Risk Of Potential Drug-drug Interactions Research Articles

Review of drug-drug interactions in patients with prostate cancer.

The objective of this review is to provide an overview of common drug-drug interactions (DDIs) associated with prostate cancer treatments and outline recommendations for managing polypharmacy. A literature search of PubMed, Embase, and CINAHL was carried out to identify pharmacokinetic and pharmacodynamic changes caused by DDIs that are relevant for prostate cancer patients, DDIs between prostate cancer therapies and co-administered medications (both prescription and over-the-counter), and measures to prevent DDIs. Medication package inserts were used to identify the impact of DDI on the prostate cancer therapy and suggested interventions. No DDIs are expected for the LHRH agonists leuprolide acetate, histrelin, goserelin, or leuprolide mesylate. However, DDIs have been reported for GnRH antagonists, anti-androgens, PARP inhibitors, and taxanes. Although there are no confirmed DDIs for sipuleucel-T to date, it is not generally recommended to use sipuleucel-T concurrently with immunosuppressive medications. Interventions to prevent DDIs include the use of software that can detect clinically significant DDIs, up-to-date medication reconciliation, the inclusion of dedicated clinical pharmacists in cancer treatment teams, and patient/caregiver education. Prostate cancer patients have a high risk of potential DDIs due to numerous new anti-cancer therapies, the increased use of treatment combinations, and the likelihood of comorbid conditions also requiring drug therapy. Drug-drug interaction screening software, up-to-date medication reconciliation, inclusion of oncology pharmacists on healthcare teams, and patient/caregiver education will aid the development of treatment plans that focus on achieving an optimal risk-benefit profile whilst reducing the risk of DDIs.

Clinical Pertinence and Determinants of Potential Drug–Drug Interactions in Chronic Kidney Disease Patients: A Cross-sectional Study

Background: Chronic kidney disease (CKD) is one of the major health issues effecting around 15% of world population, and its further complications has raised the need of polypharmacy for management. But this polypharmacy also upsurges the risk of potential drug-drug interactions (pDDIs) in CKD patients, which may further be responsible for increased morbidity and mortality. Objective: The main objective is therefore to evaluate the distribution, severity, causes, associated drug interactions, and clinical relevance of determination of pDDIs in CKD patients. Methods: Medical files of CKD patients examined at nephrology department, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Mullana, between December 2022 and May 2023 were cross-sectionally assessed for this study. Medscape drug interaction checker was used to study patient profiles for pDDIs, and suggestive measures to minimize those pDDIs were studied using DDInter to ensure better clinical decision-making and patient safety. IBM SPSS (version 24) was utilized for statistical analysis. Results: The data reveal that 74.5% of the 200 medical files being evaluated had 839 pDDIs in total, out of which nearly 78.3% of patients had moderate, 15.6% had minor, and 6.07% had serious interactions. The potential adverse outcomes of pDDIs included an irregular heartbeat, hypokalemia, central nervous system (CNS) adverse effects, hypoglycemia, and a decline in therapeutic efficacy. The prevalence of pDDIs was discovered to be substantially correlated with age ≥60 years, (odds ratio [OR] = 0.65; 95% CI = 0.4-0.9; P = 0.040), length of stay ≥10 days (OR = 4.0; 95% CI = 1.29-6.1; P = 0.016), and number of prescribed drugs ≥10 (OR = 5.5; 95% CI = 2.45-10.69; P = 0.004). Conclusion: Patients with CKD have a high incidence of pDDIs (mainly mild to moderate). Older age, duration of hospital stays, and polypharmacy all raise the risk of pDDIs. Healthcare professionals (physicians and clinical pharmacist) should use drug interaction checker software programs like Medscape and DDInter to acquire knowledge about different pDDIS and their alternative measures so that the associated adverse drug reactions (ADRs) can be controlled and rational drug combination can be prescribed for management of CKD ensuring better patient care.

The comorbidity profiles and medication issues of patients with multiple system atrophy: a systematic cross-sectional analysis

BackgroundMultiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients’ safety and management.ObjectivesTo investigate the pattern of comorbidities and aspects of drug therapy in MSA patients.MethodsCross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®.ResultsThe analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue.ConclusionsMSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients.

Potential Drug-Drug Interactions among Geriatric Patients in Medicine Department at a Tertiary Care Teaching Hospital - A Prospective Observational Study

Background Drug-drug interactions occur when therapeutic effect of one drug is altered by another drug during co-administration. These effects may result in increase or decrease in the action of either of the substances or it may cause adverse effect that is abnormally associated with either of the drugs. Data was collected from patients admitted in the Emergency Department.Aim The objective of the study was to identify evaluate and analyze the drug-drug interactions found in the prescriptions of elderly patients visiting the Medical department at a tertiary care teaching hospital.Methods This prospective observational study was undertaken in an Emergency ward for a period of six months to identify evaluate and analyze the drug-drug interactions. Ethical clearance was obtained from the Institutional Ethical Committee of SCS College of Pharmacy Harapanahalli. A total of three hundred and fifty cases were reviewed and details such as demographics past medical and medication history prescribed drugs and drug interactions were recorded.Results The data of 350 patients was included in the study. In our study a total of 405 drug-drug interactions were seen in 191 patients. The most commonly involved drugs were hydrocortisone and furosemide. Increased polypharmacy was observed in patients with co-morbid conditions leading to increased risk of potential drug-drug interactions PDDI.Conclusion Our study revealed that geriatric patients have higher risk for polypharmacy due to the presence of co-morbid conditions. Overall the incidence of PDDI was high and most interactions were pharmacodynamic in nature.nbsp

Polypharmacy and drug-drug interactions in metastatic breast cancer patients receiving cyclin-dependent kinase (CDK) 4/6 inhibitors

Introduction Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly changed the treatment strategy for patients with locally advanced or metastatic hormone receptor positive (HR+), human epidermal growth factor 2 negative (HER2) breast cancer. The purpose of the study was to determine the prevalence of drug-drug interactions (DDI) in breast cancer patients using CDK 4/6 inhibitors and the extent of DDI reflected in the clinic and to increase clinical awareness among physicians. Method The data of 115 metastatic breast cancer patients using CDK 4/6 inhibitors who were admitted to the Medical Oncology outpatient clinic between July 2021 and July 2023 were retrospectively reviewed. The Drugs.com® Drug Interaction Checker application was used for the interaction between the CDK 4/6 inhibitor and other drugs. Results Among patients included in the study, 97.3% had at least one additional drug use. We have identified a total of 170 potential DDI risks in 63.5 % of patients. Among these, 50.5% had a major potential DDI. In our study, there was a potential risk of QT prolongation in 45.2% of 170 DDI, an increase in the potential toxicity of the additional drug in 44.1%, an increase in the potential toxicity of the CDK 4/6 inhibitor in 5.3%, a decrease in the potential efficacy of the CDK 4/6 inhibitor in 2.9%, a decrease in the potential efficacy of the additional drug in 1.1%, and a serious potential infection risk in 1.1%. Most of the drug interactions were QT prolongation and increased toxicity of the additional drug. In terms of cardiovascular events, grade-2 and grade-3 QTc prolongation was found in 4.3% and 1.7% of these interactions, respectively. When evaluated in terms of CDK 4/6 inhibitor subtype, there was a potential risk of DDI at major level with Ribocilib and at moderate level with Palbociclib. Conclusion If CDK 4/6 inhibitors interact with concomitant drugs, they may cause an increase in the incidence of cardiac side effects and a decrease in the effect of the CDK 4/6 inhibitor or additional drug or an increase in toxicity. Increasing awareness of this issue will help to reduce the rates of side effects or toxicity and provide effective antitumour therapy.

A retrospective study: Can dual ART mitigate the risk of potential drug-drug interactions among PLWH under stable ART?

A retrospective study: Can dual ART mitigate the risk of potential drug-drug interactions among PLWH under stable ART?

Prevalence of potential drug-drug interactions among intensive care unit patients receiving linezolid: a cross-sectional study.

Linezolid is commonly used in intensive care units (ICU) but has the potential to interact with other drugs. This study aimed to evaluate the prevalence of potential drug-drug interactions in ICU patients receiving linezolid. Data of ICU patients receiving linezolid were extracted and included in the Hospital Prescription Analysis Program of China, and the risk of potential drug-drug interactions between concomitant drugs and linezolid was evaluated using the Lexicomp database. A total of 3,712 ICU patients from 59 hospitals were included in the analysis, and patients received an average of 17 concomitant drugs. A total of 67.9% of patients had potential drug-drug interactions. Patients receiving concomitant drugs with risk ratings of "X", "D", and "C" categories were 20.8%, 30.4%, and 35.1%, respectively. Opioids were the most frequently prescribed drug class with drug-drug interactions (DDIs) in the "X" category, whereas butorphanol, metoclopramide, and sufentanil were the most contraindicated concomitant drugs. ICU patients receiving linezolid have a high prevalence of potential drug-drug interactions, and efforts should be made to better recognize and manage this risk.

Drug-drug interactions between propofol and ART drugs: Inhibiting neuronal activity by affecting glucose metabolism.

The use of two or more drugs carries the potential risk of drug-drug interactions (DDIs), which may result in adverse reactions. Some human immunodeficiency virus (HIV)-infected patients who receive antiretroviral therapy (ART) may require general anesthesia with propofol (PRL) before undergoing surgical treatment. Both PRL and ART drugs may lead to neuronal dysfunction, which can be accompanied by energy metabolism disorders. Neurons take in glucose mainly through glucose transporter 3 (Glut3) which is specifically expressed on the cell membranes of neurons. However, to date, no study has examined whether the DDIs of PRL and ART drugs interfere with glucose metabolism and Glut3 expression in neurons. An in vitro model was constructed using the primary cultures of neurons. PRL and ART drugs (EFV, AZT, and 3TC), were added at different concentrations (low, medium, and high). The neurons were exposed to the drugs for 1, 4, 8, and 12 h. The optimal drug concentration and exposure time were selected. The cellular survival rate, glucose concentration, electrophysiology, and the expression of Glut3 were detected. There were no significant changes in the cellular survival rates of the neurons that were exposed to both PRL and ART drugs at low concentrations for 1 h. However, the survival rates of the neurons decreased significantly as the drug concentrations and durations increased. The glucose concentration of the neurons that were exposed to both PRL and the ART drugs was significantly decreased. The glucose concentration of the neurons was not affected by any individual drug. The amplitude of the action potential and the expression of Glut3 were decreased in the neurons that were exposed to both PRL and ART drugs. The main adverse reactions induced by the DDIs between PRL and the ART drugs were decreased glucose metabolism and neuronal damage, which were caused by inhibiting the expression of Glut3. More importantly, we found that decreases in glucose metabolism predated neuronal damage.

Potential risk of drug-drug interactions of ponatinib via inhibition against human UDP-glucuronosyltransferases

Ponatinib is an efficient oral tyrosine kinase inhibitor (TKI) for T315I-positive Ph + ALL and T315I-positive chronic myeloid leukemia (CML) or BCR-ABL when no other TKIs can be prescribed. In this research, we evaluated the inhibitory effects of ponatinib on human recombinant UDP-glucuronosyltransferases (UGTs) and predicted the magnitude of potential drug-drug interaction (DDI) risk of co-treatment with ponatinib and UGTs substrates by using in vitro-in vivo extrapolation (IVIVE) method. Our study presented that ponatinib showed a broad-spectrum inhibition against UGTs. Particularly, ponatinib exhibited potent inhibitory effects towards UGT1A7, UGT1A1, and UGT1A9 with IC50 values of 0.37, 0.41, and 0.89 μM, respectively, which might lead to clinically significant DDI.

Potential drug-drug interactions in hospitalized patients with COVID-19.

Most hospitalized patients with COVID-19 require complex pharmacotherapy due to underlying diseases, and polypharmacy may significantly increase the risk of drug-drug interactions (DDIs) and, in consequence, trigger adverse effects. The aim of this study was to assess the risk of potential DDIs during hospitalization in COVID-19 patients. A retrospective analysis of pharmacotherapy in 75 patients (age, Mean±SD, 63.6±14.9) with a proven diagnosis of SARS-CoV-2 infection was conducted. The analysis included drugs administered to treat comorbidities and the COVID-19 treatment. 524 moderate and 112 major interaction cases were revealed in the analyzed COVID-19 patients, and 84% of the patients were exposed to at least one major DDI. Drugs that caused the most frequently observed DDIs include macrolides, low molecular weight heparins, glucocorticosteroids, quinolones, and antihypertensive drugs. Most COVID-19 patients have comorbidities requiring polypharmacy, which increases the risk of DDIs. Therefore, additional monitoring should be considered due to potential adverse effects, drug conversion, and deprescription.

Phase 1b study of HS-10241 combined with almonertinib in pre-treated advanced non-small cell lung cancer (NSCLC) harboring EGFR mutation.

e21134 Background: MET gene amplification is one of the most frequent acquired resistance mechanisms following prior EGFR-TKI monotherapy. HS-10241, an oral and highly selective MET-TKI, may contribute to overcoming common acquired MET-based resistance mechanisms. Here, we reported the preliminary safety and efficacy data of HS-10241 with almonertinib in treatment of advanced NSCLC with EGFR mutation. Methods: This Ph1b study (NCT05430386) was composed of dose escalation part (Part 1) and dose expansion part (Part 2). In Part 1, patients (pts) with EGFR-mutated advanced NSCLC upon disease progression on EGFR-TKI received HS-10241 (BID) plus almonertinib (110 mg QD), and HS-10241 was escalated at 200 mg and 300 mg using a rolling six design. Based on the available data of Part 1, an expansion cohort was opened at HS-10241 300 mg BID with almonertinib 110mg QD to enroll pts with EGFR mutation centrally confirmed and MET-amplification detected by central FISH (MET gene copy number[GCN] ≥5 and/or MET:CEP7 signal ratio ≥2). Results: As of 16 December 2022, 10 pts in part 1, 4 pts at 200 mg and 6 pts at 300 mg HS-10241, and 35 pts in part 2 were enrolled into this study. Of these pts, 13 (28.9%) pts received previous treatment with 1st or 2nd-generation but no 3rd-generation EGFR TKI, 15 (33.3%) pts received 3rd-generation EGFR-TKI only and 15 (33.3%) pts received both 1st/2nd and 3rd-generation EGFR TKIs, whether or not they received treatment with chemotherapy. Only one dose-limiting toxicity (grade 2 Nausea with grade 2 vomiting leading to discontinuation≥14 days) was reported in the cohort with HS-10241 300 mg. The MTD was not reached. Treatment-emergent adverse events (TEAEs) occurred in 41/45 (91.1%) pts. The most common TEAEs (≥ 20%) were increased AST, increased ALT, vomiting, nausea, increased blood creatine phosphokinase, thrombocytopenia, decreased appetite, and increased GGT. Among all the pts, 22 pts with EGFR mutation regardless of the MET gene status were evaluable for efficacy, 12 of which achieved partial response (response rate 54.5%; 8 confirmed PR), and 7 had stable disease (SD). Of the 13 pts who had centrally confirmed EGFR mutation and MET-amplification (6 with GCN ≥10, and 7 with GCN ≥5 but < 10), 8 had PR (response rate 61.5%; 5 confirmed PR), and 4 had SD. Among the 8 pts achieving PR, there were 4 with GCN ≥10, and 4 with GCN ≥5 but < 10.Moreover, 9 of the 13 pts received both 1st/2nd and 3rd-generation EGFR-TKI and there were 6 PRs (response rate 66.7%;3 confirmed PR) and 2 SDs. Pharmacokinetics analysis showed low risk of potential drug-drug interactions on HS-10241 combined with almonertinib. Conclusions: HS-10241 in combination with almonertinib was well tolerated, and showed encouraging antitumor activity in treatment of advanced NSCLC with EGFR mutation and MET amplification following prior EGFR-TKI, whether MET GCN ≥10 or MET GCN ≥5 but < 10. Clinical trial information: NCT05430386 .

Drug-drug interaction potentials of tucatinib inhibition of human UDP-glucuronosyltransferases

Tucatinib is known as a tyrosine kinase inhibitor (TKI), which has been commonly approved for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer. However, there haven't been systematic study about the inhibition of tucatinib on UDP-Glucuronosyltransferases (UGTs) and the potential risk of drug-drug interactions (DDIs). In present study, we aimed to systematically investigate the inhibition of tucatinib on recombinant human UGTs and pooled human liver microsomes (HLMs), and to quantitatively evaluate its potential risk of DDIs by in vitro-in vivo extrapolation (IVIVE). Our data indicated that tucatinib exhibited extensive inhibition on recombinant UGTs. Tucatinib was a weak inhibitor of UGT1A4, 2B4 and 2B7; tucatinib possessed a strong inhibitory effect on UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B15 and UGT2B17, with IC50 values of 0.53 μM–15.50 μM. Especially, it also potently inhibited estradiol and SN-38 glucuronidation in HLMs with IC50 values of 46.83 μM and 1.33 μM. The quantitative prediction of DDIs risk indicated that the co-administration of tucatinib with drugs mainly metabolized by hepatic or intestinal UGTs (UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B15 and UGT2B17) might result in potential DDIs risk through inhibition of glucuronidation. More attention should be paid to the influence of tucatinib on UGTs in liver and intestine to avoid unnecessary clinical DDIs risk.

Inhibition of human UDP-glucuronosyltransferase enzyme by ripretinib: Implications for drug-drug interactions

Ripretinib, a tyrosine kinase inhibitor (TKI), is the first FDA approved fourth-line therapy for adults with advanced gastrointestinal stromal tumor (GIST). Studies have shown that several TKIs for treating GIST were potent inhibitors of human UDP-glucosyltransferase (UGTs) enzymes. However, whether ripretinib affects the activity of UGTs remains unclear. The aim of this study was to investigate the effects of ripretinib on major UGT isoforms, as well as to evaluate its potential drug-drug interactions (DDIs) risk caused by the inhibition of UGTs activities. The inhibitory effects and inhibition modes of ripretinib on UGTs were systematically evaluated using high-performance liquid chromatography (HPLC) and enzyme kinetic studies, respectively. Our data showed that ripretinib exhibited potent inhibition against UGT1A1, UGT1A3, UGT1A4, UGT1A7 and UGT1A8. Enzyme kinetic studies indicated that ripretinib was not only a competitive inhibitor of UGT1A1, UGT1A4 and UGT1A7, but also a noncompetitive inhibitor of UGT1A3, as well as a mixed inhibitor of UGT1A8. The prediction results of in vitro-in vivo extrapolation (IVIVE) demonstrated that ripretinib might bring the potential risk of DDIs when combined with substrates of UGT1A1, UGT1A3, UGT1A4, UGT1A7 or UGT1A8. Therefore, special attention should be paid when ripretinib is used in conjunction with other drugs metabolized by UGTs to avoid risk of DDIs in clinic.

Potential Drug-Drug Interactions in a Cardiac Center: Development of Simple Software for Pattern Identification.

Patients with cardiovascular disorders (CVD) are at higher risk for potential drug-drug interactions (pDDIs) due to complex treatment regimens. This study aimed to evaluate pDDI patterns in physicians' prescriptions in a specialized heart center using simple software. This cross-sectional study identified severe and related interactions during a 2-stage survey of experts. The data collected included age, sex, the date of admission and discharge, the length of hospital stay, drug names, inpatient wards, and the final diagnosis. The extracted drug interactions were used as a source of software knowledge. The software was designed using the SQL Server and the C # programming language. Of 24 875 patients included in the study, 14 695 (59.1%) were male. The average age was 62 years. Based on the survey of experts, only 57 pairs of severe pDDIs were identified. The designed software evaluated 185 516 prescriptions. The incidence of pDDIs was 10.5%. The average number of prescriptions per patient was 7.5. The highest frequency of pDDIs was detected in patients with lymphatic system disorders (15.0%). Aspirin with heparin (14.3%) and heparin with clopidogrel (11.7%) were the most common documented pDDIs. This study reports the prevalence of pDDIs in a cardiac center. Patients with lymphatic system disorders, male patients, and older patients were at higher risk of pDDIs. This study shows that pDDIs are common among CVD patients and highlights the need to use computer software to screen patients' prescriptions to assist in detection and prevention.

Evaluating the iatrogenic effects of polypharmacy and drug interactions in HIV-positive patients admitted to the intensive care unit: a single-center retrospective study

Background. Polypharmacy and drug interactions are of particular concern in people living with HIV/AIDS, especially those who receive antiretroviral therapy (ARVs). Polypharmacy and drug-drug interactions (DDIs) can impact the efficacy and toxicity of HIV treatment. ARVs used in HIV treatment are often prone to drug interactions if administered with other non-ARV drugs because many of them are metabolized through the cytochrome P450 system. The pharmacological management of HIV patients in the intensive care unit (ICU) is usually complex and typically involves the administration of several classes of drugs. This patient group may be at higher risk for potential DDIs due to polypharmacy in the ICU. The main objective of this study was to assess the iatrogenic effects of polypharmacy in HIV patients treated in the ICU and to describe the DDI profile between ARVs and other non-ARV medications prescribed in the ICU. Methods and materials. Between 2018 and 2020, we conducted a single-center, retrospective study evaluating the medical records of 59 HIV patients admitted to the ICU for more than 24 hours at the Infectious Disease Clinical Hospital No. 2, Moscow, Russia. We evaluated the impact of polypharmacy on renal, hepatic and haemopoietic function. The Liverpool HIV Drug Interaction database was used to identify DDIs in ART-treated HIV patients. Results. All patients received more than 5 different medications matching the definition of polypharmacy. The average number of concurrent medications prescribed was 156.713 (maximum 40, minimum 6). All drug interactions recorded were between ARVs and antibiotics: 30 cases of potential interactions in 65.5% patients who received ARV. Of such patients, 94% were exposed to at least two potential interactions. Tenofovir (TDF) and the antibiotic vancomycin underlaid the most common potential interaction (49.2%), followed by lopinavir ritonavir (LPV/RTV) and ciprofloxacin (30.3%). A significant difference in average creatinine levels was found in patients with TDF/vancomycin potential interactions (p 0.05). Conclusion. This study demonstrated that potential DDIs frequently occur in ICU patients in line with previous investigations. It is necessary to implement collaborations among clinical pharmacologists and infectious disease/HIV specialists, as well as frequent clinical and laboratory monitoring, aimed at developing effective and actionable strategies that could reduce potential DDIs in HIV patients in the ICU.

Cabozantinib Carries the Risk of Drug-Drug Interactions via Inhibition of UDPglucuronosyltransferase (UGT) 1A9.

Cabozantinib is a multiple receptor tyrosine kinases inhibitor (TKI) approved to treat progressive, metastatic medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma. Drugdrug interactions (DDIs) for cabozantinib have been identified involving the role of cytochromes P450. Although the previous study reported that cabozantinib showed a slight inhibition of UDP-glucuronosyltransferase (UGT) 1A1 at the highest concentration tested, there are no reports on the potential for UGTs-mediated-DDIs. Hence, the current study aims to address this knowledge gap. This study aimed to investigate the inhibitory effect of cabozantinib on human UGTs and to quantitatively evaluate the DDI potential via UGT inhibition. The inhibitory effects of cabozantinib on UGTs were determined by measuring the formation rates for 4- methylumbelliferone (4-MU) glucuronide and trifluoperazine N-glucuronide using recombinant human UGT isoforms in the absence or presence of cabozantinib. Inhibition kinetic studies were conducted to determine the type of inhibition of cabozantinib on UGTs and the corresponding inhibition constant (Ki) value. In vitro-in vivo extrapolation (IVIVE) was further employed to predict the potential risk of DDI in vivo. Cabozantinib displayed potent inhibition of UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15. Cabozantinib exhibited noncompetitive inhibition towards UGT1A1 and 1A3 and inhibition towards UGT1A7 and 1A9. The Ki,u values (mean ± standard deviation) were calculated to be 2.15±0.11 μM, 0.83±0.05 μM, 0.75±0.04 μM and 0.18 ± 0.10 μM for UGT1A1, 1A3, 1A7 and 1A9, respectively. Co-administration of cabozantinib at the clinically approved dose of 60 mg/day or 140 mg/day may result in approximately a 26% to 60% increase in the systemic exposure of drugs predominantly cleared by UGT1A9, implying a high risk of DDIs. Cabozantinib has the potential to cause DDIs via the inhibition of UGT1A9; therefore, additional attention should be paid to the safety of the combined use of cabozantinib and drugs metabolized by UGT1A9.

In vitro effects of opicapone on activity of human UDP-glucuronosyltransferases isoforms

Catechol-O-methyltransferase (COMT) inhibitors are widely used as an add-on treatment to levodopa in adults with Parkinson’s disease. It has been evidenced that the second-generation COMT inhibitors entacapone and tolcapone are potent inhibitors on human UDP-glucosyltransferases (UGTs), while the effect of the third-generation COMT inhibitor opicapone on human UGTs activities is unclear. The purpose of this study is to systemically investigate the effects of opicapone on human UGTs activities, and also to assess the potential risk of drug-drug interactions (DDIs) associated with opicapone. Our results indicated that opicapone is a broad-spectrum inhibitor of UGTs. Particularly, opicapone exhibited potent inhibition against UGT1A1, 1A7, 1A8, 1A9, and 1A10, with a range of inhibition constant Ki values of 1.31–10.58 µM. Furthermore, the DDI risk was quantitatively predicted by using the in vitro-in vivo extrapolation (IVIVE). The prediction suggested that co-administration of opicapone at 25 mg/day or 50 mg/day with drugs primarily cleared by hepatic UGT1A9 or intestinal UGT1A1, 1A7, 1A8, 1A9, or 1A10 might result in potential DDI via inhibition of intestinal or hepatic UGTs.

Association of polypharmacy and potential drug-drug interactions with adverse outcomes in older adults with advanced cancer receiving systemic treatment.

12053 Background: Polypharmacy (PP) is common in older adults starting cancer treatment and associated with increased risk of potential drug-drug interactions (PDI). PP and PDI may affect treatment-related outcomes in older patients. This study evaluates the association of PP and PDI with systemic treatment adverse outcomes in older adults with advanced cancer. Methods: This secondary analysis of prospectively collected data from the GAP 70+ Trial (NCT02054741; PI: Mohile) enrolled patients aged 70+ with advanced (i.e. incurable) cancer; had ≥1 geriatric assessment domain impairment; and planned to start a new chemotherapy regimen or another regimen with high risk of toxicity. PP was assessed prior to initiation of treatment and defined as concurrent use of ≥8 medications (meds). PDI among all drugs were reviewed prior to initiation of treatment using Lexi-Interact® Online with category D and X considered “major PDI”. Study outcomes were assessed within 3 months of treatment initiation and included: 1) total number of Grade ≥2 toxicities according to National Cancer Institute Common Toxicity Criteria; 2) total number of Grade ≥3 toxicities; and 3) early treatment discontinuation due to toxicity. Multivariable linear and logistic regression models were used to examine the association of PP and PDI with treatment adverse-outcomes adjusted for age, gender, cancer type, comorbidity, physical function, social support, and study arm. Results: Among 718 participants, the mean age was 77 (range 70-96); 43% were females; and 57% had lung or gastrointestinal cancers. The median number of meds was 5 (range 0-24); 28% received ≥8 concurrent meds; and 25% had ≥1 major PDI. The mean number of Grade ≥2 toxicities for patients with PP was 9.8 versus 7.7 in patients without PP (adjusted β=1.87, standard error [SE]=0.71, P<0.01). The mean number of Grade ≥3 toxicities for patients with PP was 2.9 versus 2.2 in patients without PP (adjusted β=0.59, SE=0.29, P=0.04). Patients with ≥1 major PDI had 59% higher odds of early treatment discontinuation versus those without major PDI (adjusted odds ratio 1.59, 95% confidence interval=1.03-2.46, P=0.03). There was no significant association between PP and early treatment discontinuation. Major PDI were not significantly associated with toxicity (Ps>0.05). Conclusions: In a cohort of vulnerable older adults with advanced cancer, PP and PDI are associated with increased risk of systemic treatment adverse outcomes. Providing meaningful screening and interventional tools to optimize medication use may improve treatment outcomes in these patients. Funding:UG1CA18996, U01CA233167.

Potential drug-drug interactions between antiretroviral drugs and comedications, including dietary supplements, among people living with HIV: A clinical survey.

Age-related comorbidities, polypharmacy and thereby the risk of potential drug-drug interactions (PDDIs) among people living with HIV (PLWH) have increased over the years. We estimated the prevalence of comedications, including dietary supplements, and evaluated PDDIs among PLWH receiving antiretroviral therapy (ART) in Denmark in an outpatient setting. Information on prescription medication, over-the-counter medication and dietary supplements was obtained from adult PLWH receiving ART attending two outpatient clinics in Denmark. The PDDIs were identified using the University of Liverpool's drug interaction database. Associations between PDDIs and relevant variables were compared using logistic regression models. A total of 337 PLWH receiving ART with a median age of 53 years (interquartile range: 45-61) were included; 77% were male and 96% had a HIV-RNA viral load < 50 copies/mL. Twenty-six per cent of participants received five or more comedications and 56% consumed dietary supplements. Co-administration of drugs requiring dose adjustment or monitoring was identified in the medication lists of 52% of participants, and 4.5% were on drugs that should not be co-administered. Male sex [odds ratio (OR) = 1.9, 95% confidence interval (CI): 1.0-3.4], being on a protease inhibitor (OR=4.3, 95% CI: 1.9-9.7), receiving five or more comedications (OR=3.3, 95% CI: 1.5-7.2), taking over-the-counter medications (OR=1.9, 95% CI: 1.1-3.3) and dietary supplements (OR=2.0, 95% CI: 1.2-3.3) were independent predictors of PDDIs. Potential drug-drug interactions were common among our study population Our study confirms that polypharmacy and being on a protease inhibitor-based regimen increase the risk of PDDIs considerably and highlights the importance of questioning PLWH about dietary supplement intake.

Analysis of inappropriate medication use and drug interaction in older people visiting tertiary care center of eastern Nepal

Background: Medication use in older people has been increasing as the incidence of chronic diseases increases worldwide. Use of more medicines may increase the chance of prescribing potentially inappropriate medications (PIMs) and may increases the risk of potential drug-drug interactions (pDDIs). The objective of this study was to assess PIMs and pDDIs to improve the rational use of medicationsMethods: In this study data from the older people were obtained from patient visiting medicine, OPD, BPKIHS, Dharan. Demographic and medications information were collected. PIM and pDDIs were evaluated from medication data using the Beer’s criteria for potentially inappropriate medication use in older adults, 2015 and lexicomp application respectively.Results: Among 550 patients 50.9% patients were male. Common diagnosis was systemic hypertension 335 (64.5%) followed by type 2 diabetes mellitus 276 (50.18%). The most commonly prescribed drug was metformin (215) followed by amlodipine (205), atorvastatin (176), losartan (158), glimepiride (113) and aspirin (100). One or more fixed drug combination was present in 295 prescriptions. One or more PIM were present in 29 (5.3%) prescriptions. Commonly prescribed PIM was prazosin (11) followed by nitrofurantoin (5). There were total of 753 cases of pDDIs, with 116 (15.40%) cases of risk categories X and D.Conclusions: Our findings demonstrated PIM use were relatively less. However, pDDIs were common in older people suggesting that optimal medication use and further similar studies in larger scale are necessary in this population.