Drug-drug interaction potential among patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with novel androgen receptor inhibitors.

BACKGROUND: Nonmetastatic castration-resistant prostate cancer (nmCRPC) patients are often older and use concurrent medications that increase the potential for drug-drug interactions (pDDIs). This study assessed pDDI prevalence in real-world nmCRPC patients treated with apalutamide, darolutamide, or enzalutamide. RESEARCH DESIGN AND METHODS: Castrated prostate cancer patients without metastases prior to androgen receptor inhibitor initiation were identified retrospectively via Optum Clinformatics Data Mart claims data (8/2019-3/2021). The top 100 concomitant medications were assessed for pDDIs. RESULTS: Among 1,515 patients (mean age: 77 ± 8 years; mean Charlson Comorbidity Index: 3 ± 3), 340 initiated apalutamide, 112 darolutamide, and 1,063 enzalutamide. Common concomitant medication classes were cardiovascular (80%) and central nervous system (52%). Two-thirds of the patients received ≥5 concomitant medications; 30 (30/100 medications) pDDIs were identified for apalutamide and enzalutamide each and 2 (2/100 medications) for darolutamide. Most pDDIs had risk ratings of C or D, but four for apalutamide were rated X. Approximately 58% of the patients on apalutamide, 5% on darolutamide, and 54% on enzalutamide had ≥1 identified pDDI. CONCLUSIONS: Results showed a higher frequency of pDDIs in patients receiving apalutamide and enzalutamide vs darolutamide. The impact of these could not be determined retrospectively. DDI risk should be carefully evaluated when discussing optimal therapy for patients with nmCRPC.

Best practices in designing preapproval information engagements for US health care decision makers.

As high-cost and innovative therapies continue to enter the market, health care decision makers (HCDMs) are expressing a need for early information on a product's clinical and economic impacts. Preapproval information exchange (PIE) fulfills these data needs by allowing manufacturers to share drug information with HCDMs prior to US Food and Drug Administration approval. With recent regulatory milestones, such as the Pre-approval Information Exchange Act of 2022, HCDMs look to leverage PIE to forecast budgets and inform reimbursement decisions. However, a lack of stakeholder alignment has challenged the evolving applications of PIE. In addition, manufacturers are still seeking regulatory clarity regarding best practices, and many are developing their own policies for content dissemination. Varying practices have led to heterogeneity of preapproval communications across manufacturers, which may not fully align with HCDM needs and interests. However, recently collected survey data from FormularyDecisions, which focused on HCDM perceptions of both PIE webinars and other formats of PIE (eg, PIE decks and dossiers), indicate that HCDMs have strong preferences regarding the timing and content shared in preapproval engagements. Additionally, product indication and clinical trial information are highly valued, and although desired by HCDMs in other studies, in FormularyDecisions survey data, exact pricing data do not currently appear to be a critical component of PIE. Preapproval communications are expected less than 1 year before anticipated product approval, and PIE webinars, specifically, should prioritize therapeutic areas and products anticipated to have a significant impact on organizational budgets. Although HCDMs prefer nonmanufacturer representatives for PIE webinars and virtual presentations, health outcome liaisons or medical science liaisons are ideal among manufacturer representatives for in-person preapproval engagements. The expectations of HCDMs should be considered as manufacturers establish PIE practices to ensure the exchange of quality and relevant information. DISCLOSURES: This study was funded by Xcenda. Dr Dodda, Dr Bannister, Dr Hydery, Ms Gorey, Ms Dunlap, and Dr Mody report personal fees from Xcenda during the conduct of the study.

Clinically Significant Bradycardia and Hypotension Following Consumption of Betel Leaf in a Patient Treated for Chronic Atrial Fibrillation.

Purpose: A case of new onset bradycardia and hypotension following betel leaf consumption in combination with verapamil and metoprolol in an atrial fibrillation (AF) patient. Summary: A 66-year-old Nigerian woman presented to the emergency department for evaluation of multiple near syncope episodes with underlying AF and slow ventricular response. After initial evaluation, the patient disclosed she had ingested several betel leaves that morning. She was admitted for observation of severe, progressive hypotension and symptomatic bradycardia. Her past medical history included AF, type 2 diabetes, asthma, obesity, hypertension and hypothyroidism. Her home medications consisted of spironolactone, metoprolol succinate, and verapamil ER. Upon admission, her home medications were held. She received IV fluids and atropine .4 mg IV as needed for symptomatic bradycardia. Approximately 18 h following admission, her vital signs stabilized and her labs returned to baseline. She remained stable and was discharged with a recommendation to continue her home medications at prescribed doses with reduced doses of verapamil and metoprolol and to follow-up with her primary care provider. Conclusion: A patient with a history of AF developed significant hypotension and symptomatic bradycardia after betel leaf consumption resulting in an overnight critical care unit admission. The use of betel leaf is not common in the United States; however, practitioners should be cognizant of the use of complementary and alternative medications like betel leaf and incorporate this knowledge in patient evaluation. Patients consuming betel leaf or betel nut should be evaluated for cardiovascular effects as well as laboratory evaluation for organ damage.

Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro).

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.