Significant Drug Interactions Research Articles

Combined oral contraceptives as victims of drug interactions.

Combined oral contraceptives (COCs) are widely used in women of reproductive age in the United States. Metabolism plays an important role in the elimination of estrogens and progestins contained in COCs. It is unavoidable that a woman using COCs may need to take another drug to treat a disease. If the concurrently used drug induces enzymes responsible for the metabolism of progestins and/or estrogens, unintended pregnancy or irregular bleeding may occur. If the concurrent drug inhibits the metabolism of these exogenous hormones, there may be an increased safety risk such as thrombosis. Therefore, for an investigational drug intended to be used in women with reproductive potential, evaluating its effects on the pharmacokinetics of COCs is important to determine if additional labeling is necessary for managing drug-drug interactions between the concomitant product and the COCs. It is challenging to determine when this clinical drug interaction study is needed, whether an observed exposure change of progestin/estrogen is clinically meaningful, and if the results of a clinical drug interaction study with one COC can predict exposure changes of unstudied COCs to inform labeling. In this review, we summarize the current understanding of metabolic pathways of estrogens and progestins contained in commonly used COCs, known interactions of these COCs as victim drugs, and discuss possible mechanisms of interactions for unexpected results. We also discuss recent advances, knowledge gaps, and future perspectives on this important topic. The review will enhance the understanding of DDIs with COCs and improve the safe and effective use of COCs. Significance Statement This minireview provides an overview of the metabolic pathways of ethinyl estradiol (EE) and progestins contained in commonly used COCs and significant drug interactions of these COCs as victims. It also discusses recent advances, knowledge gaps, and future perspectives and provides insights on potential mechanisms for unexpected results of clinical drug interaction studies of COCs. This minireview will help the reader understand considerations when evaluating the drug interaction potential with COCs for drugs that are expected to be used concurrently.

Abstract PD8-01: PantoCIN: Pantoprazole’s effectiveness as prophylaxis against delayed Chemotherapy-Induced Nausea and Vomiting (CINV) in patients receiving adjuvant or neoadjuvant breast cancer chemotherapy

Abstract Background: Rates of delayed CINV remain high at over 50% following adjuvant chemotherapy for breast cancer, despite the use of multiple antiemetics. Delayed CINV is complex, distressing to patients and it’s incidence is underestimated by physicians. Anti-emetics used with early breast cancer chemotherapy are often directed against acute rather than delayed CINV. Chemotherapy is virtually eliminated from the circulation prior to the delayed phase (24-120 hours post-chemotherapy), suggesting the etiologies for acute and delayed CINV may differ. Chemotherapy and steroids can alter the gastric environment and acid secretion, while chemotherapy can cause gastroesophageal mucositis. We hypothesized that the altered gastric environment, combined with disrupted gastroesophageal mucosa, could contribute to delayed nausea in a proportion of patients. Anecdotal experience suggested proton pump inhibitors, such as Pantoprazole, reduced symptoms in this setting. Methods: This study incorporated a double-blinded crossover design to determine whether Pantoprazole would reduce the incidence of delayed CINV in patients receiving adjuvant, or neoadjuvant breast cancer chemotherapy. Patients were randomized to either pantoprazole or placebo from Day 1-5 after cycle 1, changing to the other intervention for cycle 2. CINV symptoms during the delayed phase were assessed using the Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool and recorded in real time by patients using the PantoCIN ePRO application. With 160 patients, this approach had an 80% power to detect a statistically significant effect (one-sided α (type 1) error of 0.025) of Pantoprazole, if the true effect of Pantoprazole is a 10% reduction in the rates of any delayed CINV compared to placebo. The primary endpoint was the proportion of patients with complete absence of both nausea and vomiting during days 2-5, with severity of CINV and patient preference for intervention described as secondary endpoints. Results: 160 patients were recruited between June 2019 and October 2021, from 10 different cancer centers in New Zealand. Primary statistical analysis has shown a significant reduction in absolute CINV with pantoprazole as the primary end point, with incidence of any CINV symptoms reducing from 61.0% to 49.6% (OR=1.8, 95% confidence interval (1.0 to 3.3); p-value=0.04), in patients with full data. There was also a clear preference for patients to prefer the blinded pantoprazole arm of the 2 cycles of treatment under study, with the proportion of participants who preferred pantoprazole to placebo being 49% and the proportion who preferred placebo to pantoprazole was 25.2%, (difference in proportions 23.8% and 95% confidence interval 12.4 to 35.2; p=0.0017). Conclusion: CINV is a common and distressing complication of early breast cancer chemotherapy, which persists despite the use of a range of current antiemetics. Pantoprazole is a cheap, well-tolerated agent without significant drug interactions, which clearly ameliorates this symptom in a significant proportion of patients and should be considered as a standard prophylactic intervention. Citation Format: Navin Wewala, Katrina Sharples, Yujin Kim, Sarah Benge, Robert Cartwright, Louise Clement, Ying Huang, Richard Isaacs. PantoCIN: Pantoprazole’s effectiveness as prophylaxis against delayed Chemotherapy-Induced Nausea and Vomiting (CINV) in patients receiving adjuvant or neoadjuvant breast cancer chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD8-01.

Abstract P3-07-15: Preliminary data from a Phase 1b dose escalation study of OP-1250, an oral CERAN, in combination with palbociclib in patients with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer

Abstract Background: OP-1250 is a small molecule oral complete estrogen receptor antagonist (CERAN) that binds the ligand binding domain of the ER and completely blocks ER-driven transcriptional activity. CDK4/6 inhibitors in combination with endocrine therapy have improved progression free survival and overall survival for patients (pts) with metastatic breast cancer (MBC) in the first- and second-line settings. However, most patients will progress and newer combinations such as with OP-1250 may provide improved clinical outcome. OP-1250 potently inactivates both wild-type ER and mutant forms of ER. The latter confers ligand independent activity and is a mechanism of resistance to standard of care endocrine therapies. In preclinical studies, OP-1250 in combination with palbociclib demonstrated synergistic activity in models of wild-type ER and those containing ESR1 activating mutations, and in models of brain metastasis. A Phase 1/2 monotherapy study of OP-1250 is ongoing in MBC subjects who have received 1 or more prior endocrine therapies (NCT04505826). Monotherapy is well tolerated and the recommended phase 2 dose is 120 mg QD. The aim of this combination trial is to define the maximum tolerated dose (MTD), safety, tolerability, and pharmacokinetics (PK) of OP-1250 in combination with palbociclib. Methods: Eligibility criteria include pts with MBC or locally advanced breast cancer who have received no more than 1 prior line of endocrine therapy (prior CDK4/6 inhibitors and one line of chemotherapy are permitted) and measurable or non-measurable disease. Using a 3+3 design, cohorts are sequentially enrolled, and pts receive escalating doses of OP-1250 orally QD continuously in combination with 125 mg of palbociclib orally for 21 of 28 days. Pts are evaluable for dose limiting toxicities (DLTs) if >75% of both treatments were administered within the first 28-day treatment cycle. Blood is collected for PK on cycle 1 days 1, 2 and cycle 2 days 15, 16 for OP-1250 and cycle 1 day 15 for palbociclib. PK profiles, exposure parameters, and drug-drug interactions (DDIs) are assessed. Pts are monitored for adverse events (AE) and tumor assessments (RECIST 1.1) are conducted every two cycles. Results: As of July 7, 2022, 9 pts were evaluable for DLTs after 28 days of treatment in dose levels 30 mg, 60 mg, and 90 mg of OP-1250 in combination with palbociclib. No DLTs occurred at any of the dose levels. As of May 13, 2022, of the 7 pt safety data set, the most common Grade 1/2 treatment emergent adverse events (TEAE), which occurred in 2 patients, were nausea, gastroesophageal reflux, vomiting, and fatigue. Grade 3 neutropenia occurred in 4 pts and all were attributed to palbociclib by the investigator. No Grade 4 events were observed. OP-1250 was highly bioavailable and showed dose proportional exposure in combination with palbociclib. The single and multiple dose exposure of OP-1250 was consistent with that observed in the monotherapy study, indicating an absence of effect of palbociclib on OP-1250 PK. 90 mg steady-state evaluation is ongoing. Palbociclib concentrations at steady state did not demonstrate a meaningful difference from published exposure parameters for the three dose levels evaluated, indicating an absence of DDI. Conclusions: In the first three cohorts of OP-1250 and palbociclib, the combination was well tolerated and no DLTs occurred. There were no clinically significant DDIs observed between OP-1250 and palbociclib at the doses evaluated and exposure of each drug was consistent with observed monotherapy exposure levels. Dose escalation of OP-1250 continues to 120 mg, to be followed by dose expansion. Updated data will be presented. (NCT05266105) Citation Format: Arlene Chan, Daphne Day, Rina Hui, Nicole McCarthy, Rosalind Wilson, Demiana Faltaos, Morena Shaw, Caitlin Murphy. Preliminary data from a Phase 1b dose escalation study of OP-1250, an oral CERAN, in combination with palbociclib in patients with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-15.

Alliance A031902 (CASPAR): A randomized phase (ph) 3 trial of enzalutamide with rucaparib/placebo in first-line metastatic castration-resistant prostate cancer (mCRPC).

TPS277 Background: Despite a growing number of treatment options for first-line mCRPC, approximately 40% of patients (pts) have radiographic progression within the first year. Co-inhibition of androgen receptor (AR) and PARP is a promising therapeutic strategy that leverages synthetic lethality induced by impaired double-strand DNA repair. Two phase III studies have shown improvement in radiographic progression-free survival (rPFS) in HRR-mutant pts with abiraterone + PARPi combinations vs abiraterone alone. However, the results in HRR-wild type pts are conflicting, with only one of the studies demonstrating a benefit with the abiraterone + PARPi combination. ENZ + RUCA has shown an acceptable safety profile & no significant drug-drug interactions (S-DDI) in a phase 1b trial. This allows its evaluation in mCRPC. Methods: CASPAR (A031902) is a phase 3 study in which 984 pts will be randomized on a 1:1 basis to ENZ plus RUCA/PBO. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue is available). Treatment will be continued until disease progression and crossover is not allowed. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or non-measurable disease per RECIST 1.1, no prior treatment for mCRPC (prior docetaxel, abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, and no medications with S-DDI with ENZ/RUCA. Hierarchical co-primary endpoints are overall survival (OS) and rPFS. The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 and 21 months in control and combination arms, respectively), and 80% power to detect an HR of 0.80 in OS (median OS of 32 and 40 months, respectively). Key secondary endpoints are rPFS and OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 alterations; and differences in adverse events and quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF), and EQ-5D-5L. A key correlative endpoint is the sensitivity of ctDNA testing for HRR gene alterations. Enrollment began in July 2021 & the study is available for participation to all US-NCTN sites. Clinical trial information: NCT04455750 .

Current and Emerging Therapies for COVID-19 in Lung Transplantation.

The landscape of the coronavirus disease 2019 (COVID-19) pandemic has rapidly changed over the past 3 years. Paralleling this evolution, the scientific and medical communities have reported many novel findings relating to the infection's epidemiology, transmission, diagnosis, and treatment. We review pertinent studies of COVID-19 therapeutics with an emphasis on their application to lung transplant recipients. Agents that have been well-studied for treating COVID-19 include antivirals (remdesivir, nirmatrelvir/ritonavir, molnupiravir), monoclonal antibodies, and immunomodulators (for example, corticosteroids and tocilizumab). Remdesivir remains an essential therapy for managing mild-moderate COVID-19. Though highly efficacious for mild-moderate COVID-19 for outpatient therapy, ritonavir-boosted nirmatrelvir has limited use in lung transplant recipients due to significant drug-drug interactions. Monoclonal antibodies, though useful, are the most affected by the emergence of new viral variants.

Development and verification of a physiologically based pharmacokinetic model of dronedarone and its active metabolite N-desbutyldronedarone: Application to prospective simulation of complex drug-drug interaction with rivaroxaban.

Despite potential enzyme- and transporter-mediated drug-drug interactions (DDIs) between dronedarone and rivaroxaban in atrial fibrillation (AF) patients, pharmacokinetic/pharmacodynamic data remain limited to guide clinical practice. We aimed to develop, verify and validate a physiologically based pharmacokinetic (PBPK) model of dronedarone and its major metabolite, N-desbutyldronedarone (NDBD), to prospectively interrogate this clinically relevant DDI in healthy and mild renal impairment populations. The middle-out development of our PBPK model combined literature-derived or in-house in vitro data, predicted in silico data and in vivo clinical data. Model verification was performed for intravenous and oral (single and multiple) dosing regimens. Model validation for the accurate prediction of cytochrome P450 (CYP)3A4- and P-glycoprotein-mediated DDI utilized simvastatin and digoxin as respective victim drugs. Rivaroxaban-specific inhibitory parameters of dronedarone and/or NDBD against CYP3A4, CYP2J2, OAT3 and P-glycoprotein were incorporated into the PBPK-DDI model for prospective dronedarone-rivaroxaban DDI simulation. Dronedarone and NDBD PK following clinically relevant doses of 400 mg dronedarone across single and multiple oral dosing were accurately simulated by incorporating effect of auto-inactivation on dose nonlinearities. Following successful model validation, nondose-adjusted rivaroxaban-dronedarone DDI in healthy and mild renal impairment populations revealed simulated rivaroxaban area under the plasma concentration-time curve up to 24 h fold change greater than dose exposure equivalence (0.70-1.43) at 1.65 and 1.84, respectively. Correspondingly, respective major bleeding risk was 4.24 and 4.70% compared with threshold of 4.5% representing contraindicated rivaroxaban-ketoconazole DDI. Our PBPK-DDI model predicted clinically significant dronedarone-rivaroxaban DDI in both healthy and mild renal impairment subjects. Greater benefit vs. risk could be achieved with rivaroxaban dose reductions to at least 15 mg in mild renal impairment subjects on concomitant dronedarone and rivaroxaban.

Evaluation of Drug Interactions in Hospitalized Patients with Respiratory Disorders in Greece

Background: Patients with respiratory disorders often have additional diseases and are usually treated with more than one medication to manage their respiratory conditions as well as additional comorbidities. Thus, they are frequently exposed to polypharmacy (≥5 drugs), which raises the risk for drug-drug interactions (DDIs) and adverse drug reactions (ADRs). In this work, we present the results regarding the prevalence of DDIs in hospitalized patients with respiratory disorders in Greece. Methods: A 6-month descriptive single-center retrospective observational study enrolled 102 patients with acute or chronic respiratory disorders. Clinical characteristics and medication regimens were recorded upon admission, hospitalization, and discharge. The prevalence of DDIs and their clinical significance was recorded and analyzed. Results: Unspecified acute lower respiratory tract infection (25%), exacerbations of chronic obstructive pulmonary disease (12%) and pneumonia (8%) were the most frequent reasons for admission. Cardiovascular disorders (46%), co-existing respiratory disorders (32%), and diabetes (25%) were the most prevalent comorbidities. Polypharmacy was noted in 61% of patients upon admission, 98% during hospitalization, and 63% upon discharge. Associated DDIs were estimated to be 55% upon admission, 96% throughout hospitalization, and 63% on discharge. Pharmacodynamic (PD) DDIs were the most prevalent cases (81%) and referred mostly to potential risk for QT-prolongation (31.4% of PD-DDIs) or modulation of coagulation process as expressed through the international normalized ratio (INR) (29.0% of DDIs). Pharmacokinetic (PK) DDIs (19% of DDIs) were due to inhibition of Cytochrome P450 mediated metabolism that could lead to elevated systemic drug concentrations. Clinically significant DDIs characterized as "serious-use alternative" related to 7% of cases while 59% of DDIs referred to combinations that could be characterized as "use with caution-monitor". Clinically significant DDIs mostly referred to medication regimens upon admission and discharge and were associated with outpatient prescriptions. Conclusions: Hospitalized patients with respiratory disorders often experience multimorbidity and polypharmacy that raise the risk of DDIs. Clinicians should be conscious especially if any occurring arrhythmias, INR modulations, and prolonged or increased drug action is associated with DDIs.

Safety and effectiveness of anticoagulation with non-vitamin K antagonist oral anticoagulants and warfarin in patients on tuberculosis treatment

Anti-tuberculosis treatment can cause significant drug-drug interaction and interfere with effective anticoagulation. However, there is a lack of evidence and conflicting data on the optimal oral anticoagulation in patients treated for tuberculosis. We investigated the safety and effectiveness of anticoagulation with non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in patients on anti-tuberculosis treatment. Patients on concomitant oral anticoagulation and anti-tuberculosis treatment including rifampin were identified from the Korean nationwide healthcare database. Subjects were censored at discontinuation of either anticoagulation or rifampin. The outcomes of interest were major bleeding, death, and ischemic stroke. A total 2090 patients (1153 on warfarin, 937 on NOAC) were included. NOAC users, compared to warfarin users, were older, had a lower prevalence of hypertension, heart failure, ischemic stroke, and aspirin use and a higher prevalence of cancer, with no significant differences in CHA2DS2-VASc or HAS-BLED scores. There were 18 major bleeding events, 106 deaths, and 50 stroke events during a mean follow-up of 2.9 months. After multivariable adjustment, the use of NOAC was associated with a lower risk of incident ischemic stroke (HR 0.51, 95% CI 0.27–0.94), while there was no significant difference in risk for major bleeding or death compared with warfarin. These results suggest that NOACs have better effectiveness for stroke prevention and similar safety compared with warfarin in patients on concomitant anti-tuberculosis treatment. This is the first study assessing the safety and effectiveness of NOACs compared to warfarin in this clinical scenario.

Potentially clinically significant drug-drug interactions in older patients admitted to the hospital: A cross-sectional study.

Background: An international consensus list of potentially clinically significant drug-drug interactions (DDIs) in older people has been recently validated. Our objective was to describe the prevalence and characteristics of drug combinations potentially causing clinically significant DDIs identified in the medication history of older patients admitted to the hospital and the prevalence and characteristics of manifest DDIs-DDIs involved in adverse drug events present at hospital admission, DDIs that contributed to ADE-related hospital admissions, and DDIs involved in drug-related laboratory deviations. Methods: The data were obtained from our previous study that examined the drug-relatedness of hospital admissions to University Hospital Hradec Králové via the department of emergency medicine in the Czech Republic. Patients ≥ 65years old were included. Drug combinations potentially causing clinically significant DDIs were identified using the international consensus list of potentially clinically significant DDIs in older people. Results: Of the 812 older patients admitted to the hospital, 46% were exposed to drug combinations potentially causing clinically significant DDIs. A combination of medications that affect potassium concentrations accounted for 47% of all drug combinations potentially causing clinically significant DDIs. In 27 cases, potentially clinically significant DDIs were associated with drug-related hospital admissions. In 4 cases, potentially clinically significant DDIs were associated with ADEs that were present at admissions. In 4 cases, the potentially clinically significant DDIs were associated with laboratory deviations. Manifest DDIs that contributed to drug-related hospital admissions most frequently involved antithrombotic agents and central nervous system depressants. Conclusion: The results confirm the findings from the European OPERAM trial, which found that drug combinations potentially causing clinically significant DDIs are very common in older patients. Manifest DDIs were present in 4.3% of older patients admitted to the hospital. In 3.3%, manifest DDIs contributed to drug-related hospital admissions. The difference in the rates of potential and manifest DDIs suggests that if a computerized decision support system is used for alerting potentially clinically significant DDIs in older patients, it needs to be contextualized (e.g., take concomitant medications, doses of medications, laboratory values, and patients' comorbidities into account).

Medication Profiles at Hospital Discharge Predict Poor Outcomes After Acute Ischemic Stroke

Objectives: To examine the relationship between medications prescribed during the first 6-months post-stroke and functional outcome. Materials and Methods: A retrospective analysis of ischemic stroke survivors enrolled in an observational stroke recovery study from June-2017 to July-2019 was performed. Survivors with favorable outcomes (modified rankin scale (mRS) score 0-2) were compared to those with unfavorable outcomes (mRS ≥3) 6-months after stroke on the following: discharge medication classes prescribed, achievement of recommended targets for blood pressure control, glycemic control, and LDL ≤70 mg/dL, medication changes, medication interactions, and medication list discrepancies. Results: Unfavorable 6-month outcomes occurred in 36/78 (46.2%) of survivors. Survivors with unfavorable outcomes were more likely to be prescribed a central nervous system-acting agent (97.2% vs 71.4%; P = .0022) and/or an anti-hyperglycemic agent (25.0% vs 9.5%; P = .009) at discharge. After adjustment of baseline covariates, total number of medications prescribed was associated with unfavorable 6-month outcomes (OR 1.13, 95% CI 1.0-1.28). Secondary stroke prevention measures were not achieved in a high proportion of survivors. Medication changes during 6-month follow up were common and survivors with unfavorable outcomes were more likely to have clinically significant drug-drug interactions. Discussion: At 6-months, survivors with unfavorable outcomes were found to be prescribed more medications, particularly central nervous system-acting and anti-hyperglycemic agents. There were also more drug-drug interactions in the medications prescribed compared to those with favorable outcomes. Together, these data suggest the need for enhanced screening of high-risk stroke survivors focused on close monitoring of polypharmacy, drug-drug interactions, and adverse events with pharmacotherapy.

Application of anti-Xa assay in monitoring unfractionated heparin therapy in contemporary antithrombotic management

ABSTRACT Introduction Unfractionated heparin remains the most widely used agent in the prevention and acute treatment of thrombosis. Pharmacological complexities of this intriguing agent mandate frequent monitoring of its anticoagulant properties to maintain safe and effective hematological outcomes. Although activated partial thromboplastin time has been the standard test to monitor unfractionated heparin therapy for many decades, the anti-Xa assay has emerged as a substitute or adjunct in many institutions. Areas covered This brief report outlines the key features of anti-Xa assay in monitoring unfractionated heparin in acute management of thrombosis in various contemporary settings, with emphasis on evidence for clinical outcomes. PubMed.gov database was utilized to obtain the pertinent literature. Expert opinion The anti-Xa activity is primarily a reflection of UFH concentration and does not account for other hematological variables frequently present in contemporary anticoagulation management. The advantage of the anti-Xa assay in monitoring UFH therapy is predicated upon its limitations to account for global physiological hemostasis. There are significant disease and drug interactions that may potentially result in false in-vitro analysis of anti-Xa activity. Routine application of the anti-Xa assay is not evidence-based at this time.

Prevalence and associated factors of drug-drug interactions in elderly outpatients in a tertiary care hospital: a cross-sectional study based on three databases.

Drug-drug interactions (DDIs) are factors of adverse drug reactions and are more common in elderly patients. Identifying potential DDIs can prevent the related risks. Fewer studies of potential DDIs in prescribing for elderly patients in outpatient clinics. This study aimed to investigate the prevalence and associated factors with potential DDIs and potentially clinically significant DDIs (csDDIs) among elderly outpatients based on 3 DDIs databases. A cross-sectional study was carried out on outpatients (≥65 years old) of a tertiary care hospital in China between January and March 2022. Patients' prescriptions, including at least 1 systemic drug, were consecutively collected. The potential DDIs were identified by Lexicomp®, Micromedex®, and DDInter. Patient-related clinical parameter recorded at the prescriptions and DDIs with higher risk rating was analyzed. Variables showing association in univariate analysis (P<0.2) were included in logistic regression analysis. Weighted kappa analysis was used to analyze the consistencies of different databases. A total of 19,991 elderly outpatients were involved in the study, among whom 21,527 drug combinations including 486 drugs occurred. Lexicomp®, Micromedex®, and DDInter respectively identified 32.22%, 32.93%, and 22.62% of patients have at least one potential DDIs, meanwhile, 9.16%, 14.53%, and 4.56% of patients have at least one potential csDDIs. Under any evaluation criteria, polypharmacy and neurology visits were risk factors for csDDIs. Lexicomp® has the highest coverage rate (87.86%) for drugs. Micromedex® identified the most csDDIs (740 drug combinations). Drugs used in diabetes and psycholeptics were frequently found in the csDDIs of 2 commercial databases. The consistency between Lexicomp® and Micromedex® was moderate (weighted kappa 0.473). DDInter had fair consistencies with the other databases. This study showed the prevalence of potential DDIs is high in elderly outpatients and potential csDDIs were prevalent. Considering the relative risk, pre-warning of potential DDIs before outpatient prescribing is necessary. As the consistencies among identification criteria are not good, more research is needed to focus on actual adverse outcomes to promote accurate prevention of csDDIs.

Drug interactions between common dermatological medications and the oral anti-COVID-19 agents nirmatrelvir-ritonavir and molnupiravir

The oral antiviral agents nirmatrelvir-ritonavir (NMV/r) and molnupiravir are used to treat mild-to-moderate COVID-19 infection in outpatients. However, the use of NMV/r is complicated by significant drug-drug interactions (DDIs) with frequently prescribed medications. Healthcare professionals should be aware of the possible risk of DDIs, given the emergence of COVID-19 variants and the widespread use of oral COVID-19 treatments. We reviewed available data on DDIs between NMV/r, molnupiravir and common dermatological medications; summarised the potential side effects; and suggest strategies for safe COVID-19 treatment. A systematic review using PubMed was conducted on data published from inception to 18 July 2022 to find clinical outcomes of DDIs between NMV/r, molnupiravir and dermatological medications. We also searched the Lexicomp, Micromedex, Liverpool COVID-19 Drug Interactions database and the National Institutes of Health COVID-19 Treatment Guidelines for interactions between NMV/r and molnupiravir, and commonly used dermatological medications. NMV/r containing the cytochrome P-450 (CYP) 3A4 inhibitor ritonavir has DDIs with other medications similarly dependent on CYP3A4 metabolism. Dermatological medications that have DDIs with NMV/r include rifampicin, clofazimine, clarithromycin, erythromycin, clindamycin, itraconazole, ketoconazole, fluconazole, bilastine, rupatadine, dutasteride, ciclosporin, cyclophosphamide, tofacitinib, upadacitinib, colchicine and systemic glucocorticoids. With no potential DDI identified yet in in vitro studies, molnupiravir may be an alternative COVID-19 therapy in patients taking medications that have complicated interactions with NMV/r, which cannot be stopped or dose adjusted. NMV/r has significant DDIs with many common dermatological medications, which may require temporary discontinuation, dosage adjustment or substitution with other anti-COVID-19 agents such as molnupiravir.

Bleeding and venous thromboembolism events in cancer patients taking direct oral anticoagulants vs. low molecular weight heparin

IntroductionPatients with cancer have an increased risk of developing venous thromboembolism (VTE), and subsequently a higher risk of bleeding secondary to anticoagulants. Low-molecular weight heparin (LMWH) has been the standard of care for these patients, with emerging data on the use of direct oral anticoagulants (DOACs). The primary objective of the study was to determine the prevalence of major bleeding events in cancer patients taking DOACs or LMWH for VTE. Secondary objectives included the rate of first VTE recurrence and the effect of concomitant antiplatelet agents and/or significant drug interactions on major bleeding or recurrent VTE. Materials and methodsUsing the electronic medical record at the University of Rochester Medical Center, we retrospectively identified adult patients with active malignancy who had a diagnosis of VTE requiring therapeutic anticoagulation within the study period of July 1st, 2015 to June 1st, 2019. Patients were excluded if they were receiving prophylactic doses of LMWH per the institution VTE guidelines. Data on anticoagulant medications were collected as well as information on major bleeding and recurrent VTE events. Results and conclusionsThere is insufficient evidence of difference in risk of major bleeding among patients who received a DOAC vs LMWH (cause-specific hazard ratio (HR) = 0.77, 95% CI 0.29–2.04, P = 0.60). There was also no evidence of a difference in risk of recurrent VTE between patients who received DOAC vs. LMWH (cause-specific HR = 0.98, 95% CI 0.15–6.26, P = 0.98). These results suggest that DOACs are not significantly less safe than LMWH for patients with cancer.

Identifying Drug-Drug Interactions in Diabetic Patients with Chronic Kidney Disease: Pharmacist’s Interventions

Drug-drug interactions (DDIs) can negatively affect patients ‘therapeutic outcomes. Therefore, our aim was to evaluate DDIs among diabetic patients with chronic kidney disease (CKD). To achieve this aim, our objectives were to identify DDIs in diabetic patients with CKD admitted to the Medicine Department of the tertiary care hospital and to evaluate pharmacist’s interventions in managing DDIs among these patients. A prospective observational study was conducted over 6 months. The pharmacist performed a medication chart review, and DDIs were identified by using Lexicomp® drug interaction. The pharmacist informed prescribers regarding the occurrence of DDIs, and all pharmacist`s interventions were classified according to Pharmaceutical Care Network Europe. Overall 307 DDIs were identified among a total of 119 study patients with an average of 2.6 DDIs per patient. The most of identified DDIs (205, 66.7%) belonged to the interaction risk-rating category of C, which indicates that DDIs required close monitoring of patients’ therapy to avoid any potential adverse outcome. DDIs that needed to be managed by considering therapy modification (risk-rating category of D) and avoiding drug combination (risk-rating category of X) were accounted for 19.2% and 14.0% of all detected interactions, respectively. Interactions between Furosemide–Insulin (43, 14.0%), Amlodipine–Calcium carbonate/vitamin D3 (35, 11.4%) were found to be among most commonly identified DDIs. The pharmacist delivered different types of interventions to prescribers, which ranged from monitoring of therapy outcome to stopping DDIs. A great proportion of delivered pharmacist’s interventions (87%) were accepted by prescribers. Clinically significant DDIs occurred commonly in hospitalized diabetic patients with CKD. The pharmacist delivered important interventions in timely identifying DDIs.

Pharmacist-led olaparib follow-up service for ambulatory ovarian cancer patients: A prospective study in a tertiary specialized cancer hospital in China.

Purpose: To establish a pharmacist-led olaparib follow-up program for ovarian cancer patients, provide patient education, get information on adverse drug reactions (ADRs), and identify and manage drug-related problems. Methods: Ambulatory adult patients with ovarian cancer receiving olaparib were enrolled. At least one follow-up session was conducted by clinical pharmacists. Pharmacists collected data on the type and grade of ADRs, drug adherence, olaparib dosing, concomitant medications, and pharmacists' suggestions. Results: 83 patients were enrolled with the median age of 58. The average number of the follow-up sessions provided to each patient was 1.31, and the average duration of each follow-up was 17.78min. The olaparib starting dose for most patients (97.59%) was 600mg/d. 36.14% of the patients had missed olaparib doses and 27.71% of the patients had dose adjustments due to ADRs. The most common ADRs (incidence≥10%) were: fatigue (40.96%), anemia (36.14%), leukopenia (36.14%), nausea (28.92%), thrombocytopenia (16.87%), anorexia (16.87%), dyspepsia (15.66%). The tolerability profiles were generally similar between patients treated for "first-line maintenance" and those treated for "recurrence maintenance" (p > .05). There were 42% of the patients who were concomitantly taking medications without exact chemical contents (such as formulated Chinese medicines and Chinese decoctions), and common types of concomitant medications with exact drug names were antihypertensive, anti-hyperglycemic, and anti-hyperlipidemic medications. The pharmacists identified 4 clinically significant drug-drug interactions (DDIs) in two patients. Pharmacists made 196 suggestions mainly related to rational use of the medications and management of ADRs. Conclusion: The study provides the first report about pharmacist-led follow-up service for olaparib. The types of ADRs were similar to those previously observed in clinical trials, and the profiles of ADRs in different types of patients (first-line maintenance vs. recurrence maintenance) were also similar. Pharmacists identified drug-related problems (such as adherence, DDIs and management of ADRs) and offer suggestions for the patients.

Systematic review of colchicine neuromyopathy: Risk factors, duration and resolution

ObjectiveTo identify reports of colchicine-induced neuropathy and myopathy and ascertain risk factors associated with this toxicity at commonly used doses. MethodsA systematic review of case reports was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA methodology). PubMed and EMBASE were searched through October 2021 for case reports of neuropathy and/or myopathy associated with the use of colchicine at therapeutic doses. ResultsA total of 143 cases of neuromyopathy from 99 articles were identified as having a “definite” or “probable” association with colchicine usage, as assessed by the Naranjo algorithm. Most of these cases presented with features of both neuropathy and myopathy (n=72, 51%) but symptoms of myopathy were predominant. The mean total daily dose was 1.25±0.60 mg and 48% had been taking colchicine for more than 12 months before presenting with neuromyopathy. A total of 117 (82%) of all reports had either a significant co-morbidity or possible colchicine drug-drug interaction, while 57 (40%) had both risk factors. A total of 26 cases (18%) had no significant risk factor but only 15 of these reports contained complete descriptions of the patient's co-morbidities and co-medications. Cessation of colchicine generally led to complete resolution of symptoms in 70% of cases within a median of 21 days. There were 3 deaths reported which were due to multi-organ failure despite cessation of colchicine and medical management. Colchicine was restarted at reduced doses in 15 cases and 73% had no symptom recurrence. ConclusionNeuromyopathy is an uncommon but reported adverse effect of colchicine. Cases generally present with proximal myopathy symptoms. Cases of colchicine neuromyopathy are largely reported in patients on commonly used doses. Renal and hepatic dysfunction and medications that inhibit cytochrome P450 3A4 isozyme (CYP3A4) and P-glycoprotein (P-gp) appear to be the most significant risk factors. Fortunately, cessation of colchicine generally leads to complete resolution of symptoms. Recommencement of colchicine at reduced doses appeared to be usually safe.

Frequency, severity, and factors associated with clinically significant drug-drug interactions among patients with cancer attending Mbarara Regional Referral Hospital Cancer Unit, Uganda

BackgroundCancer is a major public health problem with pharmacotherapy being the cornerstone of its management. Cancer patients receive multiple drugs concurrently risking Drug-Drug Interactions (DDIs). DDIs, though avoidable, can significantly contribute to morbidity, mortality, and increased healthcare costs in this population of patients. Currently, there is no published study from Uganda on clinically significant DDIs (cs-DDIs) among cancer patients. This study identifies frequency, severity, and factors associated with cs-DDIs at Mbarara Regional Referral Hospital Cancer Unit (MRRHCU).MethodA cross-sectional study was conducted among 300 cancer patients receiving chemotherapy from a tertiary care hospital in western Uganda from January–February 2022. A questionnaire and data collection form were used to collect patient data. Lexicomp® Drug interaction software was used to screen the patient drug information for DDIs and assess their severity. Predictors of DDIs were identified using logistic regression using SPSS (Statistical Package for Social Sciences).ResultThree hundred participants were enrolled with a mean age of 48 ± 23.3 years. One hundred eighty-one patients experienced 495 cs-DDIs; with a mean of 1.7 ± 2.2. The prevalence of cs-DDI was 60.3% (55.0-66.0% at 95% CI). Digestive organ neoplasms were the most commonly (80, 26.7%) diagnosed category, and ‘plant alkaloids and other natural products were the most frequently (143, 47.7%) used chemotherapeutic drug classes. About three-quarters of cs-DDIs were rated as category C risk (367, 74.1%) whereas over two-thirds (355, 71.7%) were moderate in severity.. Being female (aOR = 2.43 [1.23–4.48 at 95% CI]; P-value = 0.011) and use of ≥ 6 drugs concurrently (aOR = 18.82 [9.58–36.95 at 95% CI]; P-value < 0.001)) were significantly associated with cs-DDIs.ConclusionMore than half of the participants experienced at-least one cs-DDI which is generally higher than what was reported in high-income settings. About three-quarters were category C and moderate in severity, and require enhanced monitoring for safety and treatment outcome. Being female and using ≥ 6 drugs were significantly associated with cs-DDIs.

Potential risk of liver injury in epileptic patients during COVID-19 pandemic.

Most of the antiseizure medications (ASMs) are metabolized in liver and many of them particularly first-generation ASMs have the potential to increase liver enzymes or induce liver injury. Hence, treatment of new onset seizures or epilepsy by ASMs during the course of coronavirus disease 2019 (COVID-19), which could potentially be complicated by hepatic dysfunction, is a challenging clinical issue. Intravenous form of levetiracetam which has no significant hepatic metabolism or drug-drug interaction is often a favorable option to control seizures in acute phase of COVID-19. Administration of enzyme inducer ASMs and valproate with the well-known hepatotoxicity and common drug interactions is not generally recommended. In patients with epilepsy who are under control with potentially hepatotoxic ASMs, close observation and cautious dose reduction or drug switch should be considered if any evidence of hepatic impairment exists. However, risks of possible breakthrough seizures should be weighed against benefits of lowering the hazard of liver injury. In patients with epilepsy who receive polytherapy with ASMs, transient dose modification with the tendency to increase the dose of ASMs with more favorable safety profile and less drug interaction and decrease the dose of drugs with main hepatic metabolism, high protein binding, potential to cause liver injury and known drug-drug reaction should be considered. Finally, decision making should be individualized based on patients' conditions and course of illness.

High-Throughput Metabolic Soft-Spot Identification in Liver Microsomes by LC/UV/MS: Application of a Single Variable Incubation Time Approach.

CYP-mediated fast metabolism may lead to poor bioavailability, fast drug clearance and significant drug interaction. Thus, metabolic stability screening in human liver microsomes (HLM) followed by metabolic soft-spot identification (MSSID) is routinely conducted in drug discovery. Liver microsomal incubations of testing compounds with fixed single or multiple incubation time(s) and quantitative and qualitative analysis of metabolites using high-resolution mass spectrometry are routinely employed in MSSID assays. The major objective of this study was to develop and validate a simple, effective, and high-throughput assay for determining metabolic soft-spots of testing compounds in liver microsomes using a single variable incubation time and LC/UV/MS. Model compounds (verapamil, dextromethorphan, buspirone, mirtazapine, saquinavir, midazolam, amodiaquine) were incubated at 3 or 5 µM with HLM for a single variable incubation time between 1 and 60 min based on predetermined metabolic stability data. As a result, disappearances of the parents were around 20-40%, and only one or a few primary metabolites were generated as major metabolite(s) without notable formation of secondary metabolites. The unique metabolite profiles generated from the optimal incubation conditions enabled LC/UV to perform direct quantitative estimation for identifying major metabolites. Consequently, structural characterization by LC/MS focused on one or a few major primary metabolite(s) rather than many metabolites including secondary metabolites. Furthermore, generic data-dependent acquisition methods were utilized to enable Q-TOF and Qtrap to continuously record full MS and MS/MS spectral data of major metabolites for post-acquisition data-mining and interpretation. Results from analyzing metabolic soft-spots of the seven model compounds demonstrated that the novel MSSID assay can substantially simplify metabolic soft-spot identification and is well suited for high-throughput analysis in lead optimization.