Methadone Conversion Using a 3-Day Switch Strategy in Patients with Cancer on High-Dose Opioids: A Retrospective Study.

INTRODUCTION: Methadone has shown effectiveness in pain control in patients with cancer who are intolerant to other opioids in China. However, the optimal strategy for methadone conversion from previous high doses of opioids in refractory cancer pain remains debatable. This study aimed to describe the efficacy and safety of a 3-day switch (3DS) strategy for methadone conversion in patients with refractory cancer pain on high doses of opioids. METHODS: We retrospectively reviewed 30-day medical records of 70 patients with refractory cancer pain who used a 3DS strategy for methadone conversion from previous high doses of opioids from July 2018 to December 2022. The 3DS strategy indicated that the methadone dose was increased by one third every day for 3 days. Data on the rate of successful conversion, the time to stable analgesia after conversion, the conversion efficiency, the corrected QT (QTc) interval, the actual conversion ratios, adverse events (AEs), and quality of life were analyzed. RESULTS: Seventy patients received 3DS methadone conversion and 64 patients were eligible for analysis. Fifty patients (78%) achieved stable analgesia, and the median time to stable analgesia was 8.14 ± 2.70 (range 6-14) days. The average dose of methadone was 77.94 ± 42.74 mg. The most common AEs (≥ 10%) included constipation, dry mouth, nausea, and cold sweats. The incidence of constipation was reduced post-methadone conversion, and a statistically significant but asymptomatic prolongation of the QTc interval was observed. Additionally, the actual conversion ratios were lower than Ayonrinde's recommended ratios. CONCLUSIONS: The 3DS strategy for methadone conversion is applicable in Chinese patients with refractory cancer pain on high doses of opioids.

Cost-effectiveness analysis of rezvilutamide versus bicalutamide in the treatment of metastatic hormone-sensitive prostate cancer.

OBJECTIVES: The economic implications of combining rezvilutamide with androgen deprivation therapy (ADT) remain uncertain, despite the observed survival advantages compared with bicalutamide plus ADT. Therefore, this study evaluates the cost-effectiveness of rezvilutamide plus ADT as the first-line treatment of metastatic hormone-sensitive prostate cancer (mHSPC) from the perspective of the Chinese healthcare system. DESIGN: A partitioned survival model was developed to assess the cost-effectiveness of rezvilutamide combined with ADT. Clinical data were obtained from the CHART trial. Costs and utility values were obtained from local estimate and published literature. Only direct medical costs were included in the model. INTERVENTIONS: Rezvilutamide was administered at 240 mg daily or bicalutamide at 50 mg daily until progression. OUTCOME MEASURES: The main outputs of the model included costs and quality-adjusted life years (QALYs), which were used to determine the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analysis (PSA) were used to explore model uncertainties. RESULTS: The rezvilutamide group showed an expected gain of 2.28 QALYs and an incremental cost of US$60 758.82 compared with the bicalutamide group. The ICER for rezvilutamide group versus bicalutamide group was US$26 656.94 per QALY. The variables with the greatest impact on the model results were the utility for progression-free survival state and the price of rezvilutamide. PSA revealed that rezvilutamide group had 100% probability of being cost-effective at a willingness-to-pay threshold of US$35707.5 per QALY. CONCLUSION: Rezvilutamide in combination with ADT is more cost-effective compared with bicalutamide plus ADT as the first-line treatment of mHSPC from the perspective of the Chinese healthcare system.

Population pharmacokinetic and exposure-toxicity analyses of nab-paclitaxel after pegylated recombinant human granulocyte colony-stimulating factor administration in patients with metastatic breast cancer.

PURPOSE: This study aimed to establish a population pharmacokinetic (PK) model to evaluate the dynamic relationship between the concentrations of total and unbound paclitaxel, and the exposure-response analysis of albumin-bound paclitaxel (nab-paclitaxel) after pegylated recombinant human granulocyte colony-stimulating factor (PEG-G-CSF) administration in patients with metastatic breast cancer. METHODS: A total of 653 concentrations corresponding to total paclitaxel and 334 concentrations corresponding to unbound paclitaxel were analyzed in 24 subjects who randomized received a single 260 mg/m2 dose of two nab-paclitaxel formulations with a 21-35-day washout period. PEG-G-CSF was administered to all the patients in each cycle to prevent neutropenia. The exposure-response relationships were evaluated using the exposure to total, albumin-coated, and unbound paclitaxel, as well as the reduction in neutrophil count. The exposure data were analyzed using nonlinear mixed-effect modeling. A linear regression model was used to test the statistical significance of the correlation between percentage of reduction in neutrophil count and exposure. RESULTS: The PK characteristics of total paclitaxel were described using a three-compartment model with first-order elimination, and a mechanism-based model incorporating linear release of nab-paclitaxel and the saturated binding of unbound paclitaxel to plasma components was established. The release ratio of paclitaxel from nab-paclitaxel was estimated to be 4.60% and the maximum unbound fraction (2.76%) was reached at the end of the infusion. The study found that a longer duration of total paclitaxel concentration > 0.19 µmol/L was significantly correlated with a reduction in neutrophil count (r2 = 0.23, P = 0.00062). Specifically, a duration of > 8.6 h was a predictor of a decreased neutrophil count. CONCLUSION: The decrease in neutrophils induced by nab-paclitaxel was significantly correlated with the duration above a total paclitaxel concentration of 0.19 µmol/L despite the use of PEG-G-CSF.

Population pharmacokinetics of free and liposome-encapsulated mitoxantrone in patients with relapsed/refractory lymphoma or small cell lung cancer.

OBJECTIVE: This study is aimed at investigating the pharmacokinetic (PK) characteristics of pegylated liposomal mitoxantrone (PLM) in patients with relapsed/refractory lymphoma or small cell lung cancer (SCLC) by constructing population pharmacokinetic (popPK) models for both liposome-encapsulated mitoxantrone and free mitoxantrone. METHODS: A total of 23 patients with relapsed/refractory lymphoma and 42 patients with SCLC were included. A popPK model was simultaneously developed utilizing a non-linear mixed effects model (NONMEM) to explore the PK profiles of liposome-encapsulated mitoxantrone and free mitoxantrone. Clearance (CL) and distribution volume (V) were calculated, and covariate analysis was employed to evaluate the influence of patient disease type, demographic information, and biochemical indicators of liver and kidney function on PK parameters. RESULTS: The concentration-time profiles for both liposome-encapsulated mitoxantrone and free mitoxantrone were described by a one-compartment model. The release (Rel) of liposome-encapsulated mitoxantrone to free mitoxantrone was determined to be 0.0191 L/h, and the V of liposome-encapsulated mitoxantrone was 2.32 L. The apparent CL of free mitoxantrone was estimated at 1.66 L/h. The apparent V of free mitoxantrone was 35.8 L in patients with relapsed/refractory lymphoma and 22.2 L for patients with SCLC. In patients with relapsed/refractory lymphoma, lower maximum concentration (Cmax) and higher apparent V of free mitoxantrone were observed compared with patients with SCLC. CONCLUSION: The popPK characteristics of both liposome-encapsulated and free mitoxantrone in patients with relapsed/refractory lymphoma or SCLC were effectively described by a one-compartment model.

Hematological toxicity of cyclin-dependent kinase 4/6 inhibitors in patients with breast cancer: a network meta-analysis and pharmacovigilance study.

OBJECTIVES: We aimed to evaluate and compare the risk of hematological adverse events (AEs) associated with CDK4/6 inhibitors using data from randomized controlled trials (RCTs) and Food and Drug Adverse Event Reporting System (FAERS) database. METHODS: The PubMed, Embase, and Cochrane Library databases were searched for RCTs related to abemaciclib, palbociclib, and ribociclib. A network meta-analysis (NMA) was conducted to compare the risks of hematological AEs, and a disproportionality analysis was performed to detect signals of hematological AEs. RESULTS: 16 RCTs comprising 16,350 breast cancer patients were included. Palbociclib and ribociclib had similar risks for hematological AEs, except a higher risk of grade 3-4 leukopenia observed with palbociclib (risk ratio [RR]: 7.84, 95% confidence interval [95%CI]: 1.33-41.28). Abemaciclib had a higher risk of anemia than both ribociclib (grade 1-4: RR: 2.23, 95% CI: 1.25 - 3.96; grade 3-4: RR: 3.52, 95% CI: 1.59 - 8.11) and palbociclib (grade 1-4: RR: 1.65, 95%CI: 1.03 - 2.59), but a lower risk of grade 3-4 of both leukopenia (RR: 0.12, 95%CI: 0.02 - 0.49) and neutropenia (RR: 0.15, 95%CI: 0.04 - 0.52) compared with palbociclib. Signals indicating occurrence of leukopenia, neutropenia, anemia, and thrombocytopenia were identified for three CDK4/6 inhibitors. CONCLUSION: Abemaciclib, palbociclib, and ribociclib showed significant but inconsistent hematological toxicity risks.

Cost-effectiveness analysis of tislelizumab plus chemotherapy as the first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma in China.

OBJECTIVE: We aimed to investigate the cost-effectiveness of tislelizumab plus chemotherapy compared to chemotherapy alone as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (OSCC). METHODS: A partitioned survival model was developed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy versus chemotherapy alone in patients with advanced or metastatic OSCC over a 10-year lifetime horizon from the perspective of the Chinese healthcare system. Costs and utilities were derived from the drug procurement platform and published literature. The model outcomes comprised of costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were conducted to address uncertainty and ensure the robustness of the model. RESULTS: Tislelizumab plus chemotherapy yielded an additional 0.337 QALYs and incremental costs of $7,117.007 compared with placebo plus chemotherapy, generating an ICER of $21,116.75 per QALY, which was between 1 time ($12,674.89/QALY) and 3 times GDP ($38,024.67/QALY) per capita. In one-way sensitivity analysis, the ICER is most affected by the cost of oxaliplatin, paclitaxel and tislelizumab. In the probabilistic sensitivity analysis, when the willingness-to-pay threshold was set as 1 or 3 times GDP per capita, the probability of tislelizumab plus chemotherapy being cost-effective was 1% and 100%, respectively. CONCLUSION: Tislelizumab plus chemotherapy was probably cost-effective compared with chemotherapy alone as the first-line treatment for advanced or metastatic OSCC in China.

Safety and hematological toxicities of PARP inhibitors in patients with cancer: a systematic review of randomized controlled trials and a pharmacovigilance analysis.

INTRODUCTION: This study aimed to estimate the toxicities of PARP inhibitors (PARPis), based on randomized controlled trials (RCTs) and the FDA Adverse Event Reporting System (FAERS) database. METHODS: Four electronic databases were searched from inception to 16 April 2024, for RCTs of approved PARPis. The primary and secondary outcomes were grade 3-5 adverse events (AEs) and grade 3-5 hematological AE, respectively. We conducted network meta-analyses to calculate the relative risks (RRs) and 95% confidence intervals (CIs) of outcomes. A disproportionality analysis was conducted to estimate the signals of hematological AEs associated with PARPis from the FAERS database. RESULTS: Overall, 27 RCTs involving 11,067 patients with cancer were included. Olaparib had the best safety profile for any grade 3-5 AEs and hematological AEs among four approved PARPis. Olaparib did not increase the risk of thrombocytopenia (RR: 1.48; 95%CI: 0.64-3.39), but other PARPis did. Furthermore 14,780 hematological AE reports associated with PARPis were identified in the FAERS database, and all PARPis were associated with strong hematological AE signals. Hematological AEs mainly occurred within the first 3 months (80.84%) after PARPi initiation. CONCLUSION: Olaparib had the best safety profile among five PARPis. PARPi-associated hematological AEs mainly occurred within the first 3 months. REGISTRATION: PROSPERO (CRD42022385274).

ADCdb: the database of antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a class of innovative biopharmaceutical drugs, which, via their antibody (mAb) component, deliver and release their potent warhead (a.k.a. payload) at the disease site, thereby simultaneously improving the efficacy of delivered therapy and reducing its off-target toxicity. To design ADCs of promising efficacy, it is crucial to have the critical data of pharma-information and biological activities for each ADC. However, no such database has been constructed yet. In this study, a database named ADCdb focusing on providing ADC information (especially its pharma-information and biological activities) from multiple perspectives was thus developed. Particularly, a total of 6572 ADCs (359 approved by FDA or in clinical trial pipeline, 501 in preclinical test, 819 with in-vivo testing data, 1868 with cell line/target testing data, 3025 without in-vivo/cell line/target testing data) together with their explicit pharma-information was collected and provided. Moreover, a total of 9171 literature-reported activities were discovered, which were identified from diverse clinical trial pipelines, model organisms, patient/cell-derived xenograft models, etc. Due to the significance of ADCs and their relevant data, this new database was expected to attract broad interests from diverse research fields of current biopharmaceutical drug discovery. The ADCdb is now publicly accessible at: https://idrblab.org/adcdb/.

Dose-sparing effect of lapatinib co-administered with a high-fat enteral nutrition emulsion: preclinical pharmacokinetic study.

Background: Lapatinib is an oral small-molecule tyrosine kinase inhibitor indicated for advanced or metastatic HER2-positive breast cancer. In order to reduce the treatment cost, a high-fat enteral nutrition emulsion TPF-T was selected as a dose-sparing agent for lapatinib-based therapies. This study aimed to investigate the effect of TPF-T on lapatinib pharmacokinetics. Methods: First, a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to quantitatively evaluate lapatinib in rabbit plasma. The method was fully validated according to the China Pharmacopoeia 2020 guidance. Rabbits and rats were chosen as the animal models due to their low and high bile flows, respectively. The proposed LC-MS/MS method was applied to pharmacokinetic studies of lapatinib, with or without TPF-T, in rabbit and rat plasma. Results: The LC-MS/MS method revealed high sensitivity and excellent efficiency. In the rabbit model, co-administration with TPF-T resulted in a 32.2% increase in lapatinib exposure. In the rat model, TPF-T had minimal influence on the lapatinib exposure. In both models, TPF-T was observed to significantly elevate lapatinib concentration in the absorption phase. Conclusion: Co-administration with TPF-T had a moderate effect on increasing exposure to lapatinib. Dose sparing using a high-fat liquid diet is potentially feasible for lapatinib-based therapies.

Caffeic acid phenethyl ester suppresses metastasis of breast cancer cells by inactivating FGFR1 via MD2.

BACKGROUND: Tumor metastasis is the main cause of death for breast cancer patients. Caffeic acid phenethyl ester (CAPE) has strong anti-tumor effects with very low toxicity and may be a potential candidate drug. However, the anti-metastatic effect and molecular mechanism of CAPE on breast cancer need more research. METHODS: MCF-7 and MDA-MB-231 breast cancer cells were used here. Wound healing and Transwell assay were used for migration and invasion detection. Western blot and RT-qPCR were carried out for the epithelial-to-myofibroblast transformation (EMT) process investigation. Western blot and immunofluorescence were performed for fibroblast growth factor receptor1 (FGFR1) phosphorylation and nuclear transfer detection. Co-immunoprecipitation was used for the FGFR1/myeloid differentiation protein2 (MD2) complex investigation. RESULTS: Our results suggested that CAPE blocks the migration, invasion, and EMT process of breast cancer cells. Mechanistically, CAPE inhibits FGFR1 phosphorylation and nuclear transfer while overexpression of FGFR1 reduces the anti-metastasis effect of CAPE. Further, we found that FGFR1 is bound to MD2, and silencing MD2 inhibits FGFR1 phosphorylation and nuclear transfer as well as cell migration and invasion. CONCLUSION: This study illustrated that CAPE restrained FGFR1 activation and nuclear transfer through MD2/FGFR1 complex inhibition and showed good inhibitory effects on the metastasis of breast cancer cells.

Reply to "A better interpretation of data regarding the opioid switching to methadone".

In our article ?Methadone switching for refractory cancer pain' (BMC palliative care, 2022) we explore the efficacy, safety and economics of methadone in treatment of patients with refractory cancer pain in China. Professor Mercadante provided a better interpretation of data regarding the opioid switching to methadone in the Matters Arising. In this article, we answered the questions in Mercadante et al.'s comments one by one.

Population pharmacokinetics and toxicity correlation analysis of free and liposome-encapsulated doxorubicin in Chinese patients with advanced breast cancer.

PURPOSE: The objective of this study was to investigate the pharmacokinetic characteristics of pegylated liposomal doxorubicin (PLD) in Chinese female patients with advanced breast cancer by constructing population pharmacokinetic (popPK) models of liposome-encapsulated and free doxorubicin. Additionally, the relationship between pharmacokinetic parameters and drug-related adverse events (AEs) was explored through toxicity correlation analysis. METHODS: A total of 20 patients with advanced breast cancer were selected from a PLD bioequivalence study. All patients received a single intravenous dose of 50 mg/m2 PLD. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A popPK model was simultaneously built to characterize the pharmacokinetic profiles of liposome-encapsulated and free doxorubicin by non-linear mixed effects model (NONMEM). PLD-related toxicities were graded according to the common terminology criteria for adverse events (CTCAE) v5.0. The Spearman correlation analysis was conducted to explore the relationship between pharmacokinetic parameters and drug-related AEs of both liposome-encapsulated doxorubicin and free doxorubicin. RESULTS: The concentration-time profiles of both liposome-encapsulated doxorubicin and free doxorubicin were well described by a one-compartment model. The most common AEs to PLD were nausea, vomiting, neutropenia, leukopenia, and stomatitis, most of which were grade I-II. The toxicity correlation analysis results indicated that stomatitis was related to the Cmax of liposome-encapsulated doxorubicin (P < 0.05). No other AEs were found to be correlated with the pharmacokinetic parameters of either free or liposome-encapsulated doxorubicin. CONCLUSION: A one-compartment model adequately described the popPK characteristics of both liposome-encapsulated and free doxorubicin in Chinese female patients with advanced breast cancer. Most AEs to PLD were mild. Additionally, the occurrence of mucositis may be positively correlated with the Cmax of liposome-encapsulated doxorubicin.

Identification and validation of the microRNAs and hub genes for pancreatic ductal adenocarcinoma by an integrated bioinformatic analysis.

Background: In the progression of pancreatic ductal adenocarcinoma (PDAC), aberrant micro RNAs (miRNAs) expression plays a crucial role. This study sought to identify and validate the key miRNAs and potential target genes involved in PDAC. A bioinformatic analysis was conducted to determine their potential use as biomarkers and therapeutic targets. Methods: Gene profiling data sets (GSE41372 and GSE32688) were retrieved from the Gene Expression Omnibus database. Differentially expressed miRNAs (DEMs) with a P value <0.05, and |fold change| >2 was identified. The prognostic value of the DEMs was accessed using the online server Kaplan-Meier plotter. Further, gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed using DAVID 6.7. The protein-protein interaction analyses were conducted with STRING, and miRNA-hub gene networks were constructed using Cytoscape software. The PDAC cells were transfected with miRNA inhibitors or mimics. Cell Counting Kit-8 assays and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to examine cell proliferation and apoptosis, respectively. Wound-healing assays were performed to evaluate cell migration. Results: Three DEMs (hsa-miR-21-5p, hsa-miR-135b-5p, and hsa-miR-222-3p) were identified. High expression levels of hsa-miR-21-5p, hsa-miR-135b-5p, or hsa-miR-222-3p predicted poor overall survival in PDAC patients. The pathway analysis revealed that the predicted target genes of the DEMs were closely related to several signaling pathways (including 'pathways in cancer', 'miRNAs in cancer', 'platinum drug resistance', 'lipid and atherosclerosis', and 'MAPK signaling pathway'). The MYC proto-oncogene (MYC), phosphate and tensin homolog gene (PTEN), poly(ADP-ribose) polymerase 1 (PARP1), von Hippel-Lindau (VHL), and fork head box p3 (FOXP3) were identified as potential target genes. The inhibition of hsa-miR-21-5p, hsa-miR-135b-5p, or hsa-miR-222-3p expression decreased cell proliferation. The overexpression of hsa-miR-21-5p, hsa-miR-135b-5p, or hsa-miR-222-3p facilitated PDAC cell migration. Conclusions: This study constructed the miRNA-hub gene network, which provides novel insights into the PDAC progression. Although further research is required, our results offer clues for new potential prognostic markers and therapeutic targets of PDAC.

Correlation of gene expression profiles to identify pancreatic cancer cell lines that best model primary human tumors.

Background: Cancer cell lines are important research models for studying tumor biology in vivo. The accuracy of such studies is highly dependent on the phenotypic and genetic similarity of cell lines to patient tumors, but this is not always the case, particularly for pancreatic cancer. Methods: We compared the gene expression profiles of various pancreatic cancer cell lines and primary human pancreatic tumor tissues to determine which pancreatic cancer cell line best models human primary tumor. Profiles of messenger RNA (mRNA) expression of 33 pancreatic cancer cell lines and 892 patient samples of pancreatic adenocarcinoma (PAAD) were obtained from the Gene Expression Omnibus (GEO) database. Microarray data were normalized using the robust multichip average (RMA) algorithm and batch effect removal was performed using ComBat. The pooled data of each PAAD cell line were compared to patient tumors based on the top 2,000 genes with largest interquartile range (IQR), 134 gene-collections of cancer-related pathways, and 504 gene-collections of cancer-related functions using pairwise Pearson's correlation analysis. Results: PAAD cell lines were poorly correlated with patient tumor tissues based on the top 2,000 genes. Up to 50% of cancer-related pathways were not strongly recommended in PAAD cell lines, and a small proportion of cancer-related functions (12-17%) were poorly correlated with PAAD cell lines. In pan-pathway analysis, the cell lines showing the highest genetic correlation to patient tumors were Panc 03.27 for PAAD cell lines from a primary lesion site and CFPAC-1 for PAAD cell lines from a metastatic lesion site. In pan-function analysis, the cell lines showing the highest genetic correlation to patient tumors were Panc 03.27 for PAAD cell lines from a primary lesion site and Capan-1 for PAAD cell lines from a metastatic lesion site. Conclusions: The gene expression profiles of PAAD cell lines correlate weakly with those of primary pancreatic tumors. Through comparison of the genetic similarity between PAAD cell lines and human tumor tissue, we have provided a strategy for choosing the appropriate PAAD cell line.

Single-cell sequencing analysis fibrosis provides insights into the pathobiological cell types and cytokines of radiation-induced pulmonary fibrosis.

BACKGROUND: Radiotherapy is an essential treatment for chest cancer. Radiation-induced pulmonary fibrosis (RIPF) is an almost irreversible interstitial lung disease; however, its pathogenesis remains unclear. METHODS: We analyzed specific changes in cell populations and potential markers by using single-cell sequencing datasets from the Sequence Read Archive database, PERFORMED from control (0 Gy) and thoracic irradiated (20 Gy) mouse lungs at day 150 post-radiation. We performed IHC and ELISA on lung tissue and cells to validate the potential marker cytokines identified by the analysis on rat thoracic irradiated molds (30 Gy). RESULTS: Single-cell sequencing analysis showed changes in abundance across cell types and at the single-cell level, with B and T cells showing the most significant changes in abundance. And four cytokines, CCL5, ICAM1, PF4, and TNF, were significantly upregulated in lung tissues of RIPF rats and cell supernatants after ionizing radiation. CONCLUSION: Cytokines CCL5, ICAM1, PF4, and TNF may play essential roles in radiation pulmonary fibrosis. They are potential targets for the treatment of radiation pulmonary fibrosis.

Population Pharmacokinetics of Anlotinib, a Multiple Receptor Tyrosine Kinase Inhibitor, in Chinese Patients With Malignant Tumors.

The objective of this study was to investigate the pharmacokinetic behavior of anlotinib in Chinese patients with malignant tumors using the population approach. A total of 407 anlotinib plasma concentrations from 16 patients were analyzed in this study. Anlotinib was administered orally 12 or 16 mg in the single-dose phase and 12 mg once daily in the multiple-dose phase. A population pharmacokinetic model was established using nonlinear mixed-effects model method. The potential influence of demographic and pathophysiological factors on oral anlotinib pharmacokinetics was investigated in a covariate analysis. The final model was evaluated using goodness-of-fit plots, visual predictive check, and bootstrap methods. The pharmacokinetic profile of anlotinib was best described by a 1-compartment model with first-order absorption and first-order elimination. The population estimates of the apparent total clearance, apparent volume of distribution, and absorption rate constant were 8.91 L/h, 1950 L, and 0.745/h, respectively. Body weight was identified as a significant covariate on apparent volume of distribution. Patients with low body weight tended to show higher exposure to anlotinib than those with high body weight. However, these differences were not clinically significant based on the simulations of the individual body weight effects. Taken together, this population pharmacokinetic model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors and supports the same starting dose among them.

Cost-effectiveness of PARP inhibitors in malignancies: A systematic review.

OBJECTIVES: Poly (ADP-ribose) polymerase inhibitor (PARPi) have become a mainstay for the treatment of BRCA-mutant malignancies. PARPis are likely to be more effective but also bring an increase in costs. Thus, we aimed at evaluating the cost effectiveness of PARPis in the treatment of malignancies. METHODS: Studies of cost effectiveness of PARPis were searched from PubMed, Web of Science, and Cochrane Library. Key information was extracted from the identified studies and reviewed. Quality of the included studies was evaluated using Quality of Health Economic Studies (QHES) instrument. Modeling techniques, measurement of parameters and uncertainty analysis were analyzed across studies. Interventions and cost-effectiveness results were reported stratified by patient population. RESULTS: Among the 25 studies identified, we included 17 on ovarian cancer, 2 on breast cancer, 3 on pancreatic cancer, and 3 on prostate cancer that involved olaparib, niraparib, rucaparib, and talazoparib. All studies had a QHES score of above 75. In the maintenance therapy of ovarian cancer, additional administration of olaparib was cost-effective for newly diagnosed patients after first-line platinum-based chemotherapy but was not cost-effective for platinum-sensitive recurrent patients in majority studies. However, the economic value of other PARPis in ovarian cancer as well as all PARPis in other tumors remained controversial. Cost-effectiveness of PARPi was primarily impacted by the costs of PARPi, survival time, health utility and discount rate. Moreover, genetic testing improved the cost-effectiveness of PARPi treatment. CONCLUSIONS: PARPi is potentially cost-effective for patients with ovarian, pancreatic, or prostate cancer. Genetic testing can improve the cost-effectiveness of PARPi.

Methadone switching for refractory cancer pain.

BACKGROUND: Methadone is commonly considered an alternative opioid treatment for refractory cancer pain. This study aims to investigate the efficacy, safety, and cost of methadone in the treatment of refractory cancer pain. METHODS: A retrospective study was conducted in patients who used methadone for refractory cancer pain from April 2016 to December 2020 at a cancer specialized hospital. Pain control, evaluated via pain score and breakthrough pain frequency, and adverse events of methadone were compared with analgesic regimens prior to methadone administration. The factors potentially affecting the switching outcome were analyzed via multivariate analysis. Moreover, the cost of pain control was estimated. RESULTS: Ninety patients received methadone for poor pain control (74.4%), intolerable adverse events (10.0%), or both (15.6%) after prior opioid treatments. Sixty-four patients (71.1%) were successfully switched to methadone with median pain score significantly decreased from 4.0 to 2.0 (p < 0.001) and median daily frequency of breakthrough pain from 3.0 to 0.0 (p < 0.001) at a maintained median conversion ratio of 6.3 [interquartile range (IQR): 4.0-10.0] to prior opioid treatment. Similar adverse event profiles of constipation, nausea, vomiting, and dizziness were observed between methadone and prior opioid regimens. The median daily cost of analgesic regimens was significantly reduced from $19.5 (IQR: 12.3-46.2) to $10.8 (IQR: 7.1-18.7) (p < 0.01) after switching to methadone. The 3-day switch method significantly improved the rate of successful switching compared with the stop and go method (odds ratio = 3.37, 95% CI: 1.30-8.76, p = 0.013). CONCLUSION: Methadone is an effective, safe, and cost-saving treatment for patients with refractory cancer pain.

Impact of individualized pharmaceutical care on efficacy and safety of opioid-tolerant outpatients with cancer pain: a multicenter randomized controlled trial.

Background: Managing cancer pain is a growing challenge. Individualized pharmaceutical care is particularly important for opioid-tolerant outpatients due to variation in terms of their knowledge about pain, treatment adherence, and risk of experiencing inadequate analgesia and severe adverse events. This study aimed to determine the influence of individualized pharmaceutical care on outcomes in opioid-tolerant outpatients with cancer pain. Methods: A multicenter, open-label, randomized, controlled study was carried out. Opioid-tolerant outpatients experiencing chronic cancer pain and receiving sustained-release opioids were randomly assigned to the intervention group and the control group with a 1:1 ratio. The intervention group received individualized pharmaceutical care, while the control group received conventional care during 4-week period. The primary endpoint was medication adherence on the intention-to-treat (ITT) population. Secondary outcomes included the patients' knowledge of cancer pain and pain medications, pain score, frequency of breakthrough pain, quality of life (QoL) which were assessed on the ITT population. Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 on the per-protocol (PP) population. Results: A total of 118 patients were enrolled, and 102 patients (51 in each group) completed the 30-day follow-up from six oncology centers in China. The proportion of patients adhering to opioid medication increased to similar levels in the two groups during the 4 weeks (P=0.149). The intervention group had a significantly lower pain score at 4 weeks compared to the control group (P=0.015), and the proportion of participants without breakthrough pain was significantly higher at 4 weeks than at baseline in the intervention group (P=0.029), but not in the control group (P=0.322). The two groups did not differ significantly in terms of QoL or adverse events. Conclusions: Our results suggest that individualized pharmaceutical care can markedly reduce patient-related problems and significantly improve pain control in opioid-tolerant outpatients. These findings validate the recommendations to include clinical pharmacists in the management of cancer pain. Trial Registration: ClinicalTrials.gov identifier: NCT03439904.

Spectrum-Effect Relationship-Based Strategy Combined with Molecular Docking to Explore Bioactive Flavonoids from Sceptridium ternatum.

Sceptridium ternatum is a herbaceous plant with significant potential for pharmaceutical and cosmetic applications. In this study, we established a spectrum-effect relationship-based strategy to investigate the bioactive basis and tissue distribution in S. ternatum. First, a phytochemical analysis on the ethanol extracts from roots, stems, and leaves of S. ternatum was performed using the colorimetric method, high-performance liquid chromatography-ultraviolet (HPLC-UV), and high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC-ESI-Q-TOF-MS/MS). Then, radical scavenging assays and the lipopolysaccharide-stimulated RAW 264.7 cell model were used to estimate the antioxidant and anti-inflammatory activities, respectively. Spectrum-effect relationship analysis and molecular docking were further employed to evaluate the correlation between the phytochemical profile and anti-inflammatory activity. Our results demonstrate that S. ternatum leaves contained the most abundant flavonoids and exerted the best biological activities. Their IC50 values for scavenging 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) and 1,1-diphenyl-2-picrylhydrazyl radicals were 2.43 ± 0.13 and 5.36 ± 0.54 mg/mL, respectively. In lipopolysaccharide-stimulated RAW 264.7 cells, the leaf extract caused the greatest reduction in nitric oxide production (38.15%) and interleukin-6 release (110.86%). Spectrum-effect relationship analysis and molecular docking indicated that quercetin 3-O-rhamnoside-7-O-glucoside possessed high anti-inflammatory activity by binding with interleukin-6. In conclusion, S. ternatum is a rich source of bioactive flavonoids with potential for exploitation in the prevention and treatment of oxidative stress and inflammation-related pathologies.