ABSTRACT
BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors marked a milestone in the breast cancer treatment. Due to the potential impact of adverse effects on treatment decisions and patient outcomes, careful consideration of the varying toxicities of CDK4/6 inhibitors is crucial, as three inhibitors-palbociclib, abemaciclib, and ribociclib-have been approved with differences in adverse event profiles. However, limitations in clinical trials call for urgent real-world safety studies to evaluate and compare the risk of adverse events (AEs) among these CDK4/6 inhibitors. Therefore, this study aimed to analyze AEs of CDK4/6 inhibitors and provide insights for clinical drug selection, using real world database. METHODS: The AEs of CDK4/6 inhibitors in the FDA Adverse Event Reporting System (2015-2022) were analyzed. Four disproportionality methods were used to detect safety signals: reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Neural Network Propagation, and Multi-Item Gamma Poisson Shrinker. Venn analysis was used to compare and select common and specific AEs. RESULTS: This study included 73,042 patients treated with palbociclib, 25,142 with ribociclib, and 7563 with abemaciclib. All three inhibitors had 27 common AEs. Palbociclib exhibited the highest ROR for hematologic toxicities, while ribociclib showed the highest ROR for macrocytosis, nail disorders, and hepatic lesions. Abemaciclib displayed the highest ROR for mucosal toxicity. Common signals for both palbociclib and ribociclib included hematologic toxicities, decreased immune responsiveness, and aphthous ulcers. Myelosuppression, oral pain, and pseudocirrhosis were common signals for palbociclib and abemaciclib. Anemia, hepatotoxicity, and pneumonitis were observed as common signals for ribociclib and abemaciclib. Furthermore, specific AEs associated with palbociclib included fatigue, alopecia, and stomatitis. For ribociclib, specific AEs included electrocardiogram QT prolongation, thrombocytopenia, and decreased hemoglobin. Abemaciclib was specifically linked to diarrhea, vomiting, and interstitial lung disease. CONCLUSION: Our analysis revealed that palbociclib showed a higher risk of hematologic toxicity. Ribociclib showed higher risks of hepatotoxicity, nephrotoxicity, and QT prolongation. Abemaciclib showed higher risks of hepatotoxicity, gastrointestinal effects, interstitial lung disease, and thrombosis. These findings provide valuable insights for CDK4/6 inhibitor selection.
Subject(s)
Adverse Drug Reaction Reporting Systems , Aminopyridines , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Pharmacovigilance , Piperazines , Protein Kinase Inhibitors , Purines , Pyridines , United States Food and Drug Administration , Humans , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , United States/epidemiology , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Purines/adverse effects , Protein Kinase Inhibitors/adverse effects , Piperazines/adverse effects , Piperazines/therapeutic use , Aminopyridines/adverse effects , Pyridines/adverse effects , Benzimidazoles/adverse effects , Case-Control Studies , Antineoplastic Agents/adverse effects , FemaleABSTRACT
We describe and analyze resistance-associated mutations (RM) and virological failures (VF) on antiretroviral therapy using the latest approved integrase inhibitors (INIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB), together with their companion drugs in fixed-dose formulations: BIC/emtricitabine/tenofovir; CAB/rilpivirine; DTG/abacavir/lamivudine; DTG/emtricitabine/tenofovir; and DTG/lamivudine. Systematic literature searches were conducted in PubMed and other electronic databases for clinical studies published between January 2010 and May 2023, according to preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA), which analyzed VFs and RMs of INIs. Fifty clinical studies were included in the synthesis. VF in antiretroviral treatment (ART)-naïve patients occurred in 0.7-4.0%, 0.6-1.4%, and 0.6-9.0% of patients treated with DTG, BIC, and CAB, respectively. VF was reported in patients with previous ART in 0-8.1%, 0-2.0%, and 0.4-2.3% of those treated with DTG, BIC, and CAB, respectively. RMs were detected in ART-naïve patients in only one study with DTG (0.3%), none of the studies with BIC, and three of the studies with CAB (0.1-5.4%). In ART-experienced patients, RMs were detected in 0-1.9% of DTG-treated patients. No cases of RM were detected in the 11 BIC studies reviewed. In the case of CAB, RMs were detected in eight studies, ranging from 0.3% to 1.9% of patients. In conclusion, RM rates in the studies reviewed were generally low using the latest INIs. This review identified BIC as the INI with the lowest number of observed VF and lack of RM.
Subject(s)
Drug Resistance, Viral , HIV Infections , HIV Integrase Inhibitors , HIV-1 , Heterocyclic Compounds, 3-Ring , Heterocyclic Compounds, 4 or More Rings , Oxazines , Piperazines , Pyridones , Humans , Pyridones/therapeutic use , Heterocyclic Compounds, 3-Ring/therapeutic use , Oxazines/therapeutic use , Piperazines/therapeutic use , HIV Infections/drug therapy , HIV Infections/virology , HIV-1/drug effects , HIV Integrase Inhibitors/therapeutic use , HIV Integrase Inhibitors/pharmacology , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Pyridazines/therapeutic use , Pyridazines/pharmacology , Treatment Failure , Amides/therapeutic use , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/pharmacology , DiketopiperazinesSubject(s)
Acrylamides , Adenocarcinoma of Lung , Afatinib , Aniline Compounds , Drug Resistance, Neoplasm , ErbB Receptors , Exons , Lung Neoplasms , Mutation , Humans , ErbB Receptors/genetics , Afatinib/therapeutic use , Afatinib/pharmacology , Acrylamides/therapeutic use , Acrylamides/pharmacology , Mutation/genetics , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/pathology , Aniline Compounds/therapeutic use , Aniline Compounds/pharmacology , Exons/genetics , Female , Piperazines/therapeutic use , Piperazines/pharmacology , Male , Indoles , PyrimidinesSubject(s)
Acrylamides , Aniline Compounds , Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Mutation , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Acrylamides/therapeutic use , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , ErbB Receptors/genetics , Aniline Compounds/therapeutic use , Antineoplastic Agents/therapeutic use , Piperazines/therapeutic use , Neoplasm Staging , Protein Kinase Inhibitors/therapeutic use , Indoles , PyrimidinesABSTRACT
OBJECTIVE: Given its key homeostatic role affecting mitochondria, ionotropic and metabotropic receptors, and voltage-gated ion channels, sigma-1 receptor (Sig1R) represents an interesting target for epilepsy management. Antiseizure effects of the positive allosteric modulator E1R have already been reported in acute seizure models. Although modulation of serotonergic neurotransmission is considered the main mechanism of action of fenfluramine, its interaction with Sig1R may be of additional relevance. METHODS: To further explore the potential of Sig1R as a target, we assessed the efficacy and tolerability of E1R and fenfluramine in two chronic mouse models, including an amygdala kindling paradigm and the intrahippocampal kainate model. The relative contribution of the interaction with Sig1R was analyzed using combination experiments with the Sig1R antagonist NE-100. RESULTS: Whereas E1R exerted pronounced dose-dependent antiseizure effects at well-tolerated doses in fully kindled mice, only limited effects were observed in response to fenfluramine, without a clear dose dependency. In the intrahippocampal kainate model, E1R failed to influence electrographic seizure activity. In contrast, fenfluramine significantly reduced the frequency of electrographic seizure events and their cumulative duration. Pretreatment with NE-100 reduced the effects of E1R and fenfluramine in the kindling model. Surprisingly, pre-exposure to NE-100 in the intrahippocampal kainate model rather enhanced and prolonged fenfluramine's antiseizure effects. SIGNIFICANCE: In conclusion, the kindling data further support Sig1R as an interesting target for novel antiseizure medications. However, it is necessary to further explore the preclinical profile of E1R in chronic epilepsy models with spontaneous seizures. Despite the rather limited effects in the kindling paradigm, the findings from the intrahippocampal kainate model suggest that it is of interest to further assess a possible broad-spectrum potential of fenfluramine.
Subject(s)
Disease Models, Animal , Epilepsy , Fenfluramine , Kindling, Neurologic , Receptors, sigma , Sigma-1 Receptor , Animals , Receptors, sigma/antagonists & inhibitors , Receptors, sigma/drug effects , Mice , Kindling, Neurologic/drug effects , Fenfluramine/pharmacology , Epilepsy/drug therapy , Male , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Dose-Response Relationship, Drug , Piperazines/pharmacology , Piperazines/therapeutic use , Amygdala/drug effects , Amygdala/physiopathology , Hippocampus/drug effects , Chronic Disease , Kainic Acid/pharmacology , Mice, Inbred C57BLABSTRACT
BACKGROUND: Treatment with different antipsychotics can lead to various metabolic side effects in patients with psychosis, impacting long-term prognosis. This study aimed to compare the changes and clinical efficacy of insulin resistance in patients treated with olanzapine and ziprasidone. METHOD: A retrospective analysis was conducted on the clinical data of 80 patients with schizophrenia. The patients were divided into olanzapine treatment group and ziprasidone treatment group. Parameters including body weight, body mass index (BMI), fasting plasma glucose (FPG), fasting plasma insulin (FPI), cholesterol (CHO), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), insulin resistance index, and Positive and Negative Syndrome Scale (PANSS) scores were recorded and compared before and after treatment. RESULTS: BMI, FPG, FPI, homeostatic model assessment of insulin resistance (HOMA-IR), CHO, TG and LDL in both groups were significantly higher than before treatment (p < 0.05). These parameters were significantly higher in the olanzapine group than in the ziprasidone group (p < 0.05). The level of HDL in both groups was significantly decreased after treatment, and the level of HDL in the olanzapine group was significantly lower than that in the ziprasidone group after treatment (p < 0.05). After treatment, the total score and score of PANSS in both groups were significantly lower than before treatment (p < 0.05). After treatment, there was no significant difference in total score and PANSS score between both groups (p > 0.05). The incidence of insulin resistance (IR) was significantly higher in the olanzapine group compared to the ziprasidone group (χ2 = 4.021, p < 0.05). In the IR group, BMI, FPG, FPI, TG, and LDL levels were higher than in the non-IR group (p < 0.05). Multivariate analysis indicated that BMI, FPG, FPI, TG, and LDL were independent risk factors for IR (odd ratio (OR) >1, p < 0.05). CONCLUSIONS: Treatment with olanzapine and ziprasidone improves clinical symptoms in patients with schizophrenia, but increases the risk of insulin resistance. The metabolic side effects of olanzapine are more pronounced.
Subject(s)
Antipsychotic Agents , Insulin Resistance , Olanzapine , Schizophrenia , Humans , Antipsychotic Agents/therapeutic use , Antipsychotic Agents/adverse effects , Antipsychotic Agents/administration & dosage , Schizophrenia/drug therapy , Schizophrenia/blood , Male , Female , Olanzapine/therapeutic use , Olanzapine/adverse effects , Retrospective Studies , Adult , Middle Aged , Thiazoles/therapeutic use , Thiazoles/adverse effects , Thiazoles/administration & dosage , Piperazines/therapeutic use , Piperazines/adverse effects , Piperazines/administration & dosage , Benzodiazepines/therapeutic use , Benzodiazepines/adverse effectsABSTRACT
PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. METHODS: This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. RESULTS: Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. CONCLUSION: Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting.
Subject(s)
Aminopyridines , Breast Neoplasms , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Piperazines , Protein Kinase Inhibitors , Purines , Pyridines , Humans , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Female , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Middle Aged , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Pyridines/therapeutic use , Retrospective Studies , Aged , Piperazines/therapeutic use , Aminopyridines/therapeutic use , Purines/therapeutic use , Taiwan , Protein Kinase Inhibitors/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Adult , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Treatment Outcome , Neoplasm Metastasis , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Asian PeopleABSTRACT
BACKGROUND: Germline breast cancer susceptibility gene (gBRCA) mutation in patients with pancreatic cancer (PC) is not common in clinical practice. Therefore, factors that efficiently show gBRCA mutations and the real-world outcomes of olaparib maintenance therapy have not been fully established. In the present study, we clarified the indicators for the effective detection of gBRCA mutation and the efficacy and safety of olaparib as maintenance therapy. METHODS: We retrospectively analyzed 84 patients with PC who underwent gBRCA testing (BRACAnalysis, Myriad Genetics, Salt Lake City, UT, USA) at our institute between January 2021 and March 2022. For each patient, clinical data were extracted from medical records. RESULTS: The median patient age was 64 y (29-85 y), and 41 patients (48.8%) were male. The gBRCA mutations were identified in 10 (11.9%) patients; two patients had BRCA1 mutation and eight had BRCA2 mutation. All patients with gBRCA mutation had a family history of any cancer, and eight of them had a family history of Hereditary Breast and Ovarian Cancer syndrome (HBOC)-related cancer. The gBRCA mutation rate was higher for patients with PC with a family history of HBOC-related cancer compared to that in patients with PC having a family history of other cancers and no family history of cancer (22.9% vs. 4.1%; P = 0.014). In our study, eight out of 10 patients with gBRCA-positive PC received olaparib after platinum-based chemotherapy. The best responses to platinum-based chemotherapy included a complete response in one patient (12.5%) and a partial response in seven patients (87.5%). The median duration of treatment with platinum-based chemotherapy plus olaparib was 17.5 months (8-87 months), and the duration of treatment with olaparib maintenance therapy was 11 months (1-30 months). During olaparib maintenance therapy, three patients showed no disease progression. One of these three patients underwent conversion surgery after receiving olaparib for 12 months. CONCLUSIONS: The gBRCA testing should be considered proactively, especially in patients with PC with a family history of HBOC-related cancer.
Subject(s)
BRCA1 Protein , BRCA2 Protein , Genetic Predisposition to Disease , Germ-Line Mutation , Pancreatic Neoplasms , Phthalazines , Piperazines , Humans , Phthalazines/therapeutic use , Middle Aged , Female , Aged , Male , Adult , Retrospective Studies , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/drug therapy , Aged, 80 and over , Piperazines/therapeutic use , Piperazines/administration & dosage , BRCA2 Protein/genetics , BRCA1 Protein/genetics , Maintenance Chemotherapy , Genetic Testing/methods , Clinical RelevanceABSTRACT
BACKGROUND: The current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 -) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib. METHODS: This multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 - ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events. RESULTS: Of the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55-1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29-1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%). CONCLUSION: This preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 - ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted.
Subject(s)
Aminopyridines , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Piperazines , Purines , Pyridines , Receptor, ErbB-2 , Receptors, Estrogen , Humans , Piperazines/administration & dosage , Piperazines/adverse effects , Piperazines/therapeutic use , Female , Pyridines/administration & dosage , Pyridines/therapeutic use , Pyridines/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Aminopyridines/adverse effects , Purines/administration & dosage , Purines/adverse effects , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Retrospective Studies , Thailand/epidemiology , Aged , Receptor, ErbB-2/metabolism , Adult , Receptors, Estrogen/metabolism , Aromatase Inhibitors/administration & dosage , Aromatase Inhibitors/therapeutic use , Receptors, Progesterone/metabolism , Progression-Free SurvivalABSTRACT
BACKGROUND: Tanzania has made significant progress in improving access to HIV care and treatment. However, virologic suppression among people living with HIV (PLHIV) has not been fully realized. In March 2019, Tanzania introduced a World Health Organization (WHO)-recommended dolutegravir-based regimen as the default first-line regimen. Eighteen months later we investigated the HIV viral suppression rates and the factors associated with lack of viral suppression among PLHIV (children and adults) in Tanzania. METHODOLOGY: A cross-sectional survey was conducted from September to December 2020 among PLHIV on antiretroviral therapy (ART) in Tanzania. Whole blood samples, demographic data and clinical information were obtained from eligible adults (≥15 years) and children (< 15 years) attending thirty-six HIV care and treatment centres located in 22 regions of Tanzania mainland. A whole blood sample from each participant was processed into plasma and HIV viral load was estimated using real-time PCR. HIV viral suppression was defined at a cut-off of < 50 copies/mL as recommended by WHO. Analyses were conducted using descriptive statistics to establish the national representative prevalence of viral suppression, and logistic regression analyses to determine independent factors associated with non-suppression. RESULTS: A total of 2,039 PLHIV on ART were recruited; of these, adults and children were 57.5% (n = 1173) and 42.5% (n = 866), respectively. Among the adult population, the mean age and standard deviation (SD) was 42.1 ± 12.4 years, with 64.7% being female. Among children, the mean age and SD were 9.6 ± 3 years, and 53.2% were female. Overall viral suppression at < 50 copies/mL (undetectable) was achieved in 87.8% of adults and 74.4% of children. Adults and children on dolutegravir-based regimen recorded viral suppression rates of 89.7% and 85.1% respectively. Factors independently associated with lack of viral suppression status in the adult population were age and ART adherence while in the children population, the factors were sex, ART adherence, and current ART regimen (p<0.05). CONCLUSION: Dolutegravir-based regimens are promising to help attain epidemic control in Tanzania. More efforts especially on ART adherence are needed to attain optimal treatment outcomes for children and adults PLHIV in Tanzania.
Subject(s)
HIV Infections , Heterocyclic Compounds, 3-Ring , Oxazines , Piperazines , Pyridones , Viral Load , Humans , Female , Tanzania/epidemiology , Heterocyclic Compounds, 3-Ring/therapeutic use , Pyridones/therapeutic use , Male , HIV Infections/drug therapy , HIV Infections/virology , HIV Infections/epidemiology , Adult , Oxazines/therapeutic use , Piperazines/therapeutic use , Child , Adolescent , Viral Load/drug effects , Cross-Sectional Studies , Middle Aged , Young Adult , Child, Preschool , HIV Integrase Inhibitors/therapeutic use , Anti-HIV Agents/therapeutic use , HIV-1/drug effects , HIV-1/geneticsSubject(s)
Mutation , Neuroblastoma , Poly(ADP-ribose) Polymerase Inhibitors , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases , Humans , Neuroblastoma/drug therapy , Neuroblastoma/genetics , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Ubiquitin-Protein Ligases/genetics , Tumor Suppressor Proteins/genetics , Phthalazines/therapeutic use , Drug Resistance, Neoplasm/genetics , Piperazines/therapeutic useABSTRACT
BACKGROUND: There is a need to understand health care resource utilization (HCRU) and costs associated with treatment-experienced people with HIV (PWH) switching treatment regimens. OBJECTIVE: To describe HCRU and cost during lines of antiretroviral therapy (ART) for treatment-experienced PWH switching to or restarting guideline-recommended, integrase strand transfer inhibitor (INSTI)-based multitablet regimens and single-tablet regimens. METHODS: This retrospective claims study used data from Optum Research Database (January 1, 2010, to March 31, 2020) to identify lines of therapy (LOTs) for treatment-experienced adults who switched to or restarted INSTI-based regimens between January 1, 2018, and December 31, 2019. The first LOT during the study period was included in the analysis. We examined all-cause HCRU and costs and HIV-related HCRU and combined costs to the health plan and direct patient costs by site of service and compared between INSTI-based regimens: bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (single tablet) vs dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) (single tablet), dolutegravir + emtricitabine/tenofovir alafenamide (DTG+FTC/TAF) (multitablet), and dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG+FTC/TDF) (multitablet). Analysis of HCRU by site of service was conducted following inverse probability treatment weighting. Multivariable regression was conducted using a generalized linear model with stepwise covariate selection to estimate HIV-related medical costs and control for remaining differences after inverse probability treatment weighting. RESULTS: 4,251 PWH were identified: B/F/TAF (n = 2,727; 64.2%), DTG/ABC/3TC (n = 898; 21.1%), DTG+FTC/TAF (n = 539; 12.7%), and DTG+FTC/TDF (n = 87; 2.1%). PWH treated with DTG+FTC/TAF had a significantly higher mean of all-cause ambulatory visits than PWH treated with B/F/TAF (1.8 vs 1.6, P < 0.001). A significantly smaller proportion of PWH treated with DTG/ABC/3TC had an all-cause ambulatory visit vs PWH treated with B/F/TAF (90.6% vs 93.9%, P < 0.001). All-cause total costs were not significantly different between regimens. Mean (SD) medical HIV-related costs per month during the LOT were not significantly different between B/F/TAF $699 (3,602), DTG/ABC/3TC $770 (3,469), DTG+FTC/TAF $817 (3,128), and DTG+FTC/TDF $3,570 (17,691). After further controlling for unbalanced measures, HIV-related medical costs during the LOT were higher (20%) but did not reach statistical significance for DTG/ABC/3TC (cost ratio = 1.20, 95% CI = 0.851-1.694; P = 0.299), 49% higher for DTG+FTC/TAF (cost ratio = 1.489, 95% CI = 1.018-2.179; P = 0.040), and almost 11 times greater for DTG+FTC/TDF (cost ratio = 10.759, 95% CI = 2.182-53.048; P = 0.004) compared with B/F/TAF. CONCLUSIONS: HIV-related medical costs during the LOT were lowest for PWH treated with INSTI-based single-tablet regimens. Simplifying treatment regimens may help PWH maintain lower health care costs.
Subject(s)
Anti-HIV Agents , HIV Infections , Pyridones , Humans , HIV Infections/drug therapy , HIV Infections/economics , Retrospective Studies , Female , Male , Adult , Middle Aged , Pyridones/economics , Pyridones/therapeutic use , Anti-HIV Agents/economics , Anti-HIV Agents/therapeutic use , Heterocyclic Compounds, 3-Ring/economics , Heterocyclic Compounds, 3-Ring/therapeutic use , Tenofovir/therapeutic use , Tenofovir/economics , Patient Acceptance of Health Care/statistics & numerical data , Health Care Costs/statistics & numerical data , Drug Combinations , Oxazines/therapeutic use , Oxazines/economics , Emtricitabine/therapeutic use , Emtricitabine/economics , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Heterocyclic Compounds, 4 or More Rings/economics , Piperazines/economics , Piperazines/therapeutic use , Lamivudine/economics , Lamivudine/therapeutic use , HIV Integrase Inhibitors/economics , HIV Integrase Inhibitors/therapeutic use , Health Resources/economics , Health Resources/statistics & numerical data , Drug Substitution/economics , Amides , Cyclopropanes , Dideoxyadenosine/analogs & derivativesSubject(s)
Antineoplastic Combined Chemotherapy Protocols , Leukemia, Myeloid, Acute , Phthalazines , Piperazines , RUNX1 Translocation Partner 1 Protein , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Piperazines/administration & dosage , Piperazines/therapeutic use , Phthalazines/administration & dosage , Phthalazines/therapeutic use , RUNX1 Translocation Partner 1 Protein/genetics , Aged , Core Binding Factor Alpha 2 Subunit/genetics , Oncogene Proteins, Fusion/genetics , Treatment Outcome , Male , Female , Recurrence , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathologyABSTRACT
The aim of this study is to share real-life data on the increase in creatinine due to CDK 4/6 inhibitor treatment and patients diagnosed with HR+/HER2-MBC and treated with ribociclib or palbociclib combined with ET were included in the study. While creatinine increase was observed in 17.9% (n = 19) of the 106 patients in the study population, 8.5% (n = 9) had Grade 1, 8.5% (n = 8) had Grade 2, and % 0.9 (n = 1) had Grade 3 creatinine elevation. The increase in creatinine occurred in 25% (n = 12) of ribociclib users and 12.1% (n = 7) of palbociclib users. No patient required a dose reduction or discontinuation of treatment due to elevated creatinine. Of the patients with high creatinine levels, 36.8% (n = 7) were over 65 years of age. Those with multiple comorbidities, blood urea nitrogen (BUN) >13.5 mg/dl, creatinine >0.66 mg/dl, BUN/creatinine ratio >19.95, glomerular filtration rate (GFR) >96.05 ml/min, and uric acid >4.69mg/dl. It was observed that the increase in the creatinine level was statistically significant (p <0.001). In conclusion, this study revealed that the increase in the serum creatinine secondary to ribociclib and palbociclib treatments is associated with kidney function tests and the number of concomitant diseases. Key Words: CDK 4/6 inhibitor, Creatinine elevation, Palbociclib, Ribociclib.
Subject(s)
Aminopyridines , Creatinine , Cyclin-Dependent Kinase 4 , Piperazines , Purines , Pyridines , Humans , Purines/adverse effects , Purines/administration & dosage , Purines/therapeutic use , Creatinine/blood , Piperazines/adverse effects , Piperazines/administration & dosage , Piperazines/therapeutic use , Aminopyridines/adverse effects , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Female , Pyridines/adverse effects , Pyridines/administration & dosage , Middle Aged , Aged , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Breast Neoplasms/drug therapy , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Adult , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/administration & dosage , MaleABSTRACT
To minimize the toxicity and impact of combined antiretroviral therapy (cART) on the lifestyle of people living with Human Immunodeficiency Virus (PLWH), scientific community evaluated the efficacy, safety and sustained virologic response of two drugs antiretroviral regimens, in particular dolutegravir (DTG). The effects of deintensification therapy on inflammatory settings are currently unknown in PLWH. Thus, our study explored the inflammatory state in virologically suppressed HIV individuals between patients in treatment with a DTG-containing dual therapy (2DR) versus triple regimen therapies (3DR). We enrolled a total of 116 subjects in 2DRs or 3DRs regimens, and the plasma levels of pro- and anti-inflammatory cytokines (in particular IL-1ß, IL-10, IL-18, IL-33, IL-36 and IFN-γ) have been evaluated. CD4 + cell's median value was 729.0 cell/µL in the 3DR group and 771.5 cell/µL in 2DR group; the viral load was negative in all patients. Significant differences were found in levels of IL-18 (648.8 cell/µL in 3DR group vs. 475.0 cell/µL in 2DR group, p = 0.034) and IL-36 (281.7 cell/µL in 3DR group vs. 247.0 cell/µL in 2DR group, p = 0.050), and a correlation between IL-18 and IL-36 was found in 3DR group (rho = 0.266, p = 0.015). This single-center retrospective pharmacological study confirms the absence of significant differences in IL-1ß, IL-10, IL-33, and IFN-γ levels between patients on two-drug antiretroviral regimens compared to patients on 3DR antiretroviral regimens. Patients in 2DR show greater control over IL-18 and IL-36 serum levels, cytokines related to an increased cardiovascular risk and development of age-related chronic diseases. Based on our results, we suggest that DTG-based 2DR antiretroviral regimens could be associated with better control of the chronic inflammation that characterizes the population living with HIV in effective ART.
Subject(s)
Cytokines , HIV Infections , Heterocyclic Compounds, 3-Ring , Oxazines , Piperazines , Pyridones , Humans , HIV Infections/drug therapy , Cytokines/blood , Male , Female , Adult , Middle Aged , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/adverse effects , Heterocyclic Compounds, 3-Ring/administration & dosage , Oxazines/therapeutic use , Piperazines/therapeutic use , Piperazines/administration & dosage , Pyridones/therapeutic use , Pyridones/administration & dosage , Viral Load/drug effects , Drug Therapy, Combination , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , CD4 Lymphocyte CountABSTRACT
Antiretroviral regimens for human immunodeficiency virus (HIV) infection have continuously evolved; however, antiretrovirals can cause severe adverse reactions. Two-drug regimen therapy can decrease lifetime cumulative drug exposure and long-term toxicities associated with multiple antiretrovirals. The preferred 2-drug regimen constitutes dolutegravir (DTG) and lamivudine (3TC). This study determined the rate of virological suppression and incidence of adverse events at week 48 in treatment-naïve people living with HIV initiated on DTGâ +â 3TC. This was a single-center, retrospective, observational study. Treatment-naïve people aged ≥18 years who received at least 1 DTGâ +â 3TC dose between May 2020 and May 2022 were included. Eighty-nine people living with HIV were enrolled. Twenty-five (28.1%) patients with a DTGâ +â 3TC regimen at baseline were analyzed because of comorbidities, and 48% because of concomitant tuberculosis (TB). Viral suppression at 48 weeks was achieved in 91.67% of patients, and TB was well controlled. At week 48, 84 (94.38%) patients had viral loadsâ <â 50 copies/mL, and 21 (91.31%) of the 23 participants with a baseline HIV-1-RNA levelâ ≥â 1â ×â 105 copies/mL achieved virological success. Fifteen (88.23%) of the 17 participants with a baseline CD4â +â cell count of <200 cells/µL achieved virological suppression. The median CD4â +â cell count change from baseline was 539.5 cells/µL. No significant changes in triglycerides, low-density lipoprotein cholesterol, weight, or creatinine were observed from baseline to 48 weeks. One patient had severe insomnia at 4 weeks. Our findings support the real-world effectiveness and low metabolic impact of DTGâ +â 3TC. Using DTGâ +â 3TC in patients coinfected with TB and HIV has favorable therapeutic outcomes.
Subject(s)
Anti-HIV Agents , Drug Therapy, Combination , HIV Infections , Heterocyclic Compounds, 3-Ring , Lamivudine , Oxazines , Piperazines , Pyridones , Tuberculosis , Humans , Pyridones/administration & dosage , Pyridones/therapeutic use , Pyridones/adverse effects , Lamivudine/therapeutic use , Lamivudine/administration & dosage , Lamivudine/adverse effects , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/adverse effects , Heterocyclic Compounds, 3-Ring/administration & dosage , Female , HIV Infections/drug therapy , HIV Infections/complications , Male , Retrospective Studies , Adult , Piperazines/therapeutic use , Piperazines/administration & dosage , Piperazines/adverse effects , China , Middle Aged , Tuberculosis/drug therapy , Tuberculosis/complications , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/adverse effects , Anti-HIV Agents/administration & dosage , Viral Load/drug effects , Coinfection/drug therapy , Treatment Outcome , CD4 Lymphocyte CountABSTRACT
Breast cancer, a predominant global health issue, requires ongoing exploration of new therapeutic strategies. Palbociclib (PAL), a well-known cyclin-dependent kinase (CDK) inhibitor, plays a critical role in breast cancer treatment. While its efficacy is recognized, the interplay between PAL and cellular autophagy, particularly in the context of the RAF/MEK/ERK signaling pathway, remains insufficiently explored. This study investigates PAL's inhibitory effects on breast cancer using both in vitro (MCF7 and MDA-MB-468 cells) and in vivo (tumor-bearing nude mice) models. Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib (TRA), an MEK inhibitor, our research seeks to address the challenge of PAL-induced drug resistance. Our findings reveal that PAL significantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells. However, PAL also induces protective autophagy, potentially leading to drug resistance via the RAF/MEK/ERK pathway activation. Introducing TRA effectively neutralized this autophagy, enhancing PAL's anti-tumor efficacy. A combination of PAL and TRA synergistically reduced cell viability and proliferation, and in vivo studies showed notable tumor size reduction. In conclusion, the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance, offering a new horizon in breast cancer treatment.
Subject(s)
Autophagy , Breast Neoplasms , Piperazines , Pyridines , Pyridones , Pyrimidinones , Xenograft Model Antitumor Assays , Humans , Animals , Autophagy/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Pyridines/pharmacology , Pyridines/therapeutic use , Pyridones/pharmacology , Pyridones/therapeutic use , Female , Pyrimidinones/pharmacology , Pyrimidinones/therapeutic use , Mice , Piperazines/pharmacology , Piperazines/therapeutic use , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Cell Proliferation/drug effects , Drug Synergism , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Mice, Nude , MAP Kinase Signaling System/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Cell Survival/drug effects , MCF-7 CellsABSTRACT
Diabetes mellitus is a severe endocrine disease that affects more and more people every year. Modern medical chemistry sets itself the task of finding effective and safe drugs against diabetes. This review provides an overview of potential antidiabetic drugs based on three heterocyclic compounds, namely morpholine, piperazine, and piperidine. Studies have shown that compounds containing their moieties can be quite effective in vitro and in vivo for the treatment of diabetes and its consequences.
Subject(s)
Hypoglycemic Agents , Morpholines , Piperazine , Piperidines , Humans , Piperidines/chemistry , Piperidines/pharmacology , Piperidines/therapeutic use , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Morpholines/chemistry , Morpholines/pharmacology , Morpholines/therapeutic use , Piperazine/chemistry , Piperazine/pharmacology , Animals , Piperazines/chemistry , Piperazines/pharmacology , Piperazines/chemical synthesis , Piperazines/therapeutic use , Diabetes Mellitus/drug therapy , Structure-Activity RelationshipABSTRACT
BACKGROUND: Current standard treatment for metastatic breast cancer (MBC) involves cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with endocrine therapy, showing potential in enhancing anti-tumor immune responses. CASE REPORT: This report details a clinical case of MBC where palbociclib was co-administered with letrozole. The integration of allogeneic tumor vaccination to this treatment led to heightened interferon-γ production, expansion of CD8+ and NK cell populations, and positive delayed-type hypersensitivity reactions, indicating successful development of anti-tumor immunity. The induced production of interferon-γ by tumor vaccination was associated with manageable modulation of sensitivity to palbociclib-letrozole therapy. Administration of the BioNTech/Pfizer Covid-19 vaccine compromised the anti-tumor immune response by reducing cytotoxic cell populations and increasing immunosuppressive cytokine production. The patient undergoing combined treatment achieved a progressive-free survival of 42 months. CONCLUSION: Incorporating active tumor vaccination with CDK4/6 inhibitor therapy presents a feasible approach for metastatic breast cancer. The precise regulation of the microenvironment emerges as a crucial factor and warrants careful consideration.