Clinically significant drug interactions of Eltrombopag: a retrospective study from the clinical pharmacist perspective

Introduction: Thrombopoietin is the main cytokine regulating megakaryopoiesis and platelet production. Eltrombopag interacts with the transmembrane domain of thrombopoietin receptors and initiates signaling cascades inducing proliferation and differentiation from bone marrow progenitor cells. The aim of the study was to determine drug interaction at patients that are receiving Eltrombopag along with other medications. Materials and methods: A retrospective, longitudinal study was conducted at the Hematology Clinic in Skopje, N. Macedonia. A clinical pharmacist, focusing on Eltrombopag and concomitant medications interactions, reviewed a total number of 16 patient’s histories for the period of 6 months (January-June 2023). Anamnestic data on additional drugs, herbal supplements, vitamins, minerals were also taken. Potential drug interactions were identified using Stockley's interactions checker, categorized by severity and subclassified into co-administered drugs altering pharmacokinetics. Results: A total number of 73 interactions were identified, of which 23 (31.51%) were with moderate clinical relevance, 14 (19.18%) were with no clinical importance and required counseling about possible adverse effects and additional monitoring. The rest of 36 (49,32%) interactions were without clinical significance. Additionally, we determine that 7 (9.59%) of total interactions directly related to patients receiving Eltrombopag (ciclosporin, atorvastatin, rosuvastatin, dexamethasone, prednisolone, valsartan, and magnesium) and categorized as moderate and needs close monitoring. Conclusion: This study demonstrates toxicity potential of Eltrombopag at patients associated with concomitant medicines. Close collaboration of physicians and clinical pharmacists is necessary in all cases where patients are receiving Eltrombopag along with other medications in order all significant interactions to be identified, prevented and managed

Безбедност на пациентите во клиничка пракса - програма за контролиран пристап до лекот леналидомид

Леналидомид е лек кој поседува антинеопластично, антиангиогено, проеритропоетско и имуномодулаторно дејство, но притоа поседува и изразено тератогено дејство. Клиничкиот фармацевт при ЈЗУ Универзитетска клиника за хематологија - Скопје е одговорен за спроведување на процесот на фармаковигиланца. Затоа, со цел подобрување на безбедноста на пациентите, на клиниката се спроведе контролирана дистрибуција на лекот таблети леналидомид од 5 mg. Kако мерка за минимализација на ризикот (ММР) за пациентите кои го примаат овој лек се спроведе програмата за контролиран пристап (CAP), според која пропишувањето на лекот го вршат исклучиво лекари кои се евидентирани во Регистарот на едуцирани лекари за спроведување на програмата за превенција на бременост (PPP). Со тоа се водеше грижа пациентот да го прими лекот само доколку се исполнети барањата од PPP. Бидејќи лекот се излачува и во спермата, во програмата покрај жени мораше да бидат вклучени и пациенти од машка популација. За лекот таблети леналидомид 5 mg, PPP е спроведена кај 36 пациенти (23 мажи и 13 жени), во тек на 18 месеци, започнувајќи од октомври 2021 година. Вo овој период лекот е издаден на 14 пациенти со мултипен миелом кои претходно примиле барем една линија на терапија (во комбинација со дексаметазон), 22 пациенти со терапија на одржување на новодијагностициран мултипен миелом кај кои е спроведена трансплантација на автологни матични клетки и 1 пациент со дијагноза Не-Хочкинов фоликуларен лимфом. Со едуцирање на пациентите и преземање на сите пропишани мерки од PPP, потенцијалниот ризик од тератогеното дејство на лекот беше сведен на минимум

Determination of non-adherence in patients receiving Eltrombopag

Eltrombopag, an orally administered thrombopoietin receptor agonist, selectively binds to the transmembrane domain of the thrombopoietin receptor on the surface of platelets, megakaryocytes and megakaryocyte precursor cells (1). The aim of our research is to determine patient non-adherence and its impact on the effectiveness and safety of prescribed therapy, as well as the possibility of treatment failure. The observational, longitudinal, and retrospective study was conducted in the PHO University Clinic of Hematology in Skopje, R.N.Macedonia. 17 patients (9 men and 8 women) were followed from January to August 2023. Five of them were with diagnose aplastic anemia and 12 with immune thrombocytopenia. All of them treated with Eltrombopag. We have systematically reviewed medical records from the Department of Hospital pharmacy, collected anamnestic data and determine non-adherence to therapy, followed by dose frequency, double taking therapy, omitted doses, drug-drug interactions and food/supplement-drug interactions. Thirteen types of non-adherence were identified, of which 3(23,08%) were related to dose frequency, 1(7,69 %) was related to double taking therapy, 5(38,46%) were related to the possibility of drug-drug interactions, 2(15,38%) with possibility for food/supplement-drug interactions and 2(15,38 %) were related with omitted doses. Failure to adherence is a serious problem which not only affects the patient but also the health care system. The clinical pharmacist intervention can improve patient adherencе, because the most important determinants effectiveness and safety are adherence to the prescribed therapy, multiple drug and food/supplement interactions which can vary on dose-response relationship, and risk of insufficient effectiveness of therapy (2)

A Rare Case of Soft Tissue Erdheim Chester Disease: Diagnostic Dilemma and Management

BACKGROUND: Erdheim Chester disease (ECD) is a rare form of non-Langerhans histiocytosis that still presents a diagnostic and clinical dilemma. CASE PRESENTATION: We present a rare case of ECD, young 31 male with atypical localisation and soft tissue presentation and no bone involvement. He started clinical investigations due to subcutaneous tumour mass in the lumbar spine that caused severe back pain. Skin biopsy revealed ECD with Immunohistochemistry CD68+, CD10+, CD11c+, vimentin+, S100A4+. Activating BRAFV600E mutation was positive from the tumour tissue. The patient was referred to the haematology department. PET CT was performed for initial disease staging. Treatment was started with corticosteroids (methylprednisolone 0.5 mg/kg per day), and after 7 days, a significant clinical improvement was noticed in terms of pain disappearance with no need for pain killers. After two weeks, treatment with interferon Alfa (IFN-α) was started in a dose of 3 million units 3 times per week. After 4 months of interim treatment PET, CT revealed a significant reduction of the tumour mass. Therapy with IFN-α was continued, and the patient is still clinically in good condition. CONCLUSION: It can be concluded that shortening the time of diagnosis of ECD is essential in treatment outcome of this disease. Still, large studies have to confirm the best treatment of this rare condition

Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies:a report from the EPICOVIDEHA registry

Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan–Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448–4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619–8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093–0.732) and obesity (aOR 0.105, 95%CI 0.014–0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).</p

Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry

Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan-Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448-4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619-8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093-0.732) and obesity (aOR 0.105, 95%CI 0.014-0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p&nbsp;=&nbsp;0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223)

Basic Science Republic of Macedonia

Abstract Aim: The aim of this study was to examine the gene frequencies of 16 KIR genes and pseudogenes and KIR genotypes in Macedonian patients with transplanted bone marrow and their sibling donors in treatment of haematological malignancy, and to analyse eventual association of the gene content with the occurrence of a graft versus host disease (GVHD). Material and Methods: The study was performed on 24 patients and their HLA-matched sibling donors. Results: Comparison of KIR gene frequencies between the total 24 donors and healthy Macedonians reveals statistically significant difference for KIR2DS1 (F= 0.481 in the controls group, and 0.76 in the patients group, p=0.004). This significance is even higher when the frequency of KIR2DS1 in controls is compared with the frequency in donors from pairs with GVHD (F= 0.923, P= 0.002). Another significant difference was observed for the frequency of the full-length allele of KIR2DS4*001-002, present in 25.2% of the control individuals, but in as much as 81.8% of the recipients of haematopoietic stem cell (P=0.0005). We did not see any statistically significant difference in distribution of the C1/C1, C1/C2 and C2/C2 groups among GVHD pairs. Conclusion: Our results address the difference between the haematopoietic stem cell transplantation settings with sibling and unrelated donors and suggest that the KIR2DS4*001/002 might be a predisposing factor for severe GVHD in sibling HSCT

Basic Science Republic of Macedonia

Abstract Aim: The aim of this study was to examine the gene frequencies of 16 KIR genes and pseudogenes and KIR genotypes in Macedonian patients with transplanted bone marrow and their sibling donors in treatment of haematological malignancy, and to analyse eventual association of the gene content with the occurrence of a graft versus host disease (GVHD). Material and Methods: The study was performed on 24 patients and their HLA-matched sibling donors. Results: Comparison of KIR gene frequencies between the total 24 donors and healthy Macedonians reveals statistically significant difference for KIR2DS1 (F= 0.481 in the controls group, and 0.76 in the patients group, p=0.004). This significance is even higher when the frequency of KIR2DS1 in controls is compared with the frequency in donors from pairs with GVHD (F= 0.923, P= 0.002). Another significant difference was observed for the frequency of the full-length allele of KIR2DS4*001-002, present in 25.2% of the control individuals, but in as much as 81.8% of the recipients of haematopoietic stem cell (P=0.0005). We did not see any statistically significant difference in distribution of the C1/C1, C1/C2 and C2/C2 groups among GVHD pairs. Conclusion: Our results address the difference between the haematopoietic stem cell transplantation settings with sibling and unrelated donors and suggest that the KIR2DS4*001/002 might be a predisposing factor for severe GVHD in sibling HSCT