Respiratory, endocrine, cardiac, and renal topics
Evelyne Jacqz-Aigrain, Imti Choonara in Paediatric Clinical Pharmacology, 2021
Carboplatin is used for the treatment of numerous malignant solid tumours such as neuroblastoma, nephroblastoma, germ cell tumours, brain tumours, and retinoblastoma. It is administered either at conventional doses of 300 to 800 mg/m2 for several days in combination with other anticancer agents, or at high doses before haematopoietic stem cell transplantation. Unlike cisplatin, carboplatin does not require hyperhydration. When the dose is being calculated as a function of the glomerular filtration rate, the AUC target is, in general, 4 to 6 mg/min/ml in combination at conventional doses and in the order of 20 mg/min/ml during the administration of high doses. More recently, a weekly administration schedule has been developed for the treatment of brain tumours in young children.
Clinical Pharmacodynamics of Anticancer Drugs
Hartmut Derendorf, Günther Hochhaus in Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Carboplatin, an analogue of cisplatin, has activity in a variety of solid tumors. The toxicological properties of carboplatin differ from those of cisplatin, with a lower incidence of nephrotoxicity, neurotoxicity, ototoxicity, and emesis. The primary dose-limiting toxicity is thrombocytopenia. The pharmacokinetics of carboplatin were studied in eight patients receiving 800 to 1600 mg/m2 administered over 1 h for the treatment of lung cancer.74 The relationship between AUC of ultrafilterable platinum, as measured by the trapezoidal rule, and platelet or WBC nadir were analyzed by linear regression. The duration of thrombocytopenia varied among the eight patients and was significantly correlated with ultrafilterable platinum AUC (r2 = 0.77). Correlations with percentage change in platelet count could not be made due to profound thrombocytopenia in all patients. Ultrafilterable platinum AUC also correlated inversely with WBC nadir (r2= 0.61). The small number of patients and lack of sophisticated pharmacokinetic/pharmacodynamic analysis limit the application of these results, which are consistent with a pharmacodynamic relationship for carboplatin.
BRCA Mutation and PARP Inhibitors
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
Recently reported results of a phase 3 trial evaluating the addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in early stage triple-negative breast cancers did not show any added efficacy with the addition of veliparib. Patients were randomized into three groups to receive veliparib/carboplatin/standard chemotherapy, carboplatin/standard chemotherapy, and standard chemotherapy only. The primary endpoint was pathologic complete response (pCR) at the time of surgery. The addition of veliparib did not show an increased pCR rate over the carboplatin/standard chemotherapy group. However, both groups that received carboplatin showed improved pCR rates over the group receiving standard chemotherapy only. Serious adverse effects of neutropenia, thrombocytopenia, anemia, nausea, and vomiting were observed in both groups receiving carboplatin. Veliparib did not appear to significantly increase toxicity [39].
Protective effect of chrysin, a flavonoid, on the genotoxic activity of carboplatin in mice
Published in Drug and Chemical Toxicology, 2022
Basit L. Jan, Ajaz Ahmad, Altaf Khan, Muneeb U. Rehman, Khalid M. Alkharfy
Genotoxic effects of chemotherapeutic drugs like carboplatin can have secondary ramifications in normal cells, typically due to the formation of a large number of free radicals and reactive oxygen species (ROS), resulting in oxidative stress (Wakabayashi et al. 2014). The accumulation of free radicals is dangerous to the genetic material and other biomolecules and multiple studies have shown that use of carboplatin increases the levels of free radicals in the host, which leads to genotoxicity and secondary malignancies (Fong 2016). Oxidative stress alters lipids, nucleic acids and proteins by the generation of oxidized purines and pyrimidines, single-strand breaks and alkali-labile sites resulting in direct damage to the DNA (Reuter et al. 2010). In an effort to prevent these dangerous side-effects, anticancer drugs are combined with known antioxidant compounds to decrease their toxicity. The natural ability of flavonoids to decrease the ability of free-radicals to react in chemically stable molecules can be used in combination with anticancer drugs to reduce oxidative stress and therefore help in preventing the oxidative damage to DNA and other cellular molecules (Treml and Smejkal 2016). The mechanism of action of carboplatin in chemotherapy is its capacity to integrate with genomic DNA. Even though carboplatin has been a highly successful drug, it has several limitations and critical side-effects, usually related with the fluctuating mechanisms of DNA repair and off the mark effects on various other cellular constituents.
Avelumab for the treatment of urothelial cancer
Published in Expert Review of Anticancer Therapy, 2018
Alejo Rodriguez-Vida, Joaquim Bellmunt
A Spanish investigator-initiated phase II study is currently assessing the role of avelumab in patients with unresectable or metastatic UC who have not received prior systemic therapy and who are ineligible to receive cisplatin-based therapy (EudraCT number: 2017–004260-36; NCT03390595). This is a multicenter, open-label, parallel-group, randomized, phase II clinical study designed to evaluate the safety and efficacy of avelumab given pre-emptively and in an alternate/sequential way (but not concomitantly) with gemcitabine/carboplatin compared to standard of care gemcitabine/carboplatin alone as first-line therapy. The rational of combining avelumab with cytotoxic chemotherapy is that the latter has been shown to induce an immunogenic type of cell death in tumor cells, resulting in the release of tumor antigens, which could ultimately result in boosting the induction of immune-mediated antitumor responses. In fact, carboplatin, as a known DNA-disrupting agent, could cause tumor cell destruction and tumor-antigen release, leading to presentation of neoepitopes and stimulation of the immune system. This effect could be subsequently exploited and enhanced with the addition of an immune checkpoint inhibitor such as avelumab. Additionally, priming the immune response with avelumab before chemotherapy could be a way to prevent the detrimental effect of chemotherapy on the immune cells [29].
A retrospective analysis of cisplatin/carboplatin plus paclitaxel in advanced or recurrent cervical cancer
Published in Journal of Obstetrics and Gynaecology, 2019
Dan Song, Weimin Kong, Tongqing Zhang, Chao Han, Tingting Liu, Simeng Jiao, Jiao Chen
Cisplatin plus paclitaxel (TP) has been regarded as the standard regimen for cervical cancer due to superior rates of response and progression-free survival in patients treated with TP relative to those treated with cisplatin monotherapy (Moore et al. 2004; Monk et al. 2009). Nevertheless, cisplatin has been associated with nephrotoxicity and requires hydration therapy (Kitagawa et al. 2015). Carboplatin is a platinum analogue with a milder nephrotoxicity than cisplatin (Anderson et al. 1988; Sebastião et al. 2016). Carboplatin has been reported to be effective for the treatment of ovarian cancer (Anderson et al. 1988; Ozols et al. 2003). A recent systemic review of the literature indicated that carboplatin might be a viable and less toxic alternative to cisplatin in the management of advanced or recurrent cervical cancer (Lorusso et al. 2014). Additionally, a recent study suggested that the therapeutic efficacy of paclitaxel plus carboplatin (TC) is non-inferior to that of TP (Kitagawa et al. 2015). However, the therapeutic equivalency of the TP and TC regimens has not been fully elucidated.
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