characterizing Interactions Through Advanced Techniques.

This study explores various aspects of Metal-Organic Frameworks (MOFs), focusing on synthesis techniques to adjust pore size and key ligands and metals for crafting carrier MOFs. It investigates MOF-drug interactions, including hydrogen bonding, van der Waals, and electrostatic interactions, along with kinetic studies. The multifaceted applications of MOFs in drug delivery systems are elucidated. The morphology and structure of MOFs are intricately linked to synthesis methodology, impacting attributes like crystallinity, porosity, and surface area. Hydrothermal synthesis yields MOFs with high crystallinity, suitable for catalytic applications, while solvothermal synthesis generates MOFs with increased porosity, ideal for gas and liquid adsorption. Understanding MOF-drug interactions is crucial for optimizing drug delivery, affecting charge capacity, stability, and therapeutic efficacy. Kinetic studies determine drug release rates and uniformity, vital for controlled drug delivery. Overall, comprehending drug-MOF interactions and kinetics is essential for developing effective and controllable drug delivery systems.

Interactions of bosutinib with drug transporters: In vitro and In vivo inhibition of organic cation transporter 2, multidrug and toxin extrusion protein 1, and breast cancer resistance protein by bosutinib.

Bosutinib has been approved for use in patients with chronic myeloid leukemia. Information regarding the effects of bosutinib on clinically important drug transporters is limited, particularly regarding its inhibitory potency on transporters and in vivo effects. Therefore, we conducted a study investigating the in vitro and in vivo effects of bosutinib on drug transporters. Bosutinib showed moderate or strong inhibitory effects on organic cation transporter 2, multidrug and toxin extrusion protein 1, and breast cancer resistance protein with IC50 values of 0.0894, 0.598, and 10.8 µM, respectively. In vivo experiments in rats showed that bosutinib significantly inhibited organic cation transporter 2 and multidrug and toxin extrusion protein 1, leading to a marked reduction in the renal clearance of metformin and an increase in systemic exposure to metformin. Bosutinib increased systemic exposure to sulfasalazine, a probe substrate of breast cancer resistance protein, by 75 % in rats, highlighting its potential to significantly affect intestinal drug efflux. These quantitative changes suggest that bosutinib may alter the in vivo pharmacokinetics of drugs that are substrates of these transporters, potentially leading to increased drug exposure and enhanced or unexpected pharmacological effects.

Roles of Individual Human Cytochrome P450 Enzymes in Drug Metabolism.

Our knowledge of the roles of individual cytochrome P450 (P450, CYP) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" of metabolism reactions with new drug candidates. Endogenous biomarkers are being used for non-invasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating inter-species differences in drug metabolism, particularly in the context of "metabolism in safety testing" (MIST) regulatory issues ("disproportionate (human) metabolites"). Significance Statement Cytochrome P450 enzymes are the major catalysts involved in drug metabolism. The characterization of their individual roles has major implications in drug development and clinical practice.

Assessing knowledge and awareness of Food and Drug Interactions among nutrition sciences students: Implications for education and clinical practice.

BACKGROUND: Chronic diseases and polymedication increase the risk of food-drug interactions (FDIs) among the population, negatively impacting health. Nutritionists, as responsible for dietary planning, have a key role in preventing these events. AIM: To assess the knowledge about FDIs among a sample of Nutrition Sciences Bachelor students. METHODS: A descriptive cross-sectional observational study was conducted, involving 44 students from the 3rd and 4th academic years of different Portuguese universities during the 2023/2024 academic year. Participants completed a self-reported questionnaire, covering general and specific FDIs knowledge, academic background, and perceptions regarding FDIs importance and training adequacy. RESULTS: Results revealed a general lack of FDIs knowledge among participants, particularly in identifying specific interactions and appropriate dietary management. While half of the students reported exposure to a subject dedicated to FDIs, only 18.18% considered the knowledge acquired sufficient. Nearly all participants (93.18%) expressed the need for further training in FDIs during their undergraduate course. Furthermore, none of the participants had received additional training or attended workshops on FDIs. Specifically, participants struggled to identify appropriate dietary choices in conjunction with certain medications. Moreover, only a minority of participants demonstrated awareness of the ideal timing for medication intake relative to food consumption. Despite these knowledge gaps, participants recognized the importance of FDIs knowledge for future clinical practice. CONCLUSION: Bridging these knowledge gaps through targeted educational interventions and interdisciplinary collaboration is essential to ensure future nutrition professionals are equipped to address the complex challenges posed by FDIs in professional practice.

Pharmacotherapy assessment and adverse drug reactions in older patients admitted to intensive care.

INTRODUCTION: Older patients are more susceptible to medication use, and physiological changes resulting from aging and organic dysfunctions presented by critically ill patients may alter the pharmacokinetic or pharmacodynamic behavior. Thus, critically ill older people present greater vulnerability to the occurrence of pharmacotherapeutic problems. OBJECTIVE: To evaluate pharmacotherapy and the development of potential adverse drug reactions (ADRs) in older patients admitted to an intensive care unit (ICU). METHOD: A cohort study was conducted in an ICU for adults of a Brazilian University Hospital during a 12-month period. The patients' pharmacotherapy was evaluated daily, considering the occurrence of ADRs and drug-drug interactions (DDIs), the use of potentially inappropriate medications (PIMs) for older people, and the pharmacotherapy anticholinergic burden (ACB). A trigger tool was used for active search of ADRs, with subsequent causality evaluation. PIM use was evaluated by means of the Beers criteria and the STOPP/START criteria. The ABC scale was employed to estimate ACB. The Micromedex® and Drugs.com® medication databases were employed to evaluate the DDIs. RESULTS: The sample of this study consisted of 41 patients, with a mean age of 66.8 years old (±5.2). The 22 triggers used assisted in identifying 15 potential ADRs, and 26.8% of the patients developed them. The mean estimated ACB score was 3.0 (±1.8), and the patients used 3.1 (±1.4) and 3.3 (±1.6) PIMs according to the Beers and the STOPP criteria, respectively. A total of 672 DDIs were identified, with a mean of 16.8 (±9.5) DDIs/patient during ICU hospitalization. Our findings show an association between occurrence of ADRs in the ICU and polypharmacy (p=.03) and DDIs (p=.007), corroborating efforts for rational medication use as a preventive strategy. CONCLUSIONS: Using tools to evaluate the pharmacotherapy for older people in intensive care can assist in the recognition and prevention of pharmacotherapeutic problems, with emphasis on the identification of ADRs through the observation of triggers and subsequent causality analysis.

Treatment of bipolar depression: clinical practice vs. adherence to guidelines-data from a Bavarian drug surveillance project.

Objectives: Pharmacotherapy of bipolar depression (BPD) is confronted with major clinical challenges, like limited evidence-based treatment options, regular cases of treatment resistance, and risk of treatment-emergent affective switches. Medical guidelines can support practitioners to make decisions based on current scientific evidence. The objective of this study is to evaluate to what extent recommendations of the 2019 German S3 guidelines "Diagnosis and Treatment of Bipolar Disorders" are reflected in clinical practice in inpatient treatment. Methods: We conducted a descriptive analysis of prescription numbers in 2,627 patients with BPD in a naturalistic inpatient setting analyzing data from the ongoing Bavarian multicenter drug safety project Pharmaco-Epidemiology and Vigilance (Pharmako-EpiVig) from the years 2014-2022. Results: Of the patients, 38% were not administered any drug explicitly recommended for treatment of BPD, that is, quetiapine, lamotrigine, carbamazepine, or olanzapine. Only 6% of the patients received monotherapy with one of those drugs. Of the patients, 34% were administered ≥4 psychotropic drugs simultaneously. Patients received 912 different therapy regimens of mono or combination therapy with mood stabilizers (MS), atypical antipsychotics (AAP), and antidepressants. Of the patients, 72% received an antidepressant and 6% without concomitant prescription of an AAP or MS. Prescription rates of venlafaxine (21% to 14%) and tricyclic antidepressants (9% to 6%) decreased significantly from the first (2014-2016) to the last (2020-2022) observed time period. Of the patients, 60% received an MS. Prescription rate of valproate (22% to 14%) decreased significantly, while lithium prescription increased significantly (29% to 35%). Of the patients, 71% were administered an AAP. Quetiapine was the most prescribed drug overall (43%). Only two patients were administered a combination of olanzapine and fluoxetine. Conclusion: Our results demonstrate a substantial gap between guideline recommendations and current clinical practice. The remarkable heterogeneity in treatment regimens, with no discernible dominant treatment approach, is in part a reflection of the complexity of bipolar disorder but also substantiates the need of comprehensive recommendations regarding combination therapies. Increase in lithium prescription is an encouraging development due to its unique efficacy in maintenance treatment. To improve the quality of clinical practice guideline implementation, more randomized controlled trials should be conducted in the future to prospectively investigate different implementation strategies.

Estimation of CDK inhibitors by RP-HPLC: application for pharmacokinetic interactions studies with PPIs.

Background: The study investigated pharmacokinetic interactions between palbociclib and ribociclib with proton pump inhibitors (PPIs) using the reverse-phase high-performance liquid chromatography (RP-HPLC) method. Methods: Developed RP-HPLC method quantified palbociclib and ribociclib in biological matrices. In vitro metabolic stability assays and in vivo studies in rats evaluated effect of omeprazole and esomeprazole on pharmacokinetics of palbociclib and ribociclib. Results: The RP-HPLC method was sensitive, accurate and linear. Esomeprazole and omeprazole decreased metabolic clearance of palbociclib and ribociclib by several folds. In vivo, esomeprazole elevated Cmax of palbociclib and ribociclib by 90.1% and 86.4%, whereas omeprazole reduced it by 32.0% and 16.8%, respectively. Conclusion: The RP-HPLC method was used to analyze in vitro and in vivo samples. Long-term treatment with PPIs affects pharmacokinetics of palbociclib and ribociclib, necessitating optimal chemotherapy regimen.

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Managing Cluster Headache in Patients with Medical, Psychiatric, and Surgical Comorbidities.

PURPOSE OF REVIEW: What should a provider know about medications and other treatments in patients with cluster headache who have medical, psychiatric, and surgical comorbidities? What conversations should providers have with patients about living with and managing cluster headache? RECENT FINDINGS: While the number of treatments used in cluster headache is relatively small, numerous considerations were identified related to managing patients with comorbidities. Many of these touch on cardiac, cardiovascular, and cerebrovascular health, but full histories are needed to guide safe and effective treatment. Both older and newer treatments may be contraindicated in certain patients with cluster headache or should be considered carefully. In addition to incorporating medical, psychiatric, and surgical histories in the management plan, collaboration with other providers may be beneficial. Providers should also inquire about patient practices and discuss participation in clinical trials that might be a good fit for the individual.

Potentially Inappropriate Medication: A Pilot Study in Institutionalized Older Adults.

Institutionalized older adults often face complex medication regimens, increasing their risk of adverse drug events due to polypharmacy, overprescribing, medication interactions, or the use of Potentially Inappropriate Medications (PIM). However, data on medication use and associated risks in this population remain scarce. This pilot study aimed to characterize the sociodemographic, clinical and pharmacotherapeutic profiles, and the use of PIM among institutionalized elders residing in Residential Structures for Elderly People (ERPI) in the Faro municipality, located in the Portuguese region of the Algarve. We conducted a cross-sectional study in a non-randomized sample of 96 participants (mean age: 86.6 ± 7.86 years) where trained researchers reviewed medication profiles and identified potentially inappropriate medications using the EU(7)-PIM list. Over 90% of participants exhibited polypharmacy (≥5 medications), with an average of 9.1 ± 4.15 medications per person. About 92% had potential drug interactions, including major and moderate interactions. More than 86% used at least one potentially inappropriate medication, most commonly central nervous system drugs. This pilot study demonstrates that institutionalized older adults may be at high risk of potential medication-related problems. Implementing comprehensive medication review programs and promoting adapted prescribing practices are crucial to optimize medication use and improve the well-being of this vulnerable population.

Population pharmacokinetics of rifabutin among HIV/TB co-infected children on lopinavir/ritonavir-based antiretroviral therapy.

In adults requiring protease inhibitor (PI)-based antiretroviral therapy (ART), replacing rifampicin with rifabutin is a preferred option, but there is lack of evidence to guide rifabutin dosing in children, especially with PIs. We aimed to characterize the population pharmacokinetics of rifabutin and 25-O-desacetyl rifabutin (des-rifabutin) in children and optimize its dose. We included children from three age cohorts: (i) <1-year-old cohort and (ii) 1- to 3-year-old cohort, who were ART naïve and received 15- to 20-mg/kg/day rifabutin for 2 weeks followed by lopinavir/ritonavir (LPV/r)-based ART with 5.0- or 2.5 mg/kg/day rifabutin, respectively, while the (iii) >3-year-old cohort was ART-experienced and received 2.5-mg/kg/day rifabutin with LPV/r-based ART. Non-linear mixed-effects modeling was used to interpret the data. Monte Carlo simulations were performed to evaluate the study doses and optimize dosing using harmonized weight bands. Twenty-eight children were included, with a median age of 10 (range 0.67-15.0) years, a median weight of 11 (range 4.5-45) kg, and a median weight-for-age z score of -3.33 (range -5.15 to -1.32). A two-compartment disposition model, scaled allometrically by weight, was developed for rifabutin and des-rifabutin. LPV/r increased rifabutin bioavailability by 158% (95% confidence interval: 93.2%-246.0%) and reduced des-rifabutin clearance by 76.6% (74.4%-78.3%). Severely underweight children showed 26% (17.9%-33.7%) lower bioavailability. Compared to adult exposures, simulations resulted in higher median steady-state rifabutin and des-rifabutin exposures in 6-20 kg during tuberculosis-only treatment with 20 mg/kg/day. During LPV/r co-treatment, the 2.5-mg/kg/day dose achieved similar exposures to adults, while the 5-mg/kg/day dose resulted in higher exposures in children >7 kg. All study doses maintained a median Cmax of <900 µg/L. The suggested weight-band dosing matches adult exposures consistently across weights and simplifies dosing.

Drug-drug interactions and synergy: from pharmacological models to clinical application.

This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions. Key concepts such as concentration-response curves, additive effects, and predictive models are discussed in detail, emphasizing the need for accurate assessment methods throughout translational drug development. While various mathematical models exist for synergy analysis, selecting the appropriate model and software tools remains a challenge, necessitating careful consideration of experimental design and data interpretation. Furthermore, this review addresses practical considerations in synergy assessment, including preclinical and clinical approaches, mechanism of action, and statistical analysis. Optimizing synergy requires attention to concentration/dose ratios, target site localization, and timing of drug administration, ensuring that the benefits of combination therapy detected at bench-side are translatable into clinical practice. Overall, the review advocates for a systematic approach to synergy assessment, incorporating robust statistical analysis, effective and simplified predictive models, and collaborative efforts across pivotal sectors such as academic institutions, pharmaceutical companies, and regulatory agencies. By overcoming critical challenges and maximizing therapeutic potential, effective synergy assessment in drug development holds promise for advancing patient care. Significance Statement Combining drugs with different mechanisms of action for synergistic interactions optimizes treatment efficacy and safety. Accurate interpretation of synergy requires the identification of the expected additive effect. Despite innovative models to predict the additive effect, consensus in drug interaction research is lacking, hindering the bench-to-bedside development of combination therapies. Collaboration among science, industry, and regulation is crucial for advancing combination therapy development, ensuring rigorous application of predictive models in clinical settings.

When Medications Backfire: A Case Report of Rifaximin-Induced Rhabdomyolysis in a Kidney Transplant Patient.

Rhabdomyolysis involves significant skeletal muscle injury and destruction, which can be triggered by trauma, intense physical activity, heat, prolonged immobility, certain medications, and endocrine disorders. Rhabdomyolysis in renal transplants can be more complicated, and the prognosis is not well known, especially in the context of coexisting rejection. We present a case of rifampicin-induced rhabdomyolysis with superimposed acute cellular rejection in a kidney transplant patient.