Require Dose Adjustment Research Articles

Coadministration of Cariprazine with a Moderate CYP3A4 Inhibitor in Patients with Schizophrenia: Implications for Dose Adjustment and Safety Monitoring.

Cariprazine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. This study aimed to evaluate the effects of erythromycin, a moderate cytochrome P450 (CYP)3A4 inhibitor, on the pharmacokinetics of cariprazine in male patients with schizophrenia, and to assess the influence of CYP2D6 phenotypes on cariprazine metabolism. Forty-two patients received oral doses of 1.5 mg cariprazine alone for 28 days (to reach steady state), followed by a co-administration of cariprazine 1.5 mg daily with erythromycin 500 mg twice daily (BID) and Enterol 250 mg BID for 21 days, followed by a 14-day post-treatment period. Blood samples were collected at predefined time points and analysed for cariprazine, its two active metabolites: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), and erythromycin using validated high performance liquid chromatography-tandem mass spectrometry methods. CYP2D6 phenotypes were determined by genotyping. The pharmacokinetic parameters were calculated using non-compartmental analysis. Erythromycin increased the area under the curve (AUCτ) and peak concentration (Cmax) of Total cariprazine (cariprazine + DCAR + DDCAR) by about 40-50% but did not affect the time to peak concentration (Tmax). The CYP2D6 phenotypes had no substantial effect on the pharmacokinetics of cariprazine and its metabolites, either alone or in combination with erythromycin. Cariprazine was well tolerated and safe. The findings suggest that co-administration of cariprazine with moderate CYP3A4 inhibitors may require dose adjustment or monitoring; however, pharmacogenetic testing for CYP2D6 is not necessary for optimising cariprazine therapy. Trial registration number (EudraCT Number): 2018-003721-28. Date of registration: 21-SEP-2018.

Population Pharmacokinetic Simulations for Dose Optimization of Tenofovir Disoproxil Fumarate in HIV-Infected Patients with Moderate-to-Severe Renal Impairment.

Tenofovir disoproxil fumarate (TDF) requires dosage adjustments from the standard 300 mg once daily to every 48-96 h for moderate-to-severe renal impairment to avoid excessive exposure. However, this extended interval can lead to variable drug exposure and inconvenience. This study aimed to utilize the population pharmacokinetic (PPK) models to optimize TDF dosing regimens for HIV-infected patients with renal impairment. A systematic literature search was conducted across PubMed, Cochrane Library, and Scopus databases to identify relevant PPK studies of TDF in HIV-infected patients. From the included studies, the PPK models and associated parameters were extracted. Monte Carlo simulations (n = 2000) were performed to generate concentration-time profiles and derive PK parameters compared against reference ranges. For moderate renal impairment, the TDF 150 mg once-daily regimen achieved cumulative exposure comparable to the approved 300 mg every-other-day regimen. In severe renal impairment, TDF 75-100 mg administered once daily provided similar cumulative exposure as 300 mg every 72-96 h regimen while maintaining daily exposure comparable to the standard dose in patients with normal renal function. The approved extended dosing intervals of 72-96 h exhibited high drug exposure variability, initially resulting in supratherapeutic levels followed by suboptimal levels preceding the subsequent dose administration. In conclusion, administering smaller once-daily doses of TDF maintains consistent daily drug exposure comparable to the standard dose in patients with normal renal function while reducing variability in drug exposure, potentially mitigating the risk of nephrotoxicity. However, additional clinical studies are required to confirm these findings.

Blood concentration monitoring and renal function changes during gentamicin administration for infective endocarditis: a retrospective observational study

BackgroundEstablished guidelines for monitoring gentamicin blood concentration are lacking; therefore, we focused on improving pharmacological interventions and ensuring their safety. We aimed to optimize gentamicin administration for infective endocarditis (IE) treatment.MethodsThe study involved adult patients diagnosed with IE and treated with gentamicin from January 2014 to December 2022. Clinical presentation and drug therapy regimen were comprehensively evaluated. We performed a retrospective chart review of the frequency of gentamicin dose adjustments and changes in renal function while on gentamicin. In addition, we attempted to extract risk factors for renal impairment using univariate analysis.ResultsOn average, a 7.1% decline [changed to − 6.7 ± 20.4 (standard deviation) mL/min/1.73 m2] in the estimated glomerular filtration rate was observed after gentamicin administration, but it was statistically insignificant. Notably, 58% of patients required dosage adjustments, with a subset requiring multiple adjustments. Among the cases in which dosage adjustments were made, 61% were within the first week of treatment. There were no patients with gentamicin levels below the target peak concentration. Furthermore, no independent risk factors were identified in patients requiring dose reduction.ConclusionsDose adjustment was necessary in many cases after treatment initiation. The time to dose adjustment varied widely. These findings highlight the importance of consistent blood concentration monitoring in patients of all demographics, at least weekly, and underscore that routine peak concentration assessments may not be essential when a 3 μg/mL target is maintained. This study provides information on monitoring gentamicin blood level, which can improve IE treatment safety.

8716 Late Onset of Temozolomide in Aggressive Pituitary Tumors: Insights From a Leading Oncology Center in Latin America

Abstract Disclosure: C.R. de Macedo: None. I.P. de Magalhães: None. A. Glezer: None. M. Berardo Carneiro da Cunha Neto: None. N.R. de Castro Musolino: None. O. Feher: None. R.L. Batista: None. Introduction: Temozolomide (TMZ) is an oral alkylating agent used in management of glioblastoma multiforme. Since 2006, TMZ is used in patients with pituitary tumors (PITNets) with yielded promising outcomes as an alternative for aggressive PITNets. Objective: To evaluate the response to TMZ in patients with aggressive or metastatic PITNets within the largest tertiary oncology service in Latin America. Patients and Methods: We screened all cases that received TMZ at our institution between 2008-2023 (n=661, primarily glioblastoma cases). We identified 7 cases that TMZ was employed for treating PITNets. We assessed for PITNet characteristics, functionality, timelines of treatment initiation, correlation with radiotherapy, duration of TMZ usage and treatment response utilizing the RECIST criteria. Results: At the time of diagnosis, all patients presented with macro-PITNets and 6 were giant (size greater than 4 cm). In terms of hormonal production, 4 cases were prolactinomas and 3 were non-functioning PITNets. Over the follow-up period, these tumors exhibited an aggressive behavior, manifesting rapid tumor growth despite optimized treatments and one case was recategorized as metastatic PitNET. All cases demonstrated a Ki-67 index greater than or equal to 3%. The initiation of TMZ occurred on average 9.48 years after diagnosis and subsequent to multiple surgical interventions (average of 1.8 surgeries). In 5 cases, TMZ followed radiotherapy. Among the cohort, 3 of 7 patients underwent 6 cycles of TMZ, one underwent 5 cycles, another had an extended treatment of 10 cycles and 2 patients received only 3 cycles due to adverse effects. In terms of treatment response, 4 patients exhibited stable disease, one achieved a partial response (PR) and 2 had disease progression. The most commonly side effect was mild nausea and vomiting and one patient required dose adjustment due to thrombocytopenia. A second course of TMZ was warranted in 2 cases that previously demonstrated a PR (on average one year after the initial treatment). While one case sustained the PR, the other experienced disease progression. Conclusion: The administration of this treatment was often postponed, potentially attributed to the significant disparities in opinions regarding the optimal timing of treatment initiation and the most suitable duration of usage. However, TMZ demonstrated its efficacy in maintaining disease stability for the majority of cases, with good tolerability and safety, even when used later, after multiple surgical procedures, and in patients with high Ki67 levels. Presentation: 6/2/2024

Neurological care and outcomes in a cohort of Canadian pregnant patients with epilepsy

PurposeTo characterize anti-seizure medication (ASM) use over time, therapeutic drug monitoring, ASM dose adjustments and gestational seizure frequency among Canadian people with epilepsy of childbearing potential seen in an urban tertiary care center. MethodsParticipants were retrospectively identified from the medical records of pregnant patients with epilepsy seen at the University Health Network Epilepsy Clinic between 2014-2020. A descriptive analysis of outcomes, a logistic regression analysis of the odds of patients being on three ASMs associated with higher rates of teratogenicity (i.e., valproate, carbamazepine, and topiramate) over time, and a second logistic regression for predictors of seizure freedom during pregnancy were performed. Results195 pregnancies were included: 52% had a maternal diagnosis of generalized epilepsy and 92% were prescribed at least one ASM, with 75% on monotherapy. The majority underwent therapeutic drug monitoring (77%) with approximately two thirds requiring dose adjustments (69%), typically dosage increases (82%). The proportion of patients on either valproate, topiramate, or carbamazepine decreased over time (OR=0.80; p<0.01). Fifty-seven percent of pregnancies maintained seizure freedom, with seizure-freedom for ≥1 year prior to conception being the strongest predictor of this outcome (OR of gestational seizure recurrence=0.04; p<0.01). ConclusionThe proportion of patients on three ASMs associated with higher rates of teratogenicity has decreased over the duration of this study. Seizure-freedom prior to conception was associated with a decreased risk of gestational seizure recurrence.

Evaluating Large Language Model–Supported Instructions for Medication Use: First Steps Toward a Comprehensive Model

ObjectiveTo assess the support of large language models (LLMs) in generating clearer and more personalized medication instructions to enhance e-prescription. Patients and MethodsWe established patient-centered guidelines for adequate, acceptable, and personalized directions to enhance e-prescription. A dataset comprising 104 outpatient scenarios, with an array of medications, administration routes, and patient conditions, was developed following the Brazilian national e-prescribing standard. Three prompts were submitted to a closed-source LLM. The first prompt involved a generic command, the second one was calibrated for content enhancement and personalization, and the third one requested bias mitigation. The third prompt was submitted to an open-source LLM. Outputs were assessed using automated metrics and human evaluation. We conducted the study between March and September 2024. ResultsAdequacy scores of our closed-source LLM’s output showed the third prompt outperforming the first and second one. Full and partial acceptability was achieved in 94.3% of texts with the third prompt. Personalization was rated highly, especially with the second and third prompts. The 2 LLMs showed similar adequacy results. Lack of scientific evidence and factual errors were infrequent and unrelated to a particular prompt or LLM. The frequency of hallucinations was different for each LLM and concerned prescriptions issued upon symptom manifestation and medications requiring dosage adjustment or involving intermittent use. Gender bias was found in our closed-source LLM’s output for the first and second prompts, with the third one being bias-free. The second LLM’s output was bias-free. ConclusionThis study demonstrates the potential of LLM-supported generation to produce prescription directions and improve communication between health professionals and patients within the e-prescribing system.

Nearly complete hair re-pigmentation in an older patient treated with hydroxyurea for essential thrombocytosis

Introduction Employed in the treatment of malignancies and non-neoplastic conditions, hydroxyurea is associated with integumentary adverse effects, including skin discoloration, xerosis, pruritus, cutaneous atrophy, chronic leg ulcers, oral ulcerations, alopecia, and some nail abnormalities. Case Report A 77-year-old woman was diagnosed with essential thrombocytosis and started on low dose hydroxyurea. After 20 weeks of treatment, she experienced an unexpected change in hair color from gray to dark brown, without using hair dye or supplements. She later developed bilateral dorsal hand melanoderma, melanonychia, and onychodystrophy. Management and outcome It was decided to monitor the patient with no action taken as she was happy with this side effect of hydroxyurea. The platelet count has remained in excellent control. The dark brown hair color persisted over time. Discussion/Conclusion Hair hyperpigmentation likely occurred through melanocyte activation via hydroxyurea. Severe side effects may require dosage adjustments, while milder effects can be monitored closely. The newly observed hair color restoration in this case highlights potential dual (therapeutic and aesthetic) applications of this class of agents.

Study of Medicine Dosage Adjustments in Inpatients with Chronic Kidney Disease

Background: Decreased kidney function in patients with Chronic Kidney Disease (CKD) necessitates dose adjustment, especially for medicines that have a narrow therapeutic index to avoid unwanted medicine effects.Objectives: The purpose of this study was to determine the medicine dosage adjustments in CKD patients and their therapy outcomes.Methods: This type of research is descriptive with a retrospective approach. The sample in this study is the medical records of inpatient CKD patients at Abdoel Wahab Sjahranie Samarinda Hospital for the period May to November 2022. Calculation of GFR (Glomerular Filtration Rate) uses the MDRD (Modification of Diet in Renal Disease) formula.Results: The results showed that the sex of most patients was male as many as 56.25%. The age of most patients in the range of 53-59 years old as many as 33.75%. Most CKD severity level is stage 5 as many as 91.25%. The most common comorbidities were hypertension (61 patients), diabetes mellitus (15 patients), and edema or pulmonary edema (11 patients). There were 77 patients requiring dose adjustment out of a total of 80 patients. There were 149 (34.89%) medicines requiring dose adjustment out of a total of 427 medicines, with the 5 most medicines being calcium carbonate (24.16%), furosemide (24.16%), metoclopramide (10.74%), paracetamol (10.74%), and ranitidine (7.39%). There were 128 (85.91%) medicines with doses appropriate to the Lexicomp 2023 or Renal Pharmacotherapy 2013. The therapy outcome improved in patients who required dose adjustments by 90.91%.Conclusion: It is recommended to calculate GFR using a new formula such as eGFR using CKD-EPI, and collecting data with a larger number of samples.

Tailored Treatment Strategies in First Line Therapy for Ovarian Cancer Patients: A Critical Review of the Literature.

Ovarian cancer (OC) is a significant cause of cancer-related mortality in women globally, with a five-year survival rate of approximately 49%. Standard therapy involves cytoreductive surgery followed by chemotherapy. Its poor prognosis has driven interest in alternative therapies such as targeted molecular agents like bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi). This review systematically searched PubMed from January 2018 to December 2023 for studies on PARPi in OC. Emphasis was on identifying relevant Phase III trials, extracting data on study design, patient demographics, and outcomes. Special focus was on assessing PARPi efficacy, safety, impact on quality of life, and ongoing trials, including those on Clinicaltrials.gov. The efficacy of PARPi in first-line therapy for OC has been extensively studied. Trials like SOLO-1, PRIMA, and ATHENA-MONO have demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS), particularly in patients with BRCA mutations. Additionally, the combination of PARPi with other agents like bevacizumab has shown promising results in extending PFS. However, PARPi treatment is associated with various adverse effects, including hematologic toxicities like anemia, thrombocytopenia, and neutropenia. While most adverse events are manageable, some patients may require dose adjustments or discontinuation of treatment. Importantly, PARPi maintenance therapy has not adversely affected health-related quality of life (HRQoL), with studies reporting similar HRQoL scores between PARPi-treated and placebo-treated patients. PARPi offer effective treatment with manageable side effects, suitable even for medically fragile patients. Individualized dosing can optimize benefits while minimizing adverse events. Exploring diverse treatment approaches, particularly in patients with limited life expectancy or high disease burden, could improve outcomes. Ongoing research is investigating alternative therapies and combinations to broaden treatment options. Combining bevacizumab with PARPi may be justified for first-line and recurrent maintenance therapy. Regardless of mutational status, PARPi should be considered for maintenance therapy in newly diagnosed advanced OC. Platinum sensitivity remains crucial for treatment decisions and predicting survival outcomes.

Using a rule‐based decision tool for medication dose selection to improve patient safety and the need for pharmacist intervention

AbstractIntroductionAn assortment of alerts has been employed to influence provider order entry, yet many medication orders still require dose adjustment by pharmacists upon order verification.ObjectivesThe primary goals of this study were to evaluate the impact of adding rule‐based decision support to the computerized provider order entry system on the need for medication dose adjustment by a pharmacist and the occurrence of acute kidney injury (AKI) among patients.MethodsThis was a retrospective, pre‐ and post‐implementation observational study on the integration of rule‐based logic into the computerized provider order entry system to automatically select default doses and frequencies for weight‐based or renally‐cleared medications in alignment with health system guidelines. The primary end points were the proportion of medication orders that required pharmacist intervention for dose adjustment and the number of times the AKI pop‐up alert was triggered.ResultsAfter inclusion and exclusion criteria were applied to all available orders, there were 47 393 and 45 767 orders included for final analysis in the pre‐ and post‐implementation periods, respectively. The post‐implementation period showed a significant reduction in pharmacist dosing interventions, with a relative risk of 0.42 (95% confidence interval [CI]: 0.40–0.43; p &lt; 0.0001) and a reduction in AKI (relative risk = 0.58 [95% CI: 0.53–0.64; p &lt; 0.0001]).ConclusionThis study demonstrates the potential of rule‐based decision support to improve initial medication dose selection, reduce the occurrence of AKI, and reduce pharmacist workload, all without increasing alert fatigue.

Real-world treatment patterns and clinical outcomes among patients with HR+/HER2- advanced/metastatic breast cancer receiving palbociclib in Brazil: IRIS study.

e13088 Background: Palbociclib was approved for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced/metastatic breast cancer (aBC/mBC) in Brazil in 2018. Worldwide studies explore palbociclib's real-world use and outcomes; however, this data is not available for Brazilian patients. IRIS Brazil study aimed to describe demographic/clinical characteristics, treatment and clinical outcomes of adult female patients who have received palbociclib as first-line treatment for HR+/HER2- aBC/mBC in private healthcare institutions in Brazil. Methods: This retrospective descriptive study included females aged 18 years or older diagnosed with HR+/HER2- aBC/mBC and those who had received palbociclib as their initial line of therapy. The study analyzed variables such as demographics, clinical characteristics, treatment history, palbociclib combinations, and clinical outcomes. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier estimates at 6- and 12-month time points. Results: A total of 121 patients were included in the study. The mean age was 54.4 years, and 82 (67.7%) were menopausal at diagnosis. A total of 51 patients (42.1%) were treated with palbociclib + fulvestrant, while 67 (55.8%) were treated with palbociclib + aromatase inhibitors. The majority of patients (n = 79; 65.3%) did not require any dose adjustments. Among the 40 patients (33.1%) who required dose adjustments, the main reason was adverse events/toxicity (n = 36; 90%). The PFS rates at 6 and 12 months were 78% and 60%, respectively. The OS rates at 6 and 12 months were 86% and 70%, respectively. Conclusions: Results from this initial real-world assessment of clinical outcomes in Brazil suggest that Palbociclib combinations exhibit favorable effectiveness in treating HR+/HER2- aBC/mBC disease, as measured by PFS and OS rates.

A real-world, patient-reported outcomes study in patients with platinum-sensitive recurrent ovarian cancer receiving long-term maintenance therapy with niraparib.

e23164 Background: Niraparib has been approved for the maintenance treatment of newly diagnosed advanced and platinum-sensitive recurrent ovarian cancer (PSR OC). The phase 3 PRIMA and NOVA studies showed that maintenance niraparib did not worsen quality of life (QoL) compared with placebo. However, no QoL data have been reported for Asian OC patients treated with niraparib. Here, we report patient-reported outcomes (PROs) for PSR OC patients who received niraparib as maintenance therapy for more than two years in a real-world setting. Methods: This prospective, real-world study included OC patients participating in the Niraparib Patient Assistance Program (PAP) in China (NCT06037213). Eligible patients had histologically confirmed PSR epithelial OC, fallopian tube, or primary peritoneal cancer, had been maintained on niraparib for more than two years without disease progression and were still receiving niraparib within 28 days. PROs were assessed every 4-6 weeks for three times using the EQ-5D-5L questionnaire and the FOSI. In addition, a 6-question niraparib medication questionnaire including starting dose, adaptive dose, dose adjustments and reasons, missed doses, concomitant medications was administered at baseline. Results: The PAP enrolled 3154 PSR OC patients, 1151 had been on niraparib for more than two years and could be followed up. From August 2023 to January 2024, 604 eligible patients were recruited and completed at least one assessment. The median age was 58 years (range, 27-82 years). The median duration of treatment with niraparib was 34.8 months (range, 30.5-46.7 months). Among 445 patients with BRCAm status, 104 were BRCAm (23.4%) and 341 were BRCAwt (76.6%). A total of 491 patients (81.3%) received niraparib 200 mg as a starting dose, while 107 (17.7%) required dose adjustments in clinical practice. Presently, 503 (83.3%) were on 200mg. 523 (86.6%) were compliant with the daily oral dose of niraparib, without missing any doses in the previous 6 months. 193 patients (32.0%) had common chronic disease, and 176 (29.1%) were taking concomitant medications during maintenance. The EQ-5D-5L HUI and VAS scores remained stable across the three assessments. The baseline mean EQ-5D-5L HUI and VAS scores were 0.98 (SD 0.05) and 84.31 (SD 10.50), respectively, and the least squares (LS) mean changes from baseline to the third assessment were -0.004 (SE 0.001) and -0.609 (SE 0.248), respectively. A similar situation was observed for the FOSI score. The baseline mean FOSI score was 31.13 (SD 1.37), and the LS mean change from baseline to the third assessment was -0.359 (SE 0.033). Conclusions: In the real world, patients with PSR OC who underwent long-term maintenance treatment with niraparib exhibited a consistently stable QoL. This finding highlights the significant clinical value of niraparib in maintaining QoL in these populations.

Embodiment of Pharmacist Intervention in Palliative Care and Augmentation of a Curriculum for its Assessment

Background Palliative care is the care of patients who have progressive, life-threatening illnesses and who are facing death in the foreseeable future. Since there is a growing need for pharmacist’s intervention in palliative care and there is a gap in the education of palliative care for pharmacy students, this study aims to identify roles and services that have to be performed by palliative care pharmacists in medication-related areas and also to formulate an add-on course to train pharmacy graduates. Materials and Methods A prospective interventional study was done in the palliative care centre in Perinthalmanna, Kerala, India. Relevant data were pooled and analysed for drug-related problems. Necessary interventions were made. Results were interpreted and an add-on course for the training of pharmacy graduates was formulated. Results A total of 88 patients were included in the study. The most prevalent conditions in our palliative setting were kidney disease, liver disease, cancer and stroke. Notably, 38 and 10 cases were found to have drug interactions and drug duplications, respectively. Four patients required dosage adjustments. Fifty cases involved pharmacist intervention which improved the outcome by 80%. At the end of the study, a curriculum was formulated to implement a 3-month add-on course entitled ‘PALLIATIVE PHARMACY’ under the guidance of an Expert committee for training pharmacists and pharmacy students. Conclusion The study identified that there are various roles a pharmacist must undertake in a palliative setup. The involvement of pharmacists in patients’ treatment helps to prevent drug-related problems to a greater extent. The addition of an integrated course for the management of palliative care patients will help to improve the learning as well as practical skills of pharmacists. Incorporating basic and clinical sciences in the therapeutic course is an effective learning plan.

#2733 Osteoporosis and CKD-MBD in hemodialysed patients: efficacy and safety of denosumab

Abstract Background and Aims Osteoporosis is a chronic progressive disease characterized by low bone mass and deterioration of bone tissue which results in a rapid increase in fracture risk. Osteoporosis in hemodialysed patients with Chronic Kidney Disease – Mineral and Bone Disorder (CKD-MBD) is a debilitating clinical condition with complex therapeutic management. In fact, most of the drugs commonly used to counteract osteoporosis are generally contraindicated when Glomerular Filtration Rate (GFR) is lower than 35 ml/min. Denosumab is approved for the treatment of osteoporosis and does not require dose adjustment in case of impaired renal function. For this reason, since 2014 this drug has been used by nephrologists for the treatment of osteoporotic patients also in hemodialysis. Although the interest and diffusion in this specialized clinical field are growing, only few data are still available in literature. The aim of the study was to evaluate the efficacy and safety of Denosumab in long-term therapies (up to 68 months of therapy) in hemodialysed patients. Method Since December 2013, a total of 22 hemodialysed patients have been treated with Denosumab annually (4) or semi-annually (18) for up to 68 consecutive months. During the treatment, we monitored the blood levels of calcium, phosphorus, PTH, beta-CrossLaps and bone alkaline phosphatase (BALP), T-SCORE and fracture risk (FR) using Qualitative UltraSonography (QUS) or Computerized Bone Mineralometry (CBM) every 30 months and every 2 years, respectively. Results 4/22 patients completed at least 48 months of follow-up, observing a substantial stability of the mean values of blood calcium (from 9.09 mg/dl to 8.63 mg/dl) and phosphorus (from 5.2 mg/dl to 4.1 mg/dl), against a reduction in the mean values of B-CrossLaps and bone alkaline phosphatase (BALP) (respectively from 2975.32 to 1452.75 pg/ml and from 32.09 to 14.58 mcg/L). Comparison of QUS exams demonstrated improved T-score (mean values from −4.71 to −4.17) and reduced fracture risk (mean value from 13% to 8%). The results of the CBMs confirmed the improvement of the bone disease at the lumbar spine (T-score from −3.8 to 2.8 after 2 years of treatment) and the substantial stability of the T-score at the femoral level (from −3.5 to −3.2 after 2 years of treatment). It should be noted that in our samples two patients achieved the longest observation period (68-month follow-up in continuous therapy), in which we observed improvement of the bone disease also at the femoral level compared to the start of treatment (T-score from −3.9 to −2.8 after 48 months of treatment). Only one fracture has been recorded. Conclusion The results obtained confirm efficacy and safety of Denosumab in reducing the risk of fractures, with the improvement of BMD and T-score at the lumbar spine using Computerized Bone Mineralometry (CBM). We underline that close biochemistry monitoring and careful evaluation of the therapeutic procedures before and after Denosumab administration helped us to minimise and promptly correct adverse effects due to hypocalcemia. In addition we are particularly satisfied to report in most patients a significant reduction of pain and an improvement of mobility. The results collected are consistent with acceptable safety and demonstrated efficacy of Denosumab in hemodialysis patients.

#2242 mTORi: edging closer to targeted therapy in tuberous sclerosis complex

Abstract Background and Aims Tuberous sclerosis complex (TSC) is an autosomal dominant condition with an estimated incidence of 1 in 6000 births. TSC is caused mostly by mutations in either TSC1 or TSC2 genes, with 70–80% of cases resulting from sporadic mutations; however in 10-15% of cases no mutations are identified. A dysregulation of these genes that encode the hamartin and tuberin proteins, respectively, results in an aberrant signaling of the mammalian target of the rapamycin (mTOR) pathway and subsequent tumor growth. Indeed, the clinical features of TSC are characterized by the proliferation of different types of hamartomas in various organs, including brain, heart, skin, lungs, eyes, bone, kidneys and less frequently pancreas. TSC is mainly diagnosed clinically according to diagnostic criteria with genetic testing performed in cases of diagnostic uncertainty or/and to support the clinic diagnosis. Renal angiomyolipomas (AMLs), observed in more than 80% of patients with TSC, are benign, mostly bilateral tumors, composed of immature smooth muscle cells, abnormal blood vessels and fat cells in variable portions. Their size and the prevalence of their vascular component are directly associated with risk of acute bleeding that in 25% of cases may require embolization or nephrectomy. As a consequence, renal complications are the leading cause of death in adult TSC patients and AML-related surgery is performed in a high percentage of these patients. In the last decade, mTOR inhibitor (mTOR-i) therapy has demonstrated to be a potential alternative to embolization and nephrectomy for managing TSC-AML. The aim of this study was to evaluate over time, potential changes in the relative tissue composition of renal AMLs and their overall size following the initiation of mTOR-i therapy based on MRI measurements. Method From August 2011 to May 2023, 86 potentially eligible adult TSC patients with AML, across a great part of Italy were referred for assessment and monitoring at our center. 14 of these patients were eligible for mTOR-i therapy. An ethics committee approved its use as a compassionate therapy as mTOR-is are not approved as a conventional therapy for renal AMLs in Italy. These patients underwent baseline renal magnetic resonance imaging (MRI) assessment and a regular follow-up with MRI scan every 6-9 months after initiation of therapy. Dose titration was guided by trough levels, side effects and lesion radiological responsiveness on MRI. Results No AML bleeding events were documented during the study. None of the 14 patients on treatment discontinued therapy. Overall, 5 of them (35.7%) required dose adjustments during the course of treatment due to adverse events (40%), sub-optimal trough levels (40%) or minimal radiological response (20%). Radiologic assessment with MRI confirmed a halted growth trend in all treatment-naive cases (100%) and in 64% of them, a regression in AML volume and a reduction of their vascular component within the first year of treatment. Conclusion Our experience confirmed results that emerged from different clinical studies evaluating mTOR inhibition in TSC patients conducted in the last decade. For renal angiomyolipoma, mTOR-i treatment, carefully monitored, fundamentally changed the approach from preventive embolization or even partial nephrectomy to pharmacological treatment; drastically limiting the number of urgent interventional procedures that TSC patients often might undergo. In conclusion, mTOR-i therapy represents a valid and important therapeutic strategy to arrest the growth or regress of renal AMLs.

Pharmacokinetics of tenofovir alafenamide, emtricitabine, and dolutegravir in a patient on peritoneal dialysis

IntroductionPeritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited.MethodsA single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose.ResultsPlasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR.ConclusionsIn a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.

Abstract PO4-04-13: Impact of dose reduction of CDK4/6 inhibitors on progression-free survival in Mexican patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a retrospective single-center study

Abstract Background Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been demonstrated to prolong survival in women with hormone receptor-positive, HER-2 negative, metastatic breast cancer. However, these treatments often require dose adjustments due to adverse effects, resulting in a reduction in 30-50% of cases. There is evidence suggesting a relationship between dose intensity and progression-free survival (PFS), but data in the Hispanic population are limited. Therefore, the objective of the study was to explore the association between dose reduction of CDK4/6/i inhibitors and PFS in patients with metastatic breast cancer. Methods We conducted a retrospective single-center study involving patients diagnosed with hormone receptor-positive, HER-2 negative metastatic breast cancer (MBC) between 2020 and 2023. Eligible patients were those who received at least one cycle of palbociclib, abemaciclib, or ribociclib and had a follow-up period of more than three months since the initiation of CDK4/6 inhibitor (CDK4/6i) treatment. Patient data were collected from electronic medical records. We analyzed demographic and clinicopathological characteristics and estimated the PFS in patients who had any dose reduction within the first 12 weeks compared to those who did not, using Kaplan-Meier plots and compared the differences in survival using the log-rank test. A Cox regression analysis was performed to estimate survival hazard ratios (HR). Results Among 41 patients, the mean age at CDK4/6i initiation was 61.0 years (SD 12.9), 22 (53.7%) were postmenopausal at diagnosis, 25 (61%) had recurrent disease, and 22 (53.7%) were receiving CDK4/6i in the first-line setting. Bone metastases were present in 30 (73.2%), and visceral metastases in 22 (53.7%). Regarding type of CDK4/6i, 33 (80.5%) received palbociclib, 7 (17.1%) ribociclib, and 1 (2.4%) abemaciclib. At 12 weeks, 12 patients (29.3%) had a dose reduction (Table 1). With a median follow-up since CDK4/6i initiation of 407 days (95% confidence interval (CI) 272-542), 19 events were recorded, with a median PFS of 12.6 months (95% CI 8.0-17.3) for the overall population. Median PFS was 9.7 months (95% CI 0.6-18.8) in patients who had a dose reduction at 12 weeks and 35.2 months (95% CI 0-72.2) in those who did not (p=0.014). The univariate Cox proportional hazard model showed that dose reduction was associated with a worse PFS (hazard ratio 3.1; 95% CI: 1.20–7.80, p = 0.0019) Conclusion In this cohort of Mexican patients with hormone receptor-positive, HER2-negative metastatic breast cancer we found that dose reduction of CDK4/6 inhibitors within the first 12 weeks of treatment was associated with worse PFS. Given the retrospective nature of this analysis, we believe that these findings should be replicated in prospective studies. Table. Patient characteristics Citation Format: Andres Meraz-Brenez, Alejandro Aranda-Gutierrez, Hector Raul Gonzalez-Sanchez, Bertha Alejandra Martinez-Cannon, Leonardo Verduzco-Rodriguez, Haydee Cristina Verduzco-Aguirre. Impact of dose reduction of CDK4/6 inhibitors on progression-free survival in Mexican patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a retrospective single-center study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-13.

Hematocrit control and thrombotic risk in patients with polycythemia vera treated with ruxolitinib in clinical practice

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by unregulated red blood cell production resulting in elevated hemoglobin and/or hematocrit levels. Patients often have symptoms such as fatigue, pruritus, and painful splenomegaly, but are also at risk of thrombosis, both venous and arterial. Ruxolitinib, a selective Janus kinase inhibitor, is approved by the US Food and Drug Administration as second-line cytoreductive treatment after intolerance or inadequate response to hydroxyurea. Although ruxolitinib has been widely used in this setting, limited data exist in the literature on ruxolitinib treatment patterns and outcomes among patients with PV in routine clinical practice. We report a retrospective, observational, cohort study of patients treated for PV with ruxolitinib across three US centers (academic and regional practice) from December 2014-December 2019. The study included 69 patients, with a median follow-up duration of 3.7 years (95% CI, 2.9–4.4). Our data demonstrate very high rates of hematocrit control (88% of patients by three months and 89% by six months); few patients required dose adjustments or suspension. No arterial thromboses were observed; however, the follow-up duration does not allow for the generation of meaningful conclusions from this. Three patients had thrombotic events; one was in the setting of a second malignancy, one post-operative, and a third related to prolonged immobility. We also found that 28% of patients initiated ruxolitinib as a result of poorly controlled platelet counts, second only to hydroxyurea intolerance (46%) as a reason to start therapy. In clinical practice, ruxolitinib continues to be effective in controlling hematocrit levels after three and six months of treatment in patients and is associated with low thrombotic risk.

599 To Titrate or Not to Titrate, That Is the Burning Question: Enoxaparin and VTE Prophylaxis

Abstract Introduction Patients who sustain burn injury undergo metabolic and physiologic changes that place them at elevated risk of developing venous thromboembolism (VTE). Although the benefit and safety of enoxaparin titration for prevention of VTE in trauma patients is well established, there is a lack of evidence regarding its applicability for burn injured patients. In this study, we sought to determine the safety and applicability of enoxaparin titration for burn injured patients admitted for treatment of their injury. Methods We performed a single center retrospective study of burn injured patients admitted to our American Burn Association verified burn center from June 2022 to June 2023. In May 2022, our burn center adopted the American Association for Surgeons in Trauma (AAST) protocol for enoxaparin dosing. This includes twice daily administration of enoxaparin, followed by measurement of anti-Xa levels prior to administration of the fourth or fifth dose. We previously administered a standard dose of 30mg twice daily. Anti-Xa levels were used to guide enoxaparin dose adjustments to remain within prophylactic range. Patients hospitalized for under 48 hours, with glomerular filtration rate less than 30, and with repeated refusal of enoxaparin were excluded. Results Eighty seven patients met our inclusion criteria. Fifty six patients started at 40mg twice daily dosing; the remainder started at 30mg twice daily dosing. Of these patients, forty two (48%) required dose adjustments by anti-Xa levels. Of those who required dose adjustment, thirty three (78%) required an increase. There was no significant difference in BMI (p=0.25) or inhalation injury (p=0.62) between patients who did and did not require enoxaparin titration. Patients who required titration had a non-significant trend toward larger percent total body surface area affected (p=0.08). There was also a significantly greater change in dosing for patients who required an increase in dose adjustment as opposed to those who required a decrease in dose adjustment (p &amp;lt; 0.0001). Finally, there was no difference in post-operative bleeding between patients who did and did not require dose titration (p=0.57). Conclusions Our results demonstrate that an individual approach to VTE prevention through enoxaparin titration is necessary in order to maintain appropriate prophylactic doses in burn injured patients. Furthermore, adoption of the AAST guidelines is safe and does not result in an increase in post-operative bleeding events. Applicability of Research to Practice This work highlights the safety and benefit of enoxaparin titration in burn injured patients to prevent VTE.

Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis

BackgroundIvacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF. MethodsIn this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. ResultsSeven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (−40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed. ConclusionsIn this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.