Cancer Chemotherapy and Pharmacology最新文献

Introduction: For drugs with a narrow therapeutic window, there is a delicate balance between efficacy and toxicity, thus it is pivotal to administer the right dose from the first administration onwards. Exposure of pemetrexed, a cytotoxic drug used in lung cancer treatment, is dictated by kidney function. To facilitate optimized dosing of pemetrexed, accurate prediction of drug clearance is pivotal. Therefore, the aim of this study was to investigate the performance of the kidney function biomarkers serum creatinine, cystatin C and pro-enkephalin in terms of predicting the elimination of pemetrexed.

Methods: We performed a population pharmacokinetic analysis using a dataset from two clinical trials containing pharmacokinetic data of pemetrexed and measurements of all three biomarkers. A three-compartment model without covariates was fitted to the data and the obtained individual empirical Bayes estimates for pemetrexed clearance were considered the "true" values (Cl_true). Subsequently, the following algorithms were tested as covariates for pemetrexed clearance: the Chronic Kidney Disease Epidemiology Collaboration equation using creatinine (CKD-EPI_CR), cystatin C (CKD-EPI_CYS), a combination of both (CKD-EPI_CR-CYS), pro-enkephalin as an absolute value or in a combined algorithm with age and serum creatinine, and lastly, a combination of pro-enkephalin with cystatin C.

Results: The dataset consisted of 66 subjects with paired observations for all three kidney function biomarkers. Inclusion of CKD-EPI_CR-CYS as a covariate on pemetrexed clearance resulted in the best model fit, with the largest decrease in objective function (p < 0.00001) and explaining 35% of the total inter-individual variability in clearance. The predictive performance of the model to containing CKD-EPI_CR-CYS to predict pemetrexed clearance was good with a normalized root mean squared error and mean prediction error of 19.9% and 1.2%, respectively.

Conclusions: In conclusion, this study showed that the combined CKD-EPI_CR-CYS performs best in terms predicting pharmacokinetics of pemetrexed. Despite the hypothesized disadvantages, creatinine remains to be a suitable and readily available marker to predict pemetrexed clearance in clinical practice.

Purpose: Cancer stem cells (CSCs) account for recurrence and resistance to breast cancer drugs, rendering them a cause of mortality and therapeutic failure. In this study, we examined the effects of exposure to low concentrations of doxorubicin (Dox) on CSCs and non-CSCs from TNBC.

Methods: The effects of Dox were studied using the SORE6 reporter system. We examined the enrichment of the CSCs population, as well as the proliferation, and death of the reporter-positive fraction (GFP + cells) by flow cytometry. The resistant and stemness phenotypes were analyzed by viability and mammosphere formation assay, respectively. We identified differentially expressed and coregulated genes by RNA-seq analysis, and the correlation between gene expression and clinical outcome was evaluated by Kaplan-Mayer analysis using public databases.

Results: In MDAMB231 and Hs578t cells, we identified enriched subsets in the CSCs population after continuous exposure to low concentrations of Dox. Cells from these enriched cultures showed resistance to toxic concentrations of Dox and increased efficiency of mammosphere formation. In purified GFP + or GFP- cells, Dox increased the mammosphere-forming efficiency, promoted phenotypic switches in non-CSCs populations to a CSC-like state, reduced proliferation, and induced differential gene expression. We identified several biological processes and molecular functions that partially explain the development of doxorubicin-resistant cells and cellular plasticity. Among the genes that were regulated by Dox exposure, the expression of ITGB1, SNAI1, NOTCH4, STAT5B, RAPGEF3, LAMA2, and GNAI1 was significantly associated with poor survival, the stemness phenotype, and chemoresistance.

Conclusion: The generation of chemoresistant cells that have characteristics of CSCs, after exposure to low concentrations of Dox, involves the differential expression of genes that have a clinical impact.

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.

Purpose: A physiologically based pharmacokinetic (PBPK) model for fedratinib was updated and revalidated to bridge a gap between the observed drug-drug interaction (DDI) of a single sub-efficacious dose in healthy participants and the potential DDI in patients with cancer at steady state. The study aimed to establish an appropriate dose for fedratinib in patients coadministered with dual CYP3A4 and CYP2C19 inhibitors, providing quantitative evidence to inform dosing guidance.

Methods: The original minimal PBPK model was developed using Simcyp^® Simulator v17. The model was updated by substituting a single distribution rate (Q_sac) with 2 separate rates (CL_in/CL_out) and transitioning to v20. Model parameter updates were further informed with 3 clinical studies, and 3 more studies served as independent validation data. The validated model was applied to simulate potential DDIs between fedratinib and a known dual inhibitor of CYP3A4 and CYP2C19 (fluconazole).

Results: Coadministration of fedratinib with fluconazole in patients was predicted to increase fedratinib exposure by < 2-fold in all simulated scenarios. For patients with cancer receiving the approved dose of fedratinib 400 mg once daily along with fluconazole 200 mg daily, the model predicted an approximate 50% increase in fedratinib exposure at steady state.

Conclusions: The updated PBPK model improved description of the observed pharmacokinetics and predicted a low risk of clinically significant DDIs between fedratinib and fluconazole. The quantitative evidence serves as a primary foundation for providing dose guidance in clinical practice for the coadministration of fedratinib with dual CYP3A4 and CYP2C19 inhibitors.

Purpose: 4-hydroxycyclophosphamide (4HCY) is the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY), which is often used as first-line treatment of children with cancer. There is conflicting data regarding the relationship between CY efficacy, toxicity, and pharmacokinetics with the genes encoding proteins involved in 4HCY pharmacokinetics, specifically its formation and elimination.

Methods: We evaluated germline pharmacogenetics in children with various malignancies receiving their first CY dose. Using linear regression, we analyzed the associations between two pharmacokinetic outcomes - how fast a child cleared CY (i.e., CY clearance) and the ratio of the 4HCY/CY exposure, specifically area under the plasma concentration-time curve (AUC), and 372 single nucleotide polymorphisms (SNP) in 14 drug-metabolizing transporters or enzymes involved in 4HCY formation or elimination.

Results: Age was associated with the ratio of 4HCY/CY AUC (P = 0.004); Chemotherapy regimen was associated with CY clearance (P = 0.003). No SNPs were associated with CY clearance or the ratio of 4HCY/CY AUC after controlling for a false discovery rate.

Conclusion: Age and chemotherapy regimen, but not germline pharmacogenomics, were associated with CY clearance or the ratio of 4HCY/CY AUC. Other methods, such as metabolomics or lipidomics, should be explored.

Purpose: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients.

Methods: Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry.

Results: We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase.

Conclusion: This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs.

Purpose: Hair cell damage is a common side effect caused by the anticancer drug cisplatin (CDDP), which reduces patient quality of life. One CDDP resistance mechanism that occurs in recurrent cancers is heavy metal detoxification by metallothionein-2 (mt2). Here, we show that in zebrafish larvae, dexamethasone (DEX) reduces CDDP-induced hair cell damage by enhancing mt2 expression.

Methods: Transgenic zebrafish (cldn: gfp; atoh1: rfp) that express green and red fluorescent proteins in neuromasts and hair cells, respectively, were used. The zebrafish were pretreated with DEX at 52 h post-fertilization (hpf) for 8 h, followed by CDDP treatment for 12 h. The lateral line hair cells of CDDP-treated zebrafish at 72 hpf were observed by fluorescence microscopy.

Results: Reporting odds ratio (ROR) analysis using an adverse event database indicated an association between a decrease in CDDP-induced ototoxicity and DEX as an antiemetic treatment for cancer chemotherapy. Pretreatment with DEX protected 72 hpf zebrafish hair cells from CDDP-induced damage. The expression of mt2 mRNA was significantly increased by the combination of 10 µM DEX with CDDP. Gene editing of mt2 reversed the protective effect of DEX against CDDP-induced damage in hair cells.

Conclusion: DEX protects hair cells from CDDP-induced damage through increased mt2 expression, which is a resistance mechanism for platinum-based anticancer drugs.

Purpose: It is highly important to be able to predict the therapeutic efficacy of chemotherapy on patients with unresectable advanced or recurrent gastric cancer (GC). The Gustave Roussy Immune Score (GRIm-s) is a predictor of therapeutic sensitivity to chemotherapy and immune checkpoint inhibitors (ICIs) in other cancers. The present study aimed to analyze the association of the GRIm-s with the therapeutic sensitivity of first-line chemotherapy in GC patients.

Methods: We included 156 patients receiving primary chemotherapy treatment for unresectable or advanced recurrent GC between January 2012 and December 2021 at our institution. We evaluated the correlation between the GRIm-s and therapeutic sensitivities to chemotherapy. The GRIm-s was assessed before the start of first-line chemotherapy.

Results: Among the 156 patients, 138 (88.5%) and 18 (11.5%) were classified in the low- and high-risk groups, respectively. The GRIm-s high-risk group was significantly older (p = 0.013), had more advanced unresectable cancer (p = 0.0098), and was significantly less likely to progress to second-line chemotherapy (p = 0.014). The overall survival rate (OS) (p = 0.039) and the progression free survival rate (PFS) (p = 0.017) were significantly worse in the GRIm-s high-risk group. The high GRIm-s was an independent prognostic factor for poor survival in multivariate analysis (p = 0.0094).

Conclusions: Focusing on the GRIm-s before first-line chemotherapy initiation for unresectable advanced or postoperative recurrent GC was useful in predicting the therapeutic resistance to chemotherapy, transition to second-line chemotherapy, and poor prognosis.

Background: Therapy-related acute myeloid leukemia (t-AML) is considered high risk as it related to prior exposure to cytotoxic chemotherapy agents for solid tumors or hematologic malignancies. Compared with de novo AML, t-AML is associated with lower remission rates, inferior overall survival (OS) and higher relapse rates. Many efforts have been devoted to improving the overall but with limited success, and novel strategy is thus highly needed.

Case description: We reported one patient with refractory/relapsed t-AML was successfully treated with Palbociclib combined with Venetoclax and Azacytidine (AZA). In this case, a 47-year-old patient with t-AML recurred during Venetoclax in combination with AZA therapy. However, the patient achieved morphological, immunophenotypic and molecular complete remission again after Palbociclib combined with Venetoclax and AZA.

Conclusions: Although only one successful case is presented here, three-drug combination regimens should be considered as another treatment option for t-AML in the future.

Cisplatin and amphotericin B are both known to be potentially nephrotoxic. We describe acute kidney injury due to the combination of Liposomal amphotericin B and cisplatin in an adolescent with osteosarcoma. Acute kidney injury (peak creatinine 431 µmol/L) consistent with drug-induced acute tubulointerstitial nephritis was observed a few days after concomitant administration of cisplatin and amphotericin B. Kidney function nearly normalised during follow-up. The timing of the concomitant administration of amphotericin B and cisplatin led us to presume that the combination was the cause of renal failure, and we conclude that concurrent administration of cisplatin and amphotericin B should be avoided.