QT time prolongation
Adverse drug events
|Loss of appetite|
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Explanations of the substances for patients
We have no additional warnings for the combination of lenvatinib 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 lenvatinib, when combined with abarelix (100%). We do not expect any change in exposure for abarelix, when combined with lenvatinib (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.
Lenvatinib has a high oral bioavailability [ F ] of 85%, which is why the maximum plasma level [Cmax] tends to change little during an interaction. The terminal half-life [ t12 ] is rather long at 28 hours and constant plasma levels [ Css ] are only reached after more than 112 hours. The protein binding [ Pb ] is very strong at 98.5%. Since the substance has a low hepatic extraction rate of 0.06, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. The metabolism mainly takes place via CYP3A4 and the active transport takes place partly via BCRP and PGP.
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 lenvatinib nor abarelix increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither lenvatinib nor abarelix increase anticholinergic activity.
QT time prolongation
Rating: In combination, lenvatinib and abarelix can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||len||aba|
|Loss of appetite||44.0 %||44.0||n.a.|
|Weight loss||41.0 %||41.0||n.a.|
|Abdominal pain||34.0 %||34.0||n.a.|
Dyspnea (29.5%): lenvatinib
Cough (29%): lenvatinib
Hand foot syndrome (29%): lenvatinib
Rash (24.5%): lenvatinib
Impaired wound healing: lenvatinib
Hemorrhage (29%): lenvatinib
Peripheral edema (28%): lenvatinib
Constipation (24%): lenvatinib
Headache (24%): lenvatinib
Intracranial hemorrhage: lenvatinib
Urinary tract infection (21%): lenvatinib
Renal failure: lenvatinib
Hepatic encephalopathy: lenvatinib
Hepatorenal syndrome: lenvatinib
Liver failure: lenvatinib
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: PURPOSE: QT assessment of oncology drugs is generally challenging because they are genotoxic and, of necessity,they require multisite evaluation in cancer patients. Lenvatinib is not genotoxic, therefore, this thorough QT (TQT)study with lenvatinib, a multityrosine kinase inhibitor, was undertaken utilizing healthy volunteers and concentration effect modeling to project the TQT effect at high plasma levels. METHODS: Fifty-two healthy subjects randomly received single doses of lenvatinib 32 mg, placebo, or moxifloxacin 400 mg in a three-way crossover study. Serial electrocardiograms were recorded, and the effect on placebo corrected change-from-baseline QTcF (ΔΔQTcF) was evaluated. The relationship between lenvatinib plasma concentrations and QTcF was analyzed with linear mixed effects modeling. RESULTS: L envatinib mildly lowered the heart rate by 5–8 bpm during the first 12 h after dosing. ΔΔQTcF was shortened with a peak effect of −5.72 ms (90 % confidence interval (90 % CI) −7.76 to −3.69 ms) at 6 h postdosing.The upper bound of mean ΔΔQTcF did not exceed 2 ms at any time point postdosing. A concentration-dependent effect of lenvatinib on ΔΔQTcF was identified with an estimated population intercept of −2.96 ms (90 % CI −4.49 to−1.43 ms; P = 0.0016) and a negative slope of −0.0045(90 % CI −4.49 to −1.43) ms per ng/mL, respectively. The safety profile after a single dose of lenvatinib was acceptable,with adverse events (AEs) of mild-to-moderate severity and no serious AEs. CONCLUSIONS: L envatinib had no clinically relevant effect on the QTc interval. Concentration-effect modeling supports the lack of QTc prolongation at high plasma concentrations.
Abstract: BACKGROUND: Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor under clinical investigation in solid tumors. In vitro evidence indicates that lenvatinib metabolism may be modulated by ketoconazole, an inhibitor of CYP3A4 and p-glycoprotein. METHODS: In this Phase I, single-center, randomized, open-label, two-period, crossover study, healthy adults (18-55 years; N = 18) were randomized to one of two sequences (ketoconazole → placebo or vice versa). Ketoconazole (400 mg) or placebo was administered orally once daily for 18 days; a 5 mg dose of lenvatinib was orally administered on Day 5 of each treatment period. Blood samples were collected over 14 days and lenvatinib plasma concentrations measured by high-performance liquid chromatography/tandem mass spectrometry. RESULTS: Systemic exposure to lenvatinib increased slightly (15-19%) with coadministration of ketoconazole. Although the 90% confidence interval (CI) for area under the plasma concentration-time curve (AUC) was within the prespecified bioequivalence interval of 80-125%, C,slightly exceeded the 125% CI bound (134%). No changes in t,, t,, or t,were observed. Thirteen subjects (72%) experienced treatment-emergent adverse events (11 mild, 2 moderate), most commonly headache (22%) and diarrhea (17%). CONCLUSIONS: Lenvatinib exposure was slightly increased by ketoconazole; however, the magnitude of the change was relatively small, and likely not clinically meaningful.
Abstract: Lenvatinib is a multikinase inhibitor that targets vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor-alpha, and RET and KIT proto-oncogenes. Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer in the United States (US), European Union (EU), Canada, Japan, and Switzerland. It is also approved in combination with everolimus for the treatment of advanced renal cell carcinoma following ≥1 VEGF-targeted treatment in the US and EU. In addition, lenvatinib is under investigation for the treatment of hepatocellular carcinoma. As lenvatinib becomes more widely available, a better understanding of its pharmacokinetic profile has become increasingly important. Following oral administration, lenvatinib is absorbed rapidly and is metabolized extensively prior to excretion. This metabolism is mediated by multiple pathways, and several metabolites of lenvatinib have been identified. The effect of food intake on lenvatinib exposure has also been studied and was found to not significantly influence overall exposure to the drug. Exposure to lenvatinib is increased in patients with severe hepatic impairment, indicating that dose reduction must be considered for those patients. The findings summarized here indicate that the clinical pharmacokinetic and pharmacodynamic profile for lenvatinib are predictable, with a dose-independent absorption and elimination profile that supports once-daily administration, and has minimal effects due to mild or moderate renal or hepatic impairment or drug interactions.