Analysis of adverse events of renal impairment related to platinum-based compounds using the Japanese Adverse Drug Event Report database
Misa NaganumaYumi MotookaSayaka SasaokaHaruna HatahiraShiori HasegawaAkiho FukudaSatoshi NakaoKazuyo ShimadaKouseki HiradeTakayuki MōriTomoaki YoshimuraTakeshi KatoMitsuhiro Nakamura
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Objectives: Platinum compounds cause several adverse events, such as nephrotoxicity, gastrointestinal toxicity, myelosuppression, ototoxicity, and neurotoxicity. We evaluated the incidence of renal impairment as adverse events are related to the administration of platinum compounds using the Japanese Adverse Drug Event Report database. Methods: We analyzed adverse events associated with the use of platinum compounds reported from April 2004 to November 2016. The reporting odds ratio at 95% confidence interval was used to detect the signal for each renal impairment incidence. We evaluated the time-to-onset profile of renal impairment and assessed the hazard type using Weibull shape parameter and used the applied association rule mining technique to discover undetected relationships such as possible risk factor. Results: In total, 430,587 reports in the Japanese Adverse Drug Event Report database were analyzed. The reporting odds ratios (95% confidence interval) for renal impairment resulting from the use of cisplatin, oxaliplatin, carboplatin, and nedaplatin were 2.7 (2.5–3.0), 0.6 (0.5–0.7), 0.8 (0.7–1.0), and 1.3 (0.8–2.1), respectively. The lower limit of the reporting odds ratio (95% confidence interval) for cisplatin was >1. The median (lower–upper quartile) onset time of renal impairment following the use of platinum-based compounds was 6.0–8.0 days. The Weibull shape parameter β and 95% confidence interval upper limit of oxaliplatin were <1. In the association rule mining, the score of lift for patients who were treated with cisplatin and co-administered furosemide, loxoprofen, or pemetrexed was high. Similarly, the scores for patients with hypertension or diabetes mellitus were high. Conclusion: Our findings suggest a potential risk of renal impairment during cisplatin use in real-world setting. The present findings demonstrate that the incidence of renal impairment following cisplatin use should be closely monitored when patients are hypertensive or diabetic, or when they are co-administered furosemide, loxoprofen, or pemetrexed. In addition, healthcare professionals should closely assess a patient’s background prior to treatment.Keywords:
Nephrotoxicity
Carboplatin
Background Drug hypersensitivity reactions (DHRs) to platinum-based drugs are heterogenous and restrict their access, and drug desensitization (DD) has provided a ground-breaking procedure for their re-introduction, although the response is heterogeneous. We aimed to identify the phenotypes, endotypes and biomarkers of reactions to carboplatin and oxaliplatin and their response to DD. Methods Seventy-nine patients presenting with DHRs to oxaliplatin (N=46), and carboplatin (N=33) were evaluated at the Allergy Departments of two tertiary care hospitals in Spain. Patient symptoms, skin testing, biomarkers, and outcomes of 267 DDs were retrospectively analyzed. Results Oxaliplatin-reactive patients presented with type I (74%), cytokine release reaction (CRR) (11%), and mixed (Mx) (15%) phenotypes. In contrast, carboplatin reactive patients presented with predominantly type I (85%) and Mx (15%) but no CRRs. Out of 267 DDs, breakthrough reactions (BTRs) to oxaliplatin occurred twice as frequently as carboplatin (32% versus 15%; p<0.05). Phenotype switching from type I to another phenotype was observed in 46% of oxaliplatin DDs compared to 21% of carboplatin DDs. Tryptase was elevated in type I and Mx reactions, and IL-6 in CRR and Mx, indicating different mechanisms and endotypes. Conclusion Carboplatin and oxaliplatin induced three different types of reactions with defined phenotypes and endotypes amendable to DD. Although most of the initial reactions for both were type I, oxaliplatin presented with unique CRR reactions. During DD, carboplatin reactive patients presented mostly type I BTR, while oxaliplatin reactive patients frequently switched from type I to CRR, providing a critical difference and the need for personalized DD protocols.
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Abstract Background Drug hypersensitivity reactions (DHRs) to platinum‐based drugs are heterogenous and restrict their access, and drug desensitization (DD) has provided a ground‐breaking procedure for their re‐introduction, although the response is heterogeneous. We aimed to identify the phenotypes, endotypes, and biomarkers of reactions to carboplatin and oxaliplatin and their response to DD. Methods Seventy‐nine patients presenting with DHRs to oxaliplatin ( N = 46) and carboplatin ( N = 33) were evaluated at the Allergy Departments of two tertiary care hospitals in Spain. Patient symptoms, skin testing, biomarkers, and outcomes of 267 DDs were retrospectively analyzed. Results Oxaliplatin‐reactive patients presented with type I (74%), cytokine release reaction (CRR) (11%), and mixed (Mx) (15%) phenotypes. In contrast, carboplatin reactive patients presented with predominantly type I (85%) and Mx (15%) but no CRRs. Out of 267 DDs, breakthrough reactions (BTRs) to oxaliplatin occurred twice as frequently as carboplatin (32% vs. 15%; p < .05). Phenotype switching from type I to another phenotype was observed in 46% of oxaliplatin DDs compared to 21% of carboplatin DDs. Tryptase was elevated in type I and Mx reactions, and IL‐6 in CRR and Mx, indicating different mechanisms and endotypes. Conclusion Carboplatin and oxaliplatin induced three different types of reactions with defined phenotypes and endotypes amendable to DD. Although most of the initial reactions for both were type I, oxaliplatin presented with unique CRR reactions. During DD, carboplatin reactive patients presented mostly type I BTR, while oxaliplatin‐reactive patients frequently switched from type I to CRR, providing a critical difference and the need for personalized DD protocols.
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背景・目的: oxaliplatin base の化学療法が大腸癌腹膜播種症例に与える影響について検討した。対象・方法: 2006 年1月～2012 年11 月の間に，腹膜播種陽性Stage IV 大腸癌と診断され，oxaliplatin base の化学療法を導入した49 例（oxaliplatin施行群）と，それ以前に5─FU 系の全身化学療法を施行した26 例（control 群）を対象。oxaliplatin 導入前後のoverall survival（OS）を比較。また，oxaliplatin 施行群のOS に関して臨床病理学的因子を共変量とし，単変量，多変量解析を行い，予後因子を検討した。結果: oxalplatin 施行群はcontrol 群より有意に生存期間が延長していた（中央値 20.5 か月 vs 11.7 か月，p＝0.04）。oxaliplatin 施行群におけるOS に対するfavorable factor として，70 歳以下（p＝0.03），原発巣切除（p＝0.02）が同定された。結語: oxaliplatin base の化学療法は大腸癌腹膜播種症例においても生存期間を改善させた。腹膜播種の程度に関係なく原発巣切除を70 歳以下の症例に行い，速やかにoxaliplatin base の化学療法を導入することが予後向上につながることが示唆された。
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shows us a way to predict hypersensitivity to carboplatin, a real problem in clinical practice. Despite prophylaxis, some patients develop a hypersensitivity reaction to carboplatin. The risk for a reaction increases with an increased number of cycles. Platin salts are considered to be one of the major drugs for first-line treatment and for platinum-sensitive recurrence of ovarian carcinoma. Although desensitization has been used successfully, 2 some severe cases of reactions have been reported for cisplatin or carboplatin despite desensitization, including anaphylaxis and death. 3 Oxaliplatin is a platin salt which has been compared with cisplatinum in an ovarian cancer first-line therapy in a multicenter phase II/III study. No significant differences were found for the efficacy parameters between the two arms. 4,5 Although some allergic reactions have been reported with oxaliplatin, 6 no cross-reactivity has been found in the literature between oxaliplatin and carboplatin or between oxaliplatin and cisplatin. We report two cases of patients with a platinum-sensitive recurrence of ovarian carcinoma treated with oxaliplatin after a severe allergic reaction to carboplatin. Before the allergic reactions, they had previously received 11 and 13 courses of carboplatin. Allergic reactions appeared at the fifth and fourth cycle of carboplatin for relapsed disease. Subsequently, three and five courses of oxaliplatin were administered under clinical surveillance during a short hospitalization. No hypersensitivity or minor reactions were reported. In both cases, however, the disease continues to respond. Replacement of carboplatin by oxaliplatin under clinical surveillance may be a solution for patients treated for ovarian carcinoma and developing a hypersensitivity to carboplatin.
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<i>Background:</i> Oxaliplatin is a 3rd generation platinum analogue, which is active in a broad spectrum of tumours. Clinical trials using this drug in bladder cancer are underway, but not yet reported. There are currently no in vitro data regarding oxaliplatin in bladder cancer. Therefore, this study compares the efficacy of oxaliplatin with cisplatin and carboplatin, which are both used widely in this tumour type, in bladder cancer cell lines. <i>Method:</i> The efficacy of oxaliplatin, carboplatin and cisplatin were compared in 4 bladder cancer cell lines (5637, J82, HT1197 and 253J). Cell parameters including cell number, viability and apoptosis were assessed after 3 days of drug exposure. The effects of the drugs on the cell cycle were also observed. <i>Results:</i> Overall cisplatin was the most potent at inducing cell death (IC<sub>50</sub> 11.5–70.6 µ<i>M</i>). Oxaliplatin was the 2nd most potent drug (IC<sub>50 </sub>15.2–126.3 µ<i>M</i>) and carboplatin the least effective (IC<sub>50 </sub>75.4–137.8 µ<i>M</i>). Carboplatin was significantly less potent at inducing cell death than the other two drugs in all 4 cell lines. Carboplatin was also inferior at inducing apoptosis in 3 of the 4 cell lines. All three drugs had a similar effect on the cell cycle, causing an initial G2 block. <i>Conclusions:</i> These data suggest that oxaliplatin is a potent agent in bladder cancer cell lines and is superior to carboplatin in this in vitro setting. It justifies the clinical studies using oxaliplatin that are underway.
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Abstract Cisplatin is a widely used anti-cancer drug used to treat a variety of cancer types. One of the side effects of this life-saving drug is irreversible ototoxicity, resulting in permanent hearing loss in many patients. In order to understand why cisplatin is particularly toxic to the inner ear, we compared the hearing loss and cochlear uptake of cisplatin to that of two related drugs, carboplatin and oxaliplatin. These three drugs are similar in that each contains a core platinum atom; however, carboplatin and oxaliplatin are considered less ototoxic than cisplatin. We delivered these three drugs to mice using a 6-week cyclic drug administration protocol. We performed the experiment twice, once using equimolar concentrations of the drugs and once using concentrations of the drugs more proportional to those used in the clinic. For both concentrations, we detected a significant hearing loss caused by cisplatin and no hearing loss caused by carboplatin or oxaliplatin. Cochlear uptake of each drug was measured using inductively coupled plasma mass spectrometry (ICP-MS) to detect platinum. Cochlear platinum levels were highest in mice treated with cisplatin followed by oxaliplatin, while carboplatin was largely excluded from the cochlea. Even when the drug doses were increased, cochlear platinum remained low in mice treated with oxaliplatin or carboplatin. We also examined drug clearance from the inner ear by measuring platinum levels at 1 h and 24 h after drug administration. Our findings suggest that the reduced cochlear platinum we observed with oxaliplatin and carboplatin were not due to increased clearance of these drugs relative to cisplatin. Taken together, our data indicate that the differential ototoxicity among cisplatin, carboplatin, and oxaliplatin is attributable to differences in cochlear uptake of these three drugs.
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