Cancer Chemotherapy and Pharmacology最新文献

Background and aim: Chronic myeloid leukemia is a myeloproliferative neoplasm associated with the specific chromosomal translocation known as the Philadelphia chromosome. Imatinib is a potent BCR-ABL tyrosine kinase inhibitor, which is approved as the first line therapy for CML patients. There are various population pharmacokinetic studies available in the literature for this population. However, their use in other populations outside of their cohort for the model development has not been evaluated. This study was aimed to perform the predictive performance of the published population pharmacokinetic models for imatinib in CML population and propose a dosing nomogram.

Methods: A systematic review was conducted through PubMed, and WoS databases to identify PopPK models. Clinical data collected in adult CML patients treated with imatinib was used for evaluation of these models. Various prediction-based metrics were used for assessing the bias and precision of PopPK models using individual predictions.

Results: Eight imatinib PopPK model were selected for evaluating the model performance. A total of 145 plasma imatinib samples were collected from 43 adult patients diagnosed with CML and treated with imatinib. The PopPK model reported by Menon et al. had better performance than all other PopPK models.

Conclusion: Menon et al. model was able to predict well for our clinical data where it had the relative mean prediction error percentage ≤ 20%, relative median absolute prediction error ≤ 30% and relative root mean square error close to zero. Based on this final model, we proposed a dosing nomogram for various weight groups, which could potentially help to maintain the trough concentrations in the therapeutic range.

Purpose: Tiragolumab is an immunoglobulin G1 monoclonal antibody targeting the immune checkpoint T cell immunoreceptor with immunoglobulin and immunoreceptor ITIM domains. Targeting multiple immune pathways may improve anti-tumor responses. The phase I YP42514 study assessed the pharmacokinetics (PK), safety, and preliminary efficacy of tiragolumab plus atezolizumab in Chinese patients with advanced solid tumors.

Methods: Adult patients from mainland China with Eastern Cooperative Oncology Group performance score 0/1, life expectancy of ≥ 12 weeks, and adequate hematologic/end organ function were eligible. Patients received tiragolumab 600 mg and atezolizumab 1200 mg intravenous every 3 weeks. Key endpoints were PK (serum concentrations of tiragolumab and atezolizumab) and safety. Results from this study were compared with the global phase I study, GO30103 (NCT02794571).

Results: In this study, 20 patients received a median of five doses of tiragolumab plus atezolizumab. Median age was 57.5 years, 85.0% of patients were male and the most common tumor type was non-small cell lung cancer. Exposures in Chinese patients were comparable to the global GO30103 population: geometric mean ratio was 1.07 for Cycle 1 tiragolumab area under the concentration-time curve_0-21 and 0.92 and 0.93 for Cycle 1 peak and trough atezolizumab exposure, respectively. Treatment-related adverse events were consistent across the Chinese and global populations. Two patients (10.0%) in this study achieved a partial response.

Conclusion: In this study, tiragolumab plus atezolizumab was tolerable and demonstrated preliminary anti-tumor activity. There were no meaningful differences in the PK or safety of tiragolumab plus atezolizumab between the Chinese and global populations.

Clinical trial registration number: China Clinical Trial Registry Identifier CTR20210219/YP42514. Date of registration 16 March 2021.

Purpose: Tiragolumab is a monoclonal antibody that binds to the inhibitory immune checkpoint TIGIT (T-cell immunoreceptor with Ig and ITIM domains). In early phase clinical trials, tiragolumab in combination with the programmed death-ligand 1-inhibitor atezolizumab was well tolerated and has demonstrated preliminary anti-tumor activity in patients with advanced/metastatic solid tumors. We report the results of a phase I study of tiragolumab plus atezolizumab in Japanese patients (jRCT2080224926).

Methods: Japanese patients ≥ 20 years old received tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until unacceptable toxicity or disease progression. Primary endpoints were safety and pharmacokinetic (PK) parameters of tiragolumab plus atezolizumab. Secondary endpoints were anti-tumor activity.

Results: Three patients were enrolled with diagnoses of non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. No dose-limiting toxicities were observed. Two patients experienced treatment-related adverse events (AEs) of any grade. There were no grade ≥ 3 AEs, serious AEs, AEs leading to discontinuation, modification or withdrawal of any study drug, or AEs leading to death. At cycle 1, mean PK parameters of tiragolumab were as follows: C_max 217 μg/mL; C_min 54.9 μg/mL; area under the concentration-time curve from 0 to the last measurable concentration, 2000 μg·day/mL; t_1/2, 17.6 days. Best overall response was stable disease in two patients.

Conclusion: Tiragolumab plus atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors, and no differences in tiragolumab PK characteristics were noted between Japanese patients enrolled in this study, and non-Japanese patients enrolled in a global phase Ia/Ib study. These results may support the inclusion of Japanese patients in ongoing global phase III clinical trials.

Trial registration number: jRCT2080224926.

Purpose: An oral docetaxel formulation boosted by the Cytochrome P450 (CYP) 3 A inhibitor ritonavir, ModraDoc006/r, is currently under clinical investigation. Based on clinical data, the incidence of grade 1-2 diarrhea is increased with this oral docetaxel formulation compared to the conventional intravenous administration. Loperamide, a frequently used diarrhea inhibitor, could be added to the regimen as symptomatic treatment. However, loperamide is also a substrate of the CYP3A enzyme, which could result in competition between ritonavir and loperamide for this protein. Therefore, we were interested in the impact of coadministered loperamide on the pharmacokinetics of ritonavir-boosted oral docetaxel.

Methods: We administered loperamide simultaneously or with an 8-hour delay to humanized CYP3A4 mice (with expression in liver and intestine) receiving oral ritonavir and docetaxel. Concentrations of docetaxel, ritonavir, loperamide and two of its active metabolites were measured.

Results: The plasma exposure (AUC and C_max) of docetaxel was not altered during loperamide treatment, nor were the ritonavir plasma pharmacokinetics. However, the hepatic and intestinal dispositions of ritonavir were somewhat changed in the simultaneous, but not 8-hour loperamide treatment groups, possibly due to loperamide-induced delayed drug absorption. The pharmacokinetics of loperamide itself did not seem to be influenced by ritonavir.

Conclusion: These results suggest that delayed loperamide administration can be added to ritonavir-boosted oral docetaxel treatment, without affecting the overall systemic exposure of docetaxel.

Background and objective: This study aims to investigate the role of Vitamin D (VD) in regulating the stemness and survival of CD133+/CD44 + breast cancer stem cells, and to explore the role of NLRP3 in this process.

Methods: Breast cancer tissues were collected for RXRα and VDR expression analysis. A triple-negative breast cancer cell line was cultured and stem-like cells (CD133 + CD44+) isolated using flow cytometry. These cells were treated with VD, analyzing their stem-like properties, apoptosis and proliferation, as well as P65 nuclear expression and NLRP3 expression. After NLRP3 inflammasome activator treatment, the parameters were reassessed. RXRα and VDR interaction was confirmed using co-immunoprecipitation (CoIP). Finally, a subcutaneous xenograft model of triple-negative breast cancer was treated with VD and subsequently analyzed for stem-like properties, proliferation, apoptosis, and NLRP3 expression levels.

Results: CD133+/CD44 + stem cells expressed high levels of SOX2 and OCT4. VD treatment resulted in a significant decrease in SOX2 and OCT4 expression, fewer sphere-forming colonies, lower proliferation ability, and more apoptosis. Additionally, VD treatment inhibited NF-κB signaling and reduced NLRP3 expression. The NLRP3 activator BMS-986,299 counteracted the effects of VD in vitro. In vivo, VD inhibited the growth of breast cancer stem cells, reducing both tumor volume and weight, and decreased NLRP3, SOX2, and OCT4 expression within tumor tissues.

Conclusion: Findings elucidate that VD mediates the modulation of stemness in CD133+/CD44 + breast cancer stem cells through the regulation of NLRP3 expression. The research represents novel insights on the implications for the application of VD in cancer therapies.

Glioblastoma multiforme (GBM) is a highly aggressive and incurable disease accounting for about 10,000 deaths in the USA each year. Despite the current treatment approach which includes surgery with chemotherapy and radiation therapy, there remains a high prevalence of recurrence. Notable improvements have been observed in persons receiving concurrent antihypertensive drugs such as renin angiotensin inhibitors (RAS) or the antidiabetic drug metformin with standard therapy. Anti-tumoral effects of RAS inhibitors and metformin have been observed in in vitro and in vivo studies. Although clinical trials have shown mixed results, the potential for the use of RAS inhibitors and metformin as adjuvant GBM therapy remains promising. Nevertheless, evidence suggest that these drugs exert multimodal antitumor actions; by particularly targeting several cancer hallmarks. In this review, we highlight the results of clinical studies using multidrug cocktails containing RAS inhibitors and or metformin added to standard therapy for GBM. In addition, we highlight the possible molecular mechanisms by which these repurposed drugs with an excellent safety profile might elicit their anti-tumoral effects. RAS inhibition elicits anti-inflammatory, anti-angiogenic, and immune sensitivity effects in GBM. However, metformin promotes anti-migratory, anti-proliferative and pro-apoptotic effects mainly through the activation of AMP-activated protein kinase. Also, we discussed metformin's potential in targeting both GBM cells as well as GBM associated-stem cells. Finally, we summarize a few drug interactions that may cause an additive or antagonistic effect that may lead to adverse effects and influence treatment outcome.

Purpose: We report the case of an adult patient diagnosed with Hodgkin's lymphoma who was scheduled for Pembrolizumab after failure of standard therapy. After three well-tolerated courses of Pembrolizumab, a PET scan showed a favorable outcome and a fourth course of Pembrolizumab was started. Unexpectedly, extremely severe toxicities (i.e., autoimmune peripheral hypothyroidism, rhabdomyolysis and severe acute renal failure) occurred after this last course, requiring transfer to the intensive care unit.

Methods: Therapeutic drug monitoring was performed to measure residual Pembrolizumab levels at intervals from the last dose (i.e., 120 and then 170 days), as well as pharmacogenetics investigations on the FCγR gene.

Results: Pembrolizumab plasma concentrations that were still pharmacologically active months after the last administration, suggesting impaired elimination of Pembrolizumab in this patient. Further pharmacokinetic modeling based on the population approach showed that both half-life (47.8 days) and clearance (0.12 L/day) values were significantly different from the standard values usually reported in patients. Further in silico simulations showed that pharmacologically active concentrations of Pembrolizumab were maintained for up to 136 days after the last dose. The search for possible polymorphisms affecting the genes coding for FCγR (i.e., rs1801274 on FCGR2A and rs396991 on FCGR3A gene) was negative. Further TDM showed that Pembrolizumab could be detected up to 263 days after the last administration.

Conclusion: This case report suggests that persistent overexposure in plasma could lead to life-threatening toxicities with Pembrolizumab.

Purpose: The intraventricular route of chemotherapy administration, via an Ommaya Reservoir (OmR) improves drug distribution in the central nervous system (CNS) compared to the more commonly used intrathecal administration. We retrospectively reviewed our experience with intraventricular chemotherapy, focused on methotrexate, in patients with Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL).

Methods: Twenty-four patients (aged 7 days - 22.2 years) with 26 OmR placements were identified for a total of 25,009 OmR days between 1990 and 2019. Methotrexate cerebrospinal fluid (CSF) concentrations (n = 124) were analyzed from 59 courses of OmR therapy in 15 patients. Twenty-one courses involved methotrexate dosing on day 0 only, whereas 38 courses involved booster dosing on days 1, 2, or both. We simulated the time CSF methotrexate concentrations remained > 1 µM for 3 days given various dosing regimens.

Results: CSF methotrexate exposure was higher in those who concurrently received systemic methotrexate than via OmR alone (p < 10^- 7). Our simulations showed that current intraventricular methotrexate boosting strategy for patients ≥ 3 years of age maintained CSF methotrexate concentrations ≥ 1 µM for 72 h 40% of the time. Alternatively, other boosting strategies were predicted to achieve CSF methotrexate concentrations ≥ 1 µM for 72 h between 46 and 72% of the time.

Conclusions: OmR were able to be safely placed and administer intraventricular methotrexate with and without boost doses in patients from 7 days to 22 years old. Boosting strategies are predicted to increase CSF methotrexate concentrations ≥ 1 µM for 72 h.

Background: Guidelines such as the National Comprehensive Cancer Network recommend mycophenolate mofetil (MMF) for the treatment of severe steroid-refractory immune-related hepatotoxicity. Mycophenolic acid (MPA) is an active form of MMF that suppresses T- and B-lymphocyte proliferation and immune-related adverse events caused by immune checkpoint inhibitors. MPA has a narrow therapeutic range (37-70 µg·h/mL) and overexposure increases the risk of leukopenia in transplantation. However, the optimal use of MMF in oncology has not yet been established; thus, monitoring plasma MPA concentrations is necessary to avoid excessive immunosuppression in oncology practice.

Case presentation: We evaluated plasma MPA concentration in a 75-year-old man with immune-related hepatotoxicity following nivolumab and ipilimumab combination therapy for malignant melanoma. The patient developed severe hepatotoxicity after immunotherapy, and immunosuppressant therapy with corticosteroids was initiated. The patient then developed steroid-refractory immune-related hepatotoxicity; therefore, MMF (1,000 mg twice daily) was co-administered. Seven days after the administration of MMF, the plasma MPA concentration was measured using an enzyme multiplied immunoassay technique. The area under the plasma concentration-time curve for MPA from 0 to 12 h was 41.0 µg·h/mL, and the same dose of MMF was continued. Grade 2 lymphocytopenia, which could be attributed to MMF, was observed during the administration period. Unfortunately, the patient was infected with SARS-CoV-2 and died from respiratory failure.

Conclusion: Our patient did not exceed the upper limit of MPA levels as an index of the onset of side effects of kidney transplantation and achieved rapid improvement in liver function. Prompt initiation of MMF after assessment of the steroid effect leads to adequate MPA exposure. Therapeutic drug monitoring should be considered when MMF is administered, to avoid overexposure.

Background and objectives: Proteinuria is a common complication after the application of bevacizumab therapy in patients with metastatic colorectal cancer, and severe proteinuria can lead to discontinuation of the drug. There is a lack of sophisticated means to predict bevacizumab-induced proteinuria, so the present study aims to predict bevacizumab-induced proteinuria using peripheral venous blood samples.

Methods: A total of 122 subjects were enrolled and underwent pre-treatment plasma markers, and we followed them for six months with proteinuria as the endpoint event. We then analyzed the clinical features and plasma markers for grade ≥ 2 proteinuria occurrence using machine learning to construct a model with predictive utility.

Results: One hundred sixteen subjects were included in the statistical analysis. We found that high baseline systolic blood pressure, low baseline HGF, high baseline ET1, high baseline MMP2, and high baseline ACE1 were risk factors for the development of grade ≥ 2 proteinuria in patients with metastatic colorectal cancer who received bevacizumab. Then, we constructed a support vector machine model with a sensitivity of 0.889, a specificity of 0.918, a precision of 0.615, and an F1 score of 0.727.

Conclusion: We constructed a machine learning model for predicting grade ≥ 2 bevacizumab-induced proteinuria, which may provide proteinuria risk assessment for applying bevacizumab in patients with metastatic colorectal cancer.