Require Dose Adjustment Research Articles

Optimizing the Use of Beta-Lactam Antibiotics in Clinical Practice: A Test of Time.

Despite their limitations, the pharmacokinetics (PK) and pharmacodynamics (PD) indices form the basis for our current understanding regarding antibiotic development, selection, and dose optimization. Application of PK-PD in medicine has been associated with better clinical outcome, suppression of resistance, and optimization of antibiotic consumption. Beta-lactam antibiotics remain the cornerstone for empirical and directed therapy in many patients. The percentage of time of the dosing interval that the free (unbound) drug concentration remains above the minimal inhibitory concentration (MIC) (%fT > MIC) has been considered the PK-PD index that best predicts the relationship between antibiotic exposure and killing for the beta-lactam antibiotics. Time dependence of beta-lactam antibiotics has its origin in the acylation process of the serine active site of penicillin-binding proteins, which subsequently results in bacteriostatic and bactericidal effects during the dosing interval. To enhance the likelihood of target attainment, higher doses, and prolonged infusion strategies, with/or without loading doses, have been applied to compensate for subtherapeutic levels of antibiotics related to PK-PD changes, especially in the early phase of severe sepsis. To minimize resistance and maximize clinical outcome, empirical therapy with a meropenem loading dose followed by high-dose-prolonged infusion should be considered in patients with high inoculum infections presenting as severe (Gram negative) sepsis. Subsequent de-escalation and dosing of beta-lactam antibiotics should be considered as an individualized dynamic process that requires dose adjustments throughout the time course of the disease process mediated by clinical parameters that indirectly assess PK-PD alterations.

Population pharmacokinetic analysis of sparsentan in healthy volunteers and patients with focal segmental glomerulosclerosis.

Sparsentan is a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) currently under investigation as a treatment for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). A population pharmacokinetic (PK) analysis was performed to characterize the PKs of sparsentan and to evaluate the impact of FSGS disease characteristics and co-medications as covariates on sparsentan PKs. Blood samples were collected from 236 healthy volunteers, 16 subjects with hepatic impairment, and 194 primary and genetic FSGS patients enrolled in nine studies ranging from phase I to phase III. Sparsentan plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry with a lower limit of quantitation of 2 ng/mL. Modeling was conducted with the first-order conditional estimation with η-ϵ interaction (FOCE-1) method in NONMEM. A total of 20 covariates were tested using a univariate forward addition and stepwise backward elimination analysis with significance level of p < 0.01 and p < 0.001, respectively. A two-compartment model with first-order absorption and an absorption lag time with proportional plus additive residual error (2 ng/mL) described sparsentan PKs. A 32% increase of clearance due to CYP3A auto-induction occurred at steady-state. Covariates retained in the final model included formulation, cytochrome P450 (CYP) 3A4 inhibitor co-administration, sex, race, creatinine clearance, and serum alkaline phosphatase. Moderate and strong CYP3A4 inhibitors comedications increased area under the concentration-time curve by 31.4% and 191.3%, respectively. This population PK model of sparsentan suggests that dose adjustments may be warranted for patients taking moderate and strong CYP3A4 inhibitors concomitantly, but other covariates analyzed may not require dose adjustments.

Hydroxyurea pharmacokinetics and precision dosing in low-resource settings.

Introduction: Hydroxyurea is effective disease-modifying treatment for sickle cell anemia (SCA). Escalation to maximum tolerated dose (MTD) achieves superior benefits without additional toxicities, but requires dose adjustments with serial monitoring. Pharmacokinetic (PK)-guided dosing can predict a personalized optimal dose, which approximates MTD and requires fewer clinical visits, laboratory assessments, and dose adjustments. However, PK-guided dosing requires complex analytical techniques unavailable in low-resource settings. Simplified hydroxyurea PK analysis could optimize dosing and increase access to treatment. Methods: Concentrated stock solutions of reagents for chemical detection of serum hydroxyurea using HPLC were prepared and stored at -80C. On the day of analysis, hydroxyurea was serially diluted in human serum, then spiked with N-methylurea as an internal standard and analyzed using two commercial HPLC machines: 1) standard benchtop Agilent with 449nm detector and 5 micron C18 column; and 2) portable PolyLC with 415nm detector and 3.5 micron C18 column. After validation in the United States, the portable HPLC and chemicals were transported to Tanzania. Results: A calibration curve using hydroxyurea 2-fold dilutions ranging from 0 to 1000µM was plotted against the hydroxyurea:N-methylurea ratio. In the United States, both HPLC systems yielded calibration curves with R2 > 0.99. Hydroxyurea prepared at known concentrations confirmed accuracy and precision within 10%-20% of the actual values. Both HPLC systems measured hydroxyurea with <10% variance from the prepared concentrations, and paired analysis of samples on both machines documented <15% variance. Serial measurements of 300 and 100μM concentrations using the PolyLC system were precise with 2.5% coefficient of variance. After transport to Tanzania with setup and training, the modified PolyLC HPLC system produced similar calibration curves with R2 > 0.99. Conclusion: Increasing access to hydroxyurea for people with SCA requires an approach that eases financial and logistical barriers while optimizing safety and benefits, especially in low-resource settings. We successfully modified a portable HPLC instrument to quantify hydroxyurea, validated its precision and accuracy, and confirmed capacity building and knowledge transfer to Tanzania. HPLC measurement of serum hydroxyurea is now feasible in low-resource settings using available laboratory infrastructure. PK-guided dosing of hydroxyurea will be tested prospectively to achieve optimal treatment responses.

Assessment of efficacy and safety of dose-dense doxorubicin and cyclophosphamide (ddAC) in combination with pembrolizumab in early-stage, triple-negative breast cancer.

e12618 Background: KEYNOTE-522 demonstrated significant improvement in pathologic complete response (pCR) and event free survival (EFS) for early stage triple negative breast cancer (TNBC) patients (pts) treated with pembrolizumab (PEMBRO) and chemotherapy (carboplatin/paclitaxel weekly followed by doxorubicin/cyclophosamide (AC) every 3 weeks) in the neo/adjuvant setting. Standard of care prior to KEYNOTE-522 was AC every 2 weeks (dd), however, implementation of ddAC becomes impractical when accommodating 21-day PEMBRO dosing and creates concern for compromised efficacy. KEYNOTE-555 demonstrated feasibility of every 6-week PEMBRO dosing. We modified the KEYNOTE-522 regimen to employ ddAC with PEMBRO every 6-weeks with the aim to maximize clinical outcomes while reducing time spent in the infusion center. The primary objective is to compare the rate of pCR using ddAC plus 6-week PEMBRO versus PEMBRO and AC every 3 weeks. Secondary objectives include: safety of concomitant chemoimmunotherapy by comparing the incidence of adverse events (AEs) with PEMBRO (every 3 or 6 weeks), assessing rates of held cycles or dose modifications, and assessing toxicity of concomitant capecitabine and PEMBRO in the adjuvant setting. Methods: This was a retrospective, single-center, cohort study at Duke University Hospital (DUH). Results reported via descriptive statistics. Adult pts with clinical stages I-III TNBC were included in this study. Pts must have completed four cycles of AC. Pre-specified data collection points were obtained from the electronic health record and entered into a secure database. Results: A total of 25 female pts treated at DUH were included. The rate of pCR was 64.3% (AC) versus 81.8% (ddAC). All patients experienced at least one adverse event with their immunochemotherapeutic regimen. The most common IO-induced toxicities included thyroid-associated AEs (37.5%) and rash (37.5%). There were no grade 3 or 4 IO-induced toxicities reported. Five patients were on concomitant adjuvant capecitabine and PEMBRO for residual disease. One patient in each arm required dose adjustments for capecitabine and 3 patients had at least one deferred cycle. One patient experienced AEs associated with capecitabine. No patients had toxicities attributable to adjuvant PEMBRO. Conclusions: In this small single center study, the administration of neoadjuvant ddAC with PEMBRO at 400mg every 6 weeks was deemed feasible with no excess toxicity. There was a trend towards improved efficacy for patients treated with ddAC with PEMBRO. Additionally, safety endpoints were similar between groups. This dosing strategy allows for optimization of therapy with the incorporation of ddAC and adjuvant capecitabine, thus potentially improving outcomes in TNBC patients. Larger cohort studies, in the real-world setting, are needed to confirm these findings.

Antifungal Stewardship Programs in Children: Challenges and Opportunities.

Antifungal Stewardship Programs in Children: Challenges and Opportunities.

Pattern, frequency and factors associated with inappropriate high dosing in chronic kidney disease patients at a tertiary care hospital in Pakistan

BackgroundPatients with chronic kidney diseases (CKD) are susceptible to the toxic drug effects if given unadjusted doses. Although Pakistan harbors a high burden of CKD patients, there is limited information available on the frequency, pattern and factors associated with unadjusted drug doses among CKD patients.MethodsThis cross-sectional study conducted at Sandeman Provincial Hospital, Quetta included 303 non-dialysis ambulatory CKD patients (glomerular filtration rate < 60 ml/min/1.73m2). The patients’ data were collected through a purpose designed data collection form. The appropriateness of doses was checked against the renal drug handbook-2018, Kidney Disease Improving Global Outcomes guidelines, British National Formulary-2022, and manufacturer leaflets. Data were analysed by SPSS 23 and multiple binary logistic regression analysis was used to assess the factors associated with receiving inappropriate high doses. A p-value < 0.05 was considered statistically significant.ResultsThe patients received a total of 2265 prescription lines, with a median of eight different drugs per patient (interquartile range: 6–9 drugs). A total of 34.5% (783/2265) drugs required dose adjustment. Of these, doses were not adjusted for 56.1% (440) drugs in 162 (53.4%) patients. The most common pharmacological class of drugs requiring dose adjustment were antibiotics (79.1%), followed by antidiabetics (59.2%), diuretics (57.0%), angiotensin converting enzyme inhibitors (56.9%), beta blockers (56.9%), analgesics (56.0%), angiotensin receptor blockers (55.2%), domperidone (53.9%) and antihyperlipidmics (46.1%). Patient’s age of 41–60 (OR = 5.76) and > 60 years (OR = 9.49), hypertension (OR = 2.68), diabetes mellitus (OR = 3.47) and cardiovascular diseases (OR = 2.82) had statistically significant association (p-value < 0.05) with inappropriate high doses.ConclusionThe high frequency of inappropriate high doses suggests an important quality gap in medication dosing for patients with ND-CKD at the study site. Special attention should be paid to the drugs and patients with identified risk factors for receiving inappropriate high doses.

STYLE (NCT03449173): A Phase 2 Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines

IntroductionThymic malignancies are rare tumors with few therapeutic options. The STYLE trial was aimed to evaluate activity and safety of sunitinib in advanced or recurrent type B3 thymoma (T) and thymic carcinoma (TC). MethodsIn this multicenter, Simon 2 stages, phase 2 trial, patients with pretreated T or TC were enrolled in two cohorts and assessed separately. Sunitinib was administered 50 mg daily for 4 weeks, followed by a 2-week rest period (schedule 4/2), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Progression-free survival, overall survival, disease control rate and safety were secondary endpoints. ResultsFrom March 2017 to January 2022, 12 patients with T and 32 patients with TC were enrolled. At stage 1, ORR was 0% (90% confidence interval [CI]: 0.0–22.1) in T and 16.7% (90% CI: 3.1–43.8) in TC, so the T cohort was closed. At stage 2, the primary endpoint was met for TC with ORR of 21.7% (90% CI: 9.0%–40.4%). In the intention-to-treat analysis, disease control rate was 91.7% (95% CI: 61.5%–99.8%) in Ts and 89.3% (95% CI: 71.8%–97.7%) in TCs. Median progression-free survival was 7.7 months (95% CI: 2.4–45.5) in Ts and 8.8 months (95% CI: 5.3–11.1) in TCs; median overall survival was 47.9 months (95% CI: 4.5–not reached) in Ts and 27.8 months (95% CI: 13.2–53.2) in TCs. Adverse events occurred in 91.7% Ts and 93.5% TCs. Grade 3 or greater treatment-related adverse events were reported in 25.0% Ts and 51.6% TCs. ConclusionsThis trial confirms the activity of sunitinib in patients with TC, supporting its use as a second-line treatment, albeit with potential toxicity that requires dose adjustment.

Observational study of HR+/HER2− metastatic breast cancer patients treated with abemaciclib in Spain in the Named Patient Use Program (AbemusS)

Introduction/objectivesTo describe abemaciclib use in patients with hormone receptor-positive, human epidermal growth factor receptor-negative (HR+/HER2−) metastatic breast cancer (mBC) who participated in the Named Patient Use program (NPU) in Spain.Material and methodsThis retrospective study was based on medical record review of patients across 20 centers during 2018/2019. Patients were followed up until death, enrolment in a clinical trial, loss of follow-up or study end. Clinical and demographic characteristics, treatment patterns and abemaciclib effectiveness were analyzed; time-to-event and median times were estimated using the Kaplan–Meier (KM) method.ResultsThe study included 69 female patients with mBC (mean age 60.4 ± 12.4 years), 86% of whom had an initial diagnosis of early BC and 20% had an ECOG ≥ 2. Median follow-up was 23 months (range 16–28). Metastases were frequently observed in bone (79%) and visceral tissue (65%), with 47% having metastases in > 2 sites. Median number of treatment lines before abemaciclib was 6 (range 1–10). Abemaciclib monotherapy was received by 72% of patients and combination therapy with endocrine therapy by 28% of patients; 54% of patients required dose adjustments, with a median time to first adjustment of 1.8 months. Abemaciclib was discontinued in 86% of patients after a median of 7.7 months (13.2 months for combination therapy and 7.0 months for monotherapy) mainly due to disease progression (69%).ConclusionThese results suggest that abemaciclib is effective, as monotherapy and in combination, for patients with heavily pretreated mBC, consistent with clinical trial results.

Effect of Roux-En-Y Gastric Bypass in the Pharmacokinetics of (R)-Carvedilol and (S)-Carvedilol.

Roux-en-Y gastric bypass is one of the most common surgical treatments for obesity due to the effective long-term weight loss and remission of associated comorbidities. Carvedilol, a third-generation β-blocker, is prescribed to treat cardiovascular diseases. This drug is a weak base with low and pH-dependent solubility and dissolution and high permeability. As the changes in the gastrointestinal tract anatomy and physiology after roux-en-Y gastric bypass can potentially affect drug pharmacokinetics, this study aimed to assess the effect of roux-en-Y gastric bypass on the pharmacokinetics of carvedilol enantiomers. Nonobese (n=15, body mass index<25kg/m2 ), obese (n=19, body mass index≥30), and post-roux-en-Y gastric bypass subjects submitted to surgery for at least 6months (n=19) were investigated. All subjects were administered a single oral dose of 25-mg racemic carvedilol, and blood was sampled for up to 24hours. Plasma concentrations of (R)- and (S)-carvedilol were determined by liquid chromatography-tandem mass spectrometry. The maximum plasma concentration (Cmax ) and the area under the plasma concentration-time curve (AUC) of (R)-carvedilol were 2- to 3-fold higher than (S)-carvedilol in all groups. Obese subjects have shown reduced Cmax of (R)- and (S)-carvedilol without changing the AUC. Post-roux-en-Y gastric bypass subjects presented a 3.5-fold reduction in the Cmax of the active (S)-carvedilol and a 1.9 reduction in the AUC from time 0 to infinity compared to nonobese subjects. The time to reach Cmax of (S)-carvedilol increased 2.5-fold in post-roux-en-Y gastric bypass subjects compared to obese or nonobese. Although the β-blockade response was not assessed, the reduced exposure to carvedilol in subjects post-roux-en-Y gastric bypass may be clinically relevant and require dose adjustment.

Comparative effectiveness and safety of a pharmacist‐managed protocol for the transition from intravenous to subcutaneous insulin

AbstractPurposeTo evaluate the effectiveness and safety of a pharmacist‐managed protocol for transitioning critically ill patients from intravenous (iv) to subcutaneous insulin compared with a provider‐managed process.MethodsThis single‐center, retrospective, observational study included patients admitted to the medical or surgical/trauma intensive care unit who received a continuous infusion of iv insulin from January 2019 to April 2021. Patients were excluded if they were less than 18 years of age, pregnant, incarcerated, or received iv insulin for the diagnosis of diabetic ketoacidosis, hyperglycemic hyperosmolar state, calcium channel blocker or beta blocker overdose, or hypertriglyceridemia. The primary outcome was the percentage of blood glucose (BG) concentrations within the target range of 70–150 mg/dL from 0 to 48 h following transition to subcutaneous insulin. Secondary outcomes included percentage of BG concentrations within goal range following transition at 0–12 h and 12–24 h, incidence of hypo‐ and hyperglycemia, and percentage of patients requiring dose adjustments after initial transition.ResultsA total of 110 unique patients were included with 70 patients in the provider‐managed group and 40 patients in the pharmacist‐managed group. On average, pharmacists transitioned patients to 63% basal insulin based on their 24‐h total day dose of insulin. The pharmacist‐managed group achieved glycemic control in 53% of transitions at 12 h, 40% at 24 h, and 47% from 0 to 48 h, while the provider group achieved glycemic control in 25% of transitions at 12 h, 12% at 24 h, and 18% from 0 to 48 h (p &lt; 0.001 for all time points). As for safety end points, the pharmacist‐managed group demonstrated lower rates of hypoglycemia (p = 0.001), severe hypoglycemia (p = 0.332), hyperglycemia (p &lt; 0.001), and severe hyperglycemia (p &lt; 0.001) compared with the provider‐managed group.ConclusionsPharmacists can effectively and safely transition critically ill patients from iv to subcutaneous insulin utilizing a standardized protocol.

Antimicrobial Stewardship and Dose Adjustment of Restricted Antimicrobial Drugs in Hospital Setting.

Antimicrobial consumption is increasing. In order to maximize the effectiveness of antimicrobial stewardship and provide safe and optimal use of restricted antimicrobial drugs, renal dosing should be evaluated. The aim of this study was to determine the prevalence of restricted antimicrobial drugs that required dose adjustment according to renal function. A retrospective, consecutive study was conducted at University Hospital Dubrava. This study analyzed requests for restricted antimicrobial drugs (n = 2890) during a 3-month period. Requests for antimicrobial agents were evaluated by the antimicrobial therapy management team (A-team). This study included 412 restricted antimicrobial drug requests requiring dose adjustment, of which 39.1% did not have an adjusted dose. Meropenem, Ciprofloxacin, Piperacillin/Tazobactam, Vancomycin, Colistin and the antimycotic Fluconazole were the most frequent restricted antimicrobial drugs that required dose adjustment according to impaired renal function. The results of this research highlight the importance of the A-team in the optimization of restricted antimicrobial therapy. Non-adjusted doses of restricted antimicrobial drugs increase the possibility of adverse drug reactions and therefore jeopardize pharmacotherapy outcomes and patient safety.

Variability in Nonvitamin K Oral Anticoagulant Dose Eligibility and Adjustment According to Renal Formulae and Clinical Outcomes in Patients With Atrial Fibrillation With and Without Chronic Kidney Disease: Insights From ORBIT‐AF II

Background Nonvitamin K oral anticoagulants require dose adjustment based on kidney function.The most common estimate of kidney function employed in clinical practice is estimated glomerular filtration rate (eGFR); however, product monographs recommend the use of the Cockcroft-Gault estimated creatinine clearance (eCrCl) for dose adjustment. Methods and Results The authors included patients enrolled in the ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation AF II) trial. Dosing was considered inappropriate when use of eGFR resulted in a lower (undertreatment) or higher (overtreatment) dose than that recommended by the eCrCl. The primary outcome of major adverse cardiovascular and neurological events was a composite of cardiovascular death, stroke or systemic embolism, new-onset heart failure, and myocardial infarction. Among 8727 in the overall cohort, agreement between eCrCl and eGFR was observed in 93.5% to 93.8% of patients. Among 2184 patients with chronic kidney disease (CKD), the agreement between eCrCl and eGFR was 79.9% to 80.7%. Dosing misclassification was more frequent in the CKD population (41.9% of rivaroxaban users, 5.7% of dabigatran users, and 4.6% apixaban users). At 1 year, undertreated patients in the CKD group had significantly greater major adverse cardiovascular and neurological events (adjusted hazard ratio, 2.93 [95% CI, 1.08-7.92]) compared with the group with appropriate nonvitamin K oral anticoagulants dosing (P=0.03). Conclusions The prevalence of misclassification of nonvitamin K oral anticoagulants dosing was high when using eGFR, particularly among patients with CKD. Among patients with CKD, potential undertreatment due to inappropriate and off-label renal formulae may result in worse clinical outcomes. These findings highlight the importance of using eCrCl, and not eGFR, for dose adjustment in all patients with AF receiving nonvitamin K oral anticoagulants.

Development of a medication review tool for community-dwelling older adults in Korea.

With the aging population, older adults are more likely to receive outpatient care. Therefore, it is necessary to identify drug-related problems (DRPs) and potentially inappropriate medications (PIMs) associated with adverse clinical outcomes in community-dwelling older adults. This study aimed to develop a medication review tool for community-dwelling older adults in Korea. We developed the tool using three steps: (i) establishment of a preliminary list by reviewing 21 existing tools, (ii) a two-round Delphi survey to evaluate clinical appropriateness and (iii) a two-round Delphi survey to evaluate applicability. The list was categorized into 23 diseases/conditions with five types of DRPs. The interventions for each item have been described. The preliminary list contained 100 items. The final list contained 81 items, including 17 general PIMs, 26 PIMs under specific disease/conditions, 16 potential drug interactions, 20 potential omissions and 2 PIMs requiring dose adjustment. We developed a disease-based explicit medication review tool that can be used in primary care. This tool would assist primary care healthcare providers in identifying inappropriate medication use, which may help reduce adverse clinical consequences in older adults. Further studies are required to validate the clinical efficacy of this tool.

Feasibility and Safety of Intravenous Sotalol Loading in Adult Patients With Atrial Fibrillation (DASH-AF)

BackgroundInpatient initiation of sotalol is recommended owing to its proarrhythmic effects. ObjectivesThe DASH-AF (Feasibility and Safety of Intravenous Sotalol Administered as a Loading Dose to Initiate Oral Sotalol Therapy in Adult Patients With Atrial Fibrillation) trial evaluates the safety and feasibility of intravenous (IV) sotalol, achieving a steady state with maximum QTc prolongation within 6 hours instead of the traditional 5-dose inpatient oral (PO) titration. MethodsDASH-AF is a prospective, nonrandomized, multicenter, open-label trial consisting of patients who underwent IV sotalol loading dose to initiate rapid oral therapy for atrial arrhythmias. IV dose was calculated based on the target oral dose as indicated by baseline QTc and renal function. Patients’ QTc (in sinus) was measured via electrocardiography at 15-minute intervals and after IV loading completion. Patients were discharged 4 hours after first oral dose. All patients were monitored via mobile cardiac outpatient telemetry for 72 hours. The control group was composed of patients admitted for the traditional 5 PO doses. Safety outcomes were assessed in both groups. ResultsA total of 120 patients from 3 centers were enrolled from 2021 to 2022 in the IV loading group (compared with type of AF– and renal function–matched patients in the conventional PO loading cohort). This study demonstrated no significant change in ΔQTc in both groups, with a significantly lower number of patients requiring dose adjustment in the IV arm compared with the PO arm (4.1% vs 16.6%; P = 0.003). This led to potential cost savings of up to $3,500.68 per admission. ConclusionsThe DASH-AF trial shows that rapid IV sotalol loading in atrial fibrillation/flutter patients for rhythm control is feasible and safe compared with conventional oral loading with significant cost reduction. (Feasibility and Safety of Intravenous Sotalol Administered as a Loading Dose to Initiate Oral Sotalol Therapy in Adult Patients With Atrial Fibrillation [DASH-AF]; NCT04473807)

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors

(1) Background: Despite the prognostic improvements achieved with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), a minority of patients still fail TKIs. The recent introduction of asciminib may be a promising option in intolerant patients, as it is a first-in-class inhibitor with a more selective mechanism of action different from the ATP-competitive inhibition that occurs with TKIs. Therefore, our goal was to analyze toxicities shown with asciminib as well as to study cross-toxicity with previous TKIs. (2) Methods: An observational, multicenter, retrospective study was performed with data from 77 patients with CML with therapeutic failure to second-generation TKIs who received asciminib through a managed-access program (MAP) (3) Results: With a median follow-up of 13.7 months, 22 patients (28.5%) discontinued treatment: 32% (7/22) due to intolerance and 45% (10/22) due to resistance. Fifty-five percent of the patients reported adverse effects (AEs) with asciminib and eighteen percent grade 3-4. Most frequent AEs were: fatigue (18%), thrombocytopenia (17%), anemia (12%), and arthralgias (12%). None of the patients experienced cardiovascular events or occlusive arterial disease. Further, 26%, 25%, and 9% of patients required dose adjustment, temporary suspension, or definitive discontinuation of treatment, respectively. Toxicities under asciminib seemed lower than with prior TKIs for anemia, cardiovascular events, pleural/pericardial effusion, diarrhea, and edema. Cross-toxicity risk was statistically significant for thrombocytopenia, anemia, neutropenia, fatigue, vomiting, and pancreatitis. (4) Conclusion: Asciminib is a molecule with a good safety profile and with a low rate of AEs. However, despite its new mechanism of action, asciminib presents a risk of cross-toxicity with classical TKIs for some AEs.

Renally inappropriate medications in elderly outpatients and inpatients with an impaired renal function

ABSTRACT Background and aims The purpose of this study was to investigate differences in the frequency of renally inappropriate medications (RIMs) in outpatient and inpatient among three institutions. Methods We collected prescription and renal function data for patients over 65 years of age from the drug department system. We selected 50 kinds of the most frequently used medicines which require dose adjustment according to a patient’s renal function. Results Outpatient RIM was seen in 611 cases (6.17%), and inpatient prescription RIM was seen in 317 cases (5.29%), showing a significant difference between the groups (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.02–1.35). However, in a multivariate analysis, when the renal function was included, that difference between outpatients and inpatients became insignificant (OR 1.16, 95% CI 0.98–1.37). The distribution of prescription with or without RIM in outpatient and inpatient settings depended on the CKD stage. Outpatients with a better CKD stage (stage 1–3) had a higher rate of RIM than inpatients, while patients with a worse CKD stage (stage 4 or 5) had a higher rate of RIM than outpatients. Conclusion The rate of RIM in outpatients tends to be high, and attention should be paid to RIM in inpatients with a severe CKD stage.

Direct oral anticoagulants for venous thromboembolism prophylaxis in orthopaedic trauma: a clear first choice?

‘The brain may devise laws for the blood’ William Shakespeare, Merchant of Venice (1598)1 Prevention of venous thromboembolism (VTEp) is an integral part in the care of orthopaedic patients. VTE the leading cause of preventable mortality in hospital2 and orthopaedic surgery confers particularly high-risk.3 VTE currently complicates 2%–7% of all orthopaedic surgery.2 Symptomatic VTE results in reduced quality of life and causes mortality in 6%–12% of cases.4 VTE may increase length of stay (LOS) in hospital and confers large economic costs.5 Biological rationale supports the efficacy of direct oral anticoagulants (DOACs) for VTEp in orthopaedic surgery. Orthopaedic surgery accentuates all aspects of Virchow's Triad due to trauma-induced thromboplastin upregulation, intraoperative torniquet use, immobilization, bed rest and polymethylmethacrylate cement.6 DOACs prevent subsequent coagulation by inhibiting Factor Xa or II.6 Factor Xa inactivation is also the mechanism of action for low-molecular-weight heparins (LMWH) which are commonly used for VTEp after orthopaedic surgery.3 However, DOACs act directly on coagulation factors, unlike LMWH which is reliant on the presence of antithrombin III. DOACs do not require dose adjustment in obesity and avoid the gastrointestinal and renal side-effects of aspirin. The disadvantage of DOACs is that they are not all reversible and have a longer washout time than LMWH. DOACs have already demonstrated utility for VTEp in alternative domains. Most notably, DOACs are now suitable first-line options for VTEp after hip and knee arthroplasty. LMWHs such as enoxaparin, had historically been the gold-standard for VTEp after arthroplasty.7 However rivaroxaban and apixaban have demonstrated superior VTEp than LMWH in recent meta-analyses of randomized controlled trials (RCT).8, 9 Rivaroxaban was associated with a greater bleeding risk than LMWH.8, 9 This is important to note as, even minor bleeding is a concern to orthopaedic surgeons as it may increase risk of infection. However, apixaban has demonstrated a lesser bleeding risk than LMWH.8, 9 Meanwhile, aspirin has shown significantly increased VTE and mortality rates when compared to DOACs and LMWH.10, 11 Apixaban and rivaroxaban have also demonstrated reduced rates of symptomatic VTE than LMWH without increased incidences of major bleeding, when used for VTEp in oncology.12 Studies from the last decade have consistently demonstrated the benefits of DOACs over LMWH for VTEp in orthopaedic trauma surgery.13, 14 A recent systematic review and meta-analysis reported significantly reduced deep venous thrombosis rates when Factor Xa inhibiting DOACs were compared to LMWH for VTEp after lower limb fracture surgery.14 DOACs were also not inferior to LMWH for prevention of mortality, pulmonary embolism and bleeding, both major and minor. A RCT not included in the aforementioned study demonstrated reduced VTE risk with no increase bleeding risk, including minor bleeding, when rivaroxaban was compared to LMWH.13 Therefore the increased bleeding with rivaroxaban in some arthroplasty data is not reflected in orthopaedic trauma. Aspirin has not demonstrated effective VTEp after orthopaedic trauma surgery when compared to LMWH.15 The results of these studies have not yet effected an update to international guidelines for VTEp after orthopaedic trauma surgery (Table 1). DOACs also offer large economic savings, superior patient experience and improved adherence when compared to LMWH. In analyses for total hip replacement and total knee replacement, dabigatran, rivaroxaban and apixaban demonstrate saving of €152 and €116, €177 and €85, €223 and €135 per patient respectively.5 DOACs are administered orally compared to LMWH administration by subcutaneous injection. LMWH has subsequently been associated with high rates of non-adherence after hospital discharge.16 This is particularly concerning as the majority of VTE occurs following hospital discharge.17 Evidence suggests DOACs are the first choice over LMWH for VTEp after orthopaedic trauma surgery due to reduced rates of VTE, equivocal bleeding risk and mortality, reduced cost and improved patient experience. Where bleeding risk is high, apixaban may be used instead of rivaroxaban. Where risk of reoperation is high, DOACs should be avoided as they are not reversible. Open access publishing facilitated by The University of Adelaide, as part of the Wiley - The University of Adelaide agreement via the Council of Australian University Librarians. Bhuvanesh Ravichandran: Investigation; methodology; writing – review and editing. Brandon Stretton: Conceptualization; formal analysis; investigation; methodology; writing – review and editing. Joshua G. Kovoor: Conceptualization; formal analysis; investigation; methodology; writing – review and editing. Stephen Bacchi: Formal analysis; supervision; writing – review and editing. Joseph N. Hewitt: Investigation; resources; writing – review and editing. Christopher D. Ovenden: Formal analysis; investigation; supervision; writing – review and editing. Aashray K. Gupta: Conceptualization; investigation; resources; supervision; writing – review and editing. Ruurd L. Jaarsma: Conceptualization; supervision; validation; visualization; writing – review and editing. Guy J. Maddern: Conceptualization; supervision; validation; visualization; writing – review and editing. Ameya Bhanushali: Writing – review and editing.

Dermatologic toxicities of chemotherapy: an educational intervention for skin of color women with breast cancer.

We sought to pilot an educational intervention, in the form of a pamphlet, to evaluate the effectiveness of this tool in teaching skin of color (SoC) patients about potential dermatologic toxicities of chemotherapy that are relevant to their skin type. At a chemotherapy infusion center, SoC patients (n = 26) who were receiving chemotherapy for breast cancer voluntarily consented to read an educational pamphlet and complete a series of survey questions before and after this educational intervention. Most participants identified as female (96%), African American/Black (81%), and non-Hispanic (85%); all respondents had obtained at least a high school degree. Survey responses revealed a significant increase in knowledge about the potential dermatologic effects of cancer treatment after this intervention. Notably, 100% of participants either agreed or strongly agreed that they would like to see other doctors use this educational tool as a form of patient education, that they would recommend this pamphlet to other patients who are starting cancer treatment, and that the pamphlet was easy to understand. Limitations of this study include small sample size and single-institution recruitment, which may limit generalizability. Furthermore, this study only included patients who are proficient in English. This study pilots an effective educational tool that addresses dermatologic toxicities of chemotherapy that are relevant to SoC patients. Further multi-institutional studies with larger sample sizes and translation to other languages can overcome the limitations of this pilot study.

Frequent need for apixaban dose adjustment for atrial fibrillation in an unselected acute medical admission population during the COVID 19 pandemic

Abstract Funding Acknowledgements Type of funding sources: None. Background During the COVID-19 pandemic, systematic switching patients of eligible patients with atrial fibrillation from warfarin to direct oral anticoagulants (DOACs) was encouraged to simplify drug dosing and obviate the need for regular monitoring. Regional exclusions to switching included mechanical heart valves, moderate to severe mitral stenosis and stage 5 chronic kidney disease (estimated glomerular filtration rate [eGFR]&amp;lt; 15ml/min/1.73m2). However, each DOAC requires dose adjustment depending on renal function and other patient factors. Purpose Failure to dose reduce when indicated leads to excessive serum drug concentration and increased risk of major haemorrhage, particularly in patients who are acutely unwell. We thus quantified the likelihood of need for dose adjustment in an unselected acute medical admission population. Methods While on call, a single investigator prospectively identified all patients admitted on the acute medical or cardiology take-in between 1/12/21 and 1/2/22 who were taking apixaban for atrial fibrillation. Apixaban was selected as the study DOAC as it was the most commonly used DOAC but had the most complex dose adjustment algorithm and hence risk of dose error. In order to determine the appropriate drug dosage, patient age, weight, serum creatinine and eGFR were recorded. Dose reduction to 2.5mg was required if the patient meet 2 of the following 3 criteria of [age&amp;gt;80 years, weight &amp;lt;60kg, serum creatinine &amp;gt;133umol/l], or a single criterion, had an eGFR &amp;lt;30ml/min/1.73m2. Drug discontinuation was required if eGFR was &amp;lt;15ml/min/1.73m2. Results All patients identified (n=50) had a CHA2DS2-VASc score of ≥2. Patients with active COVID-19 infection were excluded. Mean age was 77.2 years (range 46-102). Mean weight was 78kg (range 52-101). Mean serum creatinine was 212umol/l (range 62-595). Mean eGFR was 33ml/min/1.73m2 (range 8 to &amp;gt;60). Of the 50 patients, 24 (48%) were taking the appropriate apixaban dose on admission which did not require dose adjustment (18 of whom were appropriately taking 5mg bd and 6 were taking 2.5mg bd). Dose reduction from 5mg bd to 2.5mg bd was required in 17 (34%) patients. Stopping treatment, at least temporarily due to eGFR&amp;lt;15ml/min/1.73m2, was indicated in 9 (18%) of patients. No patient required an increase in drug dose. (Graph 1) Conclusion Over half of acute medical or cardiology patients admitted within a COVID-19 setting and taking apixaban for atrial fibrillation required at least temporary drug dose adjustment or discontinuation. Clinicians should expect that adjustment of apixaban dose may be required during acute admission.

PRESCRIPTION PATTERN OF ANTIBIOTICS AND THEIR APPROPRIATENESS IN PATIENTS WITH CHRONIC KIDNEY DISEASE-AN OBSERVATIONAL STUDY IN A TERTIARY CARE TEACHING HOSPITAL IN SOUTH INDIA

Objective: The primary objective of the study was to assess the prescribing pattern of antimicrobial agents in patients with chronic kidney disease. The secondary objectives of this study are to assess antibiotic appropriateness and dose optimization in patients with chronic kidney disease in relation to their comorbidities.&#x0D; Methods: A retrospective study was conducted, and medical records of all patients with CKD who were admitted in the nephrology department of Sri Venkateswara Institute of Medical Sciences, Tirupati, during Jan 2018-Dec 2018 were reviewed for antibiotic prescriptions. A total of 200 medical records were selected and assessed for antimicrobial prescriptions. A p-value &lt;0.05 was considered significant throughout the statistical analysis.&#x0D; Results: Analysis showed that overall 163 drugs were prescribed to CKD patients, of which nearly 96 (58.9%) required dosage adjustment. Of those 163 drugs, the majority N= 25 (26%), were unadjusted, and the remaining N = 71 (74%) were properly adjusted. The length of hospitalization of CKD patients was below 7 was 13.5%, above 7 was 86.5%. Mean and SD was 10.27±7.18 d, (Range: 1–35 d). The Chi-square analysis confirmed that out of the seven studied variables, two i.e. Length of stay days; p&lt;0.001.&#x0D; Conclusion: It is concluded that the occurrence of medication dosing errors was moderate in hospitalized chronic kidney disease patients in our study. Nearly 20% of patients who had prolonged stays were prescribed antibiotics for a prolonged period. The predictors of medication dosing errors in CKD patients were the severe-to-end stages of chronic kidney disease, the number of prescribed antibiotics, and the length of hospitalization.