QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of oxaliplatin and abarelix. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for oxaliplatin, when combined with abarelix (100%). We do not expect any change in exposure for abarelix, when combined with oxaliplatin (100%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
The bioavailability of oxaliplatin is unknown. The terminal half-life [ t12 ] is rather short at 0.29166667 hours and constant plasma levels [ Css ] are reached quickly. Protein binding [ Pb ] is not known. The metabolism does not take place via the common cytochromes.
The bioavailability of abarelix is unknown. The terminal half-life [ t12 ] is rather long at 316.8 hours and constant plasma levels [ Css ] are only reached after more than 1267.2 hours. The protein binding [ Pb ] is 97.5% strong. The metabolism via cytochromes is currently still being worked on.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither oxaliplatin nor abarelix increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither oxaliplatin nor abarelix increase anticholinergic activity.
QT time prolongation
Rating: In combination, oxaliplatin and abarelix can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||oxa||aba|
|Abdominal pain||31.0 %||31.0||n.a.|
|Loss of appetite||20.0 %||20.0||n.a.|
Stomatitis (14%): oxaliplatin
Bowel obstruction: oxaliplatin
Leukopenia (13%): oxaliplatin
Neutropenia (7%): oxaliplatin
Hemolytic anemia: oxaliplatin
Dyspnea (13%): oxaliplatin
Cough (11%): oxaliplatin
Pulmonary fibrosis: oxaliplatin
Backache (11%): oxaliplatin
Peripheral edema (5%): oxaliplatin
Hearing loss: oxaliplatin
Veno occlusive disease of the liver: oxaliplatin
Hypersensitivity reaction: oxaliplatin
Metabolic acidosis: oxaliplatin
Hemolytic uremic syndrome: oxaliplatin
Proximal tubulopathy: oxaliplatin
Tubulointerstitial nephritis: oxaliplatin
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: Oxaliplatin is a novel platinum complex used for the treatment of metastatic colorectal carcinoma. The pharmacokinetics of the free fraction of oxaliplatin in blood were evaluated in 10 patients given 85 mg/m2 of oxaliplatin using an infusion time of 2 h. Blood samples were collected during and after the infusion and immediately placed on ice. The samples were ultrafiltrated centripetally and the concentration of oxaliplatin in the ultrafiltrate was determined by liquid chromatography in combination with postcolumn derivatization. The in vitro degradation rate was determined in blood from the patients taken immediately before drug administration. The maximal blood concentration (C(max)) and terminal half-life (t1/2) were 1.44 +/- 0.20 (SD) microg/mL and 14.1 min (range: 10.2-24.5), respectively. The area under the blood concentration time curve (AUC), clearance (CL), and distribution volume (V(ss)) were (means +/- SD) 161 +/- 22 microg min/mL, 32.1 +/- 4.2 L/h/m2, and 0.26 +/- 0.06 L/kg, respectively. There was a significant correlation between the clearance of oxaliplatin in the patients and the degradation rate in whole blood (r = 0.746; p = 0.017). Oxaliplatin has a short elimination half-life, which is in a sharp contrast to previously reported elimination half-lives obtained by analysis of the platinum content in plasma and ultrafiltrate. The correlation between in vivo and in vitro data suggests that the degradation in whole blood plays a role for the elimination of the drug.
Abstract: PURPOSE: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function. EXPERIMENTAL DESIGN: Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, >or=60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2. RESULTS: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (Cmax) were consistent across all renal impairment groups. However, only the beta-half-life was significantly prolonged by renal impairment, with values of 14.0 +/- 4.3, 20.3 +/- 17.7, 29.2 +/- 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m2, the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 +/- 5.03, 39.7 +/- 11.5, and 44.6 +/- 14.6 mug.h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, -5.0 mL/min). CONCLUSIONS: Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.
Abstract: No Abstract available
Abstract: Proximal renal tubular acidosis (RTA) (Type II RTA) is characterized by a defect in the ability to reabsorb HCO(3) in the proximal tubule. This is usually manifested as bicarbonate wastage in the urine reflecting that the defect in proximal tubular transport is severe enough that the capacity for bicarbonate reabsorption in the thick ascending limb of Henle's loop and more distal nephron segments is overwhelmed. More subtle defects in proximal bicarbonate transport likely go clinically unrecognized owing to compensatory reabsorption of bicarbonate distally. Inherited proximal RTA is more commonly autosomal recessive and has been associated with mutations in the basolateral sodium-bicarbonate cotransporter (NBCe1). Mutations in this transporter lead to reduced activity and/or trafficking, thus disrupting the normal bicarbonate reabsorption process of the proximal tubules. As an isolated defect for bicarbonate transport, proximal RTA is rare and is more often associated with the Fanconi syndrome characterized by urinary wastage of solutes like phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins as well as bicarbonate. A vast array of rare tubular disorders may cause proximal RTA but most commonly it is induced by drugs. With the exception of carbonic anhydrase inhibitors which cause isolated proximal RTA, drug-induced proximal RTA is associated with Fanconi syndrome. Drugs that have been recently recognized to cause severe proximal RTA with Fanconi syndrome include ifosfamide, valproic acid and various antiretrovirals such as Tenofovir particularly when given to human immunodeficiency virus patients receiving concomitantly protease inhibitors such as ritonavir or reverse transcriptase inhibitors such as didanosine.
Abstract: A 67-year-old woman presented with a history of dilated cardiomyopathy with congestive heart failure since 2003, who subsequently developed lower rectal cancer (adenocarcinoma) with liver, bone, and lymph node metastasis. Abdominoperineal resection and hepatectomy were performed. The patient received two rounds of intravenous chemotherapy, including 12 and six courses of FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin; 85 mg/m(2) per cycle). She underwent a third round of intravenous FOLFOX4 because of tumor progression. During the 21(st) course of FOLFOX4 regimen, the patient developed ST segment depression in lead II and prolongation of QT interval with polymorphic ventricular tachycardia, torsades de pointes right after the start of oxaliplatin infusion. Immediate defibrillation and cardiopulmonary resuscitation were administered, and the patient regained spontaneous circulation and consciousness. Twelve-lead electrocardiogram showed ST segment elevation in III, aVF, and ST segment depression in V4-6 after resuscitation. To our knowledge, prolongation of QT interval with torsades de pointes and coronary spasm with myocardial injury that were stabilized in one patient following oxaliplatin infusion has not been reported. We present a patient with these rare complications.
Abstract: No Abstract available
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.