Cancer Chemotherapy and Pharmacology最新文献

{"title":"Acute kidney injury in a child treated with cisplatin and amphotericin B.","authors":"Torjus Skajaa, Mia Faerch, Henrik Hasle","doi":"10.1007/s00280-024-04705-0","DOIUrl":"10.1007/s00280-024-04705-0","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"623-626"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successful use of Palbociclib combined with Venetoclax and Azacitidine in an adult with refractory/relapsed therapy-related acute myeloid leukemia.","authors":"Wenqiang Qu, Jialing Lu, Yujie Ji, Zhewei He, Mengjia Hou, Dongyang Li, Yan Yang, Dan Liu, Suning Chen","doi":"10.1007/s00280-024-04642-y","DOIUrl":"10.1007/s00280-024-04642-y","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Case description: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"635-639"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Darifenacin: a promising chitinase 3-like 1 inhibitor to tackle drug resistance in pancreatic ductal adenocarcinoma.","authors":"Sofia M Sousa, Helena Branco, Amir Avan, Andreia Palmeira, Luca Morelli, Lúcio L Santos, Elisa Giovannetti, M Helena Vasconcelos, Cristina P R Xavier","doi":"10.1007/s00280-024-04712-1","DOIUrl":"10.1007/s00280-024-04712-1","url":null,"abstract":"<p><strong>Purpose: </strong>Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies. Our previous work revealed Chitinase 3-like 1 (CHI3L1) involvement in PDAC resistance to gemcitabine, identifying it as a promising therapeutic target. Here, we aimed to identify putative CHI3L1 inhibitors and to investigate their chemosensitizing potential in PDAC.</p><p><strong>Methods: </strong>Docking analysis for CHI3L1 identified promising CHI3L1 inhibitors, including darifenacin (muscarinic receptor antagonist). PDAC cell lines (BxPC-3, PANC-1) and primary PDAC cells were used to evaluate darifenacin's effects on cell growth (Sulforhodamine B, SRB), alone or in combination with gemcitabine or gemcitabine plus paclitaxel. Cytotoxicity against normal immortalized pancreatic ductal cells (HPNE) was assessed. Recombinant protein was used to confirm the impact of darifenacin on CHI3L1-induced PDAC cellular resistance to therapy (SRB assay). Darifenacin's effect on Akt activation was analysed by ELISA. The association between cholinergic receptor muscarinic 3 (CHRM3) expression and therapeutic response was evaluated by immunohistochemistry of paraffin-embedded tissues from surgical resections of a 68 patients' cohort.</p><p><strong>Results: </strong>In silico screening revealed the ability of darifenacin to target CHI3L1 with high efficiency. Darifenacin inhibited PDAC cell growth, with a GI₅₀ of 26 and 13.6 µM in BxPC-3 and PANC-1 cells, respectively. These results were confirmed in primary PDAC-3 cells, while darifenacin showed no cytotoxicity against HPNE cells. Importantly, darifenacin sensitized PDAC cells to standard chemotherapies, reverted CHI3L1-induced PDAC cellular resistance to therapy, and decreased Akt phosphorylation. Additionally, high CHMR3 expression was associated with low therapeutic response to gemcitabine.</p><p><strong>Conclusion: </strong>This work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"585-597"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Avermectin B1 mediates antitumor activity and induces autophagy in osteosarcoma through the AMPK/ULK1 signaling pathway.","authors":"Xiang Fei, Zhaohui Li, Zhen Pan, Yonghui Liang, Chen Tan, Dongdong Cheng, Qingcheng Yang","doi":"10.1007/s00280-024-04695-z","DOIUrl":"10.1007/s00280-024-04695-z","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma is the most common malignant bone tumor in children and adolescents. Conventional chemotherapy remains unsatisfactory due to drug toxicity and resistance issues. Therefore, there is an urgent need to develop more effective treatments for advanced osteosarcoma. In the current study, we focused on evaluating the anticancer efficacy of avermectin B1, a novel avermectin analog, against osteosarcoma cells.</p><p><strong>Methods: </strong>The half-inhibitory concentration of avermectin B1 was calculated in three osteosarcoma cell lines. Then, functional experiments were conducted to evaluate the effects of avermectin B1 on cell proliferation, the cell cycle, apoptosis and autophagy. Moreover, the AMPK/ULK1 signaling pathway was detected by Western blot assay. Finally, the in vivo effect of avermectin B1 on tumor growth and metastasis was investigated using the xenograft mouse model. To examine the role of the AMPK/ULK1 pathway, an AMPK-specific inhibitor (dorsomorphin) was used in combination with avermectin B1.</p><p><strong>Results: </strong>Avermectin B1 inhibited the proliferation of osteosarcoma cells in a dose-dependent manner based on CCK8 and colony formation assays. Then, it was found to inhibit migration and invasion by wound healing assay and cell migration and invasion assay. In addition, avermectin B1 induced osteosarcoma cell apoptosis and autophagy. In vivo, avermectin B1 effectively inhibited osteosarcoma cell growth and pulmonary metastasis. Mechanistically, avermectin B1 activated the AMPK/ULK1 pathway to exert antitumor activity in vitro and in vivo. Dorsomorphin significantly attenuated the Avermectin B1-induced antitumor activities.</p><p><strong>Conclusion: </strong>Our study suggests that avermectin B1 is a potential agent to treat osteosarcoma cells through the AMPK/ULK1 signaling pathway.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"599-613"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis - a potential feature underlying neratinib-induced colonic epithelial injury.","authors":"Triet P M Nguyen, Susan L Woods, Kate R Secombe, Simon Tang, Aurelia S Elz, Scott Ayton, John Finnie, Aadya Nagpal, Normand Pouliot, Joanne M Bowen","doi":"10.1007/s00280-024-04699-9","DOIUrl":"10.1007/s00280-024-04699-9","url":null,"abstract":"<p><strong>Purpose: </strong>Neratinib, a small-molecule tyrosine kinase inhibitor (TKI) that irreversibly binds to human epidermal growth factor receptors 1, 2 and 4 (HER1/2/4), is an approved extended adjuvant therapy for patients with HER2-amplified or -overexpressed (HER2-positive) breast cancers. Patients receiving neratinib may experience mild-to-severe symptoms of gut toxicity including abdominal pain and diarrhoea. Despite being a highly prevalent complication in gut health, the biological processes underlying neratinib-induced gut injury, especially in the colon, remains unclear.</p><p><strong>Methods: </strong>Real-time quantitative polymerase chain reaction (RT-qPCR) and histology were integrated to study the effect of, and type of cell death induced by neratinib on colonic tissues collected from female Albino Wistar rats dosed with neratinib (50 mg/kg) daily for 28 days. Additionally, previously published bulk RNA-sequencing and CRISPR-screening datasets on human glioblastoma SF268 cell line and glioblastoma T895 xenograft, and mouse TBCP1 breast cancer cell line were leveraged to elucidate potential mechanisms of neratinib-induced cell death.</p><p><strong>Results: </strong>The severity of colonic epithelial injury, especially degeneration of surface lining colonocytes and infiltration of immune cells, was more pronounced in the distal colon than the proximal colon. Sequencing showed that apoptotic gene signature was enriched in neratinib-treated SF268 cells while ferroptotic gene signature was enriched in neratinib-treated TBCP1 cells and T895 xenograft. However, we found that ferroptosis, but less likely apoptosis, was a potential histopathological feature underlying colonic injury in rats treated with neratinib.</p><p><strong>Conclusion: </strong>Ferroptosis is a potential feature of neratinib-induced colonic injury and that targeting molecular machinery governing neratinib-induced ferroptosis may represent an attractive therapeutic approach to ameliorate symptoms of gut toxicity.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"493-505"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic and bioequivalence study of two capecitabine tablets in Chinese patients with solid tumor cancer.","authors":"Guangnan Zong, Jinlin Li, Xiushan Gong, Yuanyuan Liu, Xiuli Guo","doi":"10.1007/s00280-024-04652-w","DOIUrl":"10.1007/s00280-024-04652-w","url":null,"abstract":"<p><p>Capecitabine (CAP) is one of the fluoropyrimidine deoxynucleoside carbamates, which can be converted to 5-fluorouracil (5-FU) by thymine deoxynucleoside phosphorylase (dThdPase) to exert antitumor effects. The purpose of this study is to compare the pharmacokinetics (PK), bioequivalence (BE), and safety of two CAP tablets in Chinese patients with solid tumor cancer. The results showed that the geometric mean ratios (GMRs) of C_max, AUC_0-t and AUC_0-∞ of CAP T/R reagent were 90.26%, 95.27%, and 95.07, respectively. The values and 90% confidence intervals (CI) of AUC_0-t, AUC_0-∞, and C_max all fall within the range of 80.00-125.00%. In addition, a total of 22 subjects in this study had 30 adverse events, with an incidence of 45.83%, and there were no serious adverse events and adverse events that led to withdrawal from the trial.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"641-645"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of ALDH1A1 and NQO1 gene polymorphisms on the response and toxicity of chemotherapy in Bangladeshi breast cancer patients.","authors":"Md Siddiqul Islam, Ferdowsi Akter, Md Mosiqur Rahman, Md Rajdoula Rafe, Md Abdul Aziz, Salma Parvin, Abu Syed Md Mosaddek, Mohammad Safiqul Islam, Md Wahid Akter","doi":"10.1007/s00280-024-04700-5","DOIUrl":"10.1007/s00280-024-04700-5","url":null,"abstract":"<p><strong>Purpose: </strong>Cyclophosphamide, Epirubicin/Doxorubicin, 5-fluorouracil (CEF or CAF) chemotherapy has long been a standard first-line treatment for breast cancer. The genetic variations of enzymes that are responsible for the metabolism of these drugs have been linked to altered treatment response and toxicity. Two drug-metabolizing enzymes ALDH1A1 and NQO1 are critically involved in the pathways of CEF/CAF metabolism. This study aimed to evaluate the effect of ALDH1A1 (rs13959) and NQO1 (rs1800566) polymorphisms on treatment response and toxicities caused by adjuvant (ACT) and neoadjuvant chemotherapy (NACT) where CEF/CAF combination was used to treat Bangladeshi breast cancer patients.</p><p><strong>Methods: </strong>A total of 330 patients were recruited from various hospitals, with 150 receiving neoadjuvant chemotherapy and 180 receiving adjuvant chemotherapy. To extract genomic DNA, a non-enzymatic simple salting out approach was adopted. The polymerase chain reaction-restriction fragment length polymorphism method was used to detect genetic polymorphisms. Unconditional logistic regression was used to derive odds ratios (ORs) with 95% confidence intervals (CIs) to study the association between genetic polymorphisms and clinical outcome and toxicity.</p><p><strong>Results: </strong>A statistically significant association was observed between ALDH1A1 (rs13959) polymorphism and treatment response (TT vs. CC: aOR = 6.40, p = 0.007; recessive model: aOR = 6.38, p = 0.002; allele model: p = 0.032). Patients with the genotypes TT and CT + TT of the NQO1 (rs1800566) polymorphism had a significantly higher risk of toxicities such as anemia (aOR = 0.34, p = 0.006 and aOR = 0.58, p = 0.021), neutropenia (aOR = 0.42, p = 0.044 and aOR = 0.57, p = 0.027), leukopenia (aOR = 0.33, p = 0.010 and aOR = 0.46, p = 0.005), and gastrointestinal toxicity (aOR = 0.30, p = 0.02 and aOR = 0.38, p = 0.006) when compared to the wild CC genotype, while patients with the genotype CT had a significant association with gastrointestinal toxicity (aOR = 0.42, p = 0.02) and leukopenia (aOR = 0.52, p = 0.010). The TT and CT + TT genotypes of rs13959 had a significantly higher risk of anemia (aOR = 2.00, p = 0.037 and aOR = 1.68, p = 0.029). There was no significant association between rs1800566 polymorphism and treatment response.</p><p><strong>Conclusion: </strong>Polymorphisms in ALDH1A1 (rs13959) and NQO1 (rs1800566) may be useful in predicting the probability of treatment response and adverse effects from CEF or CAF-based chemotherapy in breast cancer patients.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"507-516"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of midostaurin on the pharmacokinetics of P-gp, BCRP, and CYP2D6 substrates: assessing potential drug-drug interactions in healthy participants : Brief title: Drug-drug interaction of midostaurin.","authors":"Romain Sechaud, Helen Gu, Gholamreza Rahmanzadeh, Ovidiu Chiparus, Astrid Breitschaft, Hans D Menssen","doi":"10.1007/s00280-024-04683-3","DOIUrl":"10.1007/s00280-024-04683-3","url":null,"abstract":"<p><strong>Purpose: </strong>Midostaurin, approved for FLT3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is mainly metabolized by cytochrome P450 (CYP) 3A4. Midostaurin exhibited potential inhibitory effects on P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polyprotein 1B1, and CYP2D6 in in vitro studies. This study investigated the pharmacokinetic (PK) effects of midostaurin on P-gp (digoxin), BCRP (rosuvastatin) and CYP2D6 (dextromethorphan) substrates in healthy adults.</p><p><strong>Methods: </strong>This was an open-label, single-sequence, phase I clinical study evaluating the effect of single-dose midostaurin (100 mg) on the PK of digoxin and rosuvastatin (Arm 1), and dextromethorphan (Arm 2). Participants were followed up for safety 30 days after last dose. In addition, the effect of midostaurin on the PK of dextromethorphan metabolite (dextrorphan) was assessed in participants with functional CYP2D6 genes in Arm 2.</p><p><strong>Results: </strong>The effect of midostaurin on digoxin was minor and resulted in total exposure (AUC) and peak plasma concentration (C_max) that were only 20% higher. The effect on rosuvastatin was mild and led to an increase in AUCs of approximately 37-48% and of 100% in C_max. There was no increase in the primary PK parameters (AUCs and C_max) of dextromethorphan in the presence of midostaurin. The study treatments were very well tolerated with no occurance of severe adverse events (AEs), AEs of grade ≥ 2, or deaths.</p><p><strong>Conclusion: </strong>Midostaurin showed only a minor inhibitory effect on P-gp, a mild inhibitory effect on BCRP, and no inhibitory effect on CYP2D6. Study treatments were well tolerated in healthy adults.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"535-547"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination of S-1 and the oral ATR inhibitor ceralasertib is effective against pancreatic cancer cells","authors":"Yoshihito Morimoto, Kimihiko Takada, Ami Nakano, Osamu Takeuchi, Kazuhiro Watanabe, Masayoshi Hirohara, Yutaka Masuda","doi":"10.1007/s00280-024-04716-x","DOIUrl":"https://doi.org/10.1007/s00280-024-04716-x","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Purpose</h3><p>In our previous study, we found that the Chk1 inhibitor prexasertib enhances the antitumour effect of the oral anticancer drug S-1 against pancreatic cancer cells. In this study, we investigated the effect of combining S-1 and ceralasertib, an oral inhibitor of ATR, which is located upstream of Chk1. Ceralasertib is currently being investigated in multiple clinical trials for various cancers.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The cell-proliferation inhibitory effect was measured by MTT assay, using the pancreatic cancer cell lines BxPC-3, SUIT-2, PANC-1, and MIA PaCa-2, while apoptosis was measured by flow cytometry using PI/Annexin staining. The mechanism underlying the combined effect was analysed using western blotting, and the antitumor effect was analysed using a mouse xenograft model.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>MTT assay revealed that the combination of S-1 and ceralasertib had a synergistic effect, leading to the suppression of cell proliferation. Measurement with PI/Annexin staining revealed that the combination of S-1 and ceralasertib induced apoptosis more efficiently than either drug alone. Western blotting results showed that ceralasertib inhibited S-1-induced activation of ATR and Chk1. The average estimated tumour volume after 3 weeks of administration was 601 mm³ in the S-1 group, 580 mm³ in the ceralasertib group, and 298 mm³ in the combination group.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>The combination of S-1 and ceralasertib demonstrated a high antiproliferative effect in inhibiting tumour growth in vitro.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"119 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing pharmacokinetics and drug-drug interactions of the combination therapy of myelofibrosis with ruxolitinib and lenalidomide by a new eco-friendly HPLC method for their simultaneous determination in plasma","authors":"Rashed N. Herqash, Fai A. Alkathiri, Ibrahim A. Darwish","doi":"10.1007/s00280-024-04715-y","DOIUrl":"https://doi.org/10.1007/s00280-024-04715-y","url":null,"abstract":"<p>Ruxolitinib (RUX), a Janus kinase 2 (JAK2) inhibitor, and lenalidomide (LEN), an immunomodulatory agent, have recently been proposed as a combined treatment for myelofibrosis (MF). This combination has demonstrated improved efficacy, safety, and tolerability compared to monotherapy. To further refine these findings, an efficient analytical tool is needed to simultaneously determine RUX and LEN concentrations in blood plasma. This tool would enable the study of their pharmacokinetics, drug-drug interactions, and therapeutic monitoring during MF therapy. Unfortunately, such a method has not been existed in the literature. This study presents the first HPLC method with UV detection for the simultaneous quantitation of RUX and LEN in plasma. The method was validated according to the ICH guidelines for bioanalytical method validation. It exhibited linearity in the concentration ranges of 10 to 3150 ng mL^− 1 for RUX and 80 to 5200 ng mL^− 1 for LEN. The limits of quantitation were determined to be 25 and 90 ng mL^− 1 for RUX and LEN, respectively. All other validation parameters were satisfactory. The HPLC-UV method was successfully employed to study the pharmacokinetics and drug-drug interactions of RUX and LEN in rats following oral administration of single doses. The results demonstrated that the pharmacokinetics of both drugs were changed substantially by their coadministration. LEN exhibited synergistic effects on the maximum plasma concentration (C_max) and total bioavailability of RUX, meanwhile it exhibited diminishing effect on the values of volume of distribution (Vd) and clearance (CL). Additionally, RUX decreased the C_max and total bioavailability of LEN, meanwhile it increased its Vd and CL. These data suggest that the use of RUX, as a combination with LEN, is a better therapeutic approach for MF, compared with RUX as a monotherapy. The effects of LEN on the pharmacokinetics of RUX should be considered and can be useful in determining the appropriate RUX dosage and dosing regimen to achieve the desired therapeutic effect when used as a combination therapy with LEN. The method’s environmental friendliness was confirmed through three comprehensive tools. This method represents a valuable tool for determining the appropriate dosage and dosing regimen of RUX in combination therapy with LEN to achieve the desired therapeutic effect. Furthermore, it can aid in predicting drug distribution in different patients and assessing the drug accumulation or insufficient drug levels in specific body compartments.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"24 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142190754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}