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 clarithromycin and crizotinib. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. Crizotinib exposure increases to 230%, when combined with clarithromycin (230%). This can lead to higher incidence rate of side effects. Clarithromycin exposure increases to 175%, when combined with crizotinib (175%). This can lead to higher incidence rate of side effects.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Clarithromycin has a mean oral bioavailability [ F ] of 53%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 4.6 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is rather weak at 70% and the volume of distribution [ Vd ] is very large at 176 liters. Since the substance has a low hepatic extraction rate of 0.13, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. About 27.5% of an administered dose is excreted unchanged via the kidneys and this proportion is seldom changed by interactions. The metabolism mainly takes place via CYP3A4 and the active transport takes place in particular via PGP.
Crizotinib has a mean oral bioavailability [ F ] of 43%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather long at 39 hours and constant plasma levels [ Css ] are only reached after more than 156 hours. The protein binding [ Pb ] is moderately strong at 91% and the volume of distribution [ Vd ] is very large at 1772 liters, which is why, with a mean hepatic extraction rate of 0.51, both liver blood flow [Q] and a change in protein binding [Pb] are relevant. The metabolism mainly takes place via CYP3A4 and the active transport takes place in particular via PGP.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither clarithromycin nor crizotinib increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither clarithromycin nor crizotinib increase anticholinergic activity.
QT time prolongation
Rating: In combination, clarithromycin and crizotinib can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||cla||cri|
|Blurred vision||65.5 %||n.a.||65.5↑|
|Peripheral edema||49.0 %||n.a.||49.0↑|
|Musculoskeletal pain||16.0 %||n.a.||16.0↑|
|Elevated ALT||15.0 %||n.a.||15.0↑|
|Disorder of taste||13.5 %||13.5||n.a.|
Neutropenia (11%): clarithromycin, crizotinib
Lymphocytopenia (7%): crizotinib
Hypophosphatemia (10%): crizotinib
Headache (9%): clarithromycin
Elevated AST (8%): crizotinib
Cholestatic hepatitis: clarithromycin
Hepatotoxicity: clarithromycin, crizotinib
Abdominal pain (4.5%): clarithromycin
Dyspepsis (4%): clarithromycin
Clostridium difficile diarrhea: clarithromycin
Pneumonia (4.1%): crizotinib
Dyspnea (2.3%): crizotinib
Interstitial lung disease (2%): crizotinib
Renal polycystosis (4%): crizotinib
Pulmonary embolism (3.5%): crizotinib
Syncope (2.4%): crizotinib
Stevens johnson syndrome: clarithromycin
Toxic epidermal necrolysis: clarithromycin
Anaphylactic reaction: clarithromycin
Visual loss: crizotinib
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: Erythromycin, clarithromycin, and azithromycin are clinically effective for the treatment of common respiratory and skin/skin-structure infections. Erythromycin and azithromycin are also effective for treatment of nongonococcal urethritis and cervicitis due to Chlamydia trachomatis. Compared with erythromycin, clarithromycin and azithromycin offer improved tolerability. Clarithromycin, however, is more similar to erythromycin in pharmacokinetic measures such as half-life, tissue distribution, and drug interactions. Misunderstandings about differences among the macrolides (erythromycin and clarithromycin) and the azalide (azithromycin) in terms of pharmacokinetics and pharmacodynamics, spectrum of activity, safety, and cost are common. The uptake and release of these compounds by white blood cells and fibroblasts account for differences in tissue half-life, volume of distribution, intracellular:extracellular ratio, and in vivo potency. Although microbiologic studies reveal that gram-positive pathogens are equally susceptible to these agents, significantly more isolates of Haemophilus influenzae are susceptible to azithromycin than to erythromycin or clarithromycin. Concentrations achieved at the infection site and duration above the minimum inhibitory concentration are as important as in vitro activity in determining in vivo activity against bacterial pathogens. Analysis of safety data indicates differences among these agents in drug interactions and use in pregnancy. Analysis of safety data reveals pharmacokinetic drug interactions for erythromycin and clarithromycin with theophylline, terfenadine, and carbamazepine that are not found with azithromycin. Both erythromycin and azithromycin are pregnancy category B drugs; clarithromycin is a category C drug. The numerous differences in pharmacokinetics, microbiology, safety, and costs among erythromycin, clarithromycin, and azithromycin can be used in the judicious selection of treatment for indicated infections.
Abstract: To investigate whether grapefruit juice inhibits the metabolism of clarithromycin, 12 healthy subjects were given water or grapefruit juice before and after a clarithromycin dose of 500 mg in a randomized crossover study. Administration of grapefruit juice increased the time to peak concentration of both clarithromycin (82 +/- 35 versus 148 +/- 83 min; P = 0.02) and 14-hydroxyclarithromycin (84 +/- 38 min versus 173 +/- 85; P = 0.01) but did not affect other pharmacokinetic parameters.
Abstract: No Abstract available
Abstract: Clarithromycin is a macrolide antibacterial that differs in chemical structure from erythromycin by the methylation of the hydroxyl group at position 6 on the lactone ring. The pharmacokinetic advantages that clarithromycin has over erythromycin include increased oral bioavailability (52 to 55%), increased plasma concentrations (mean maximum concentrations ranged from 1.01 to 1.52 mg/L and 2.41 to 2.85 mg/L after multiple 250 and 500 mg doses, respectively), and a longer elimination half-life (3.3 to 4.9 hours) to allow twice daily administration. In addition, clarithromycin has extensive diffusion into saliva, sputum, lung tissue, epithelial lining fluid, alveolar macrophages, neutrophils, tonsils, nasal mucosa and middle ear fluid. Clarithromycin is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and has an active metabolite, 14-hydroxyclarithromycin. The reported mean values of total body clearance and renal clearance in adults have ranged from 29.2 to 58.1 L/h and 6.7 to 12.8 L/h, respectively. In patients with severe renal impairment, increased plasma concentrations and a prolonged elimination half-life for clarithromycin and its metabolite have been reported. A dosage adjustment for clarithromycin should be considered in patients with a creatinine clearance < 1.8 L/h. The recommended goal for dosage regimens of clarithromycin is to ensure that the time that unbound drug concentrations in the blood remains above the minimum inhibitory concentration is at least 40 to 60% of the dosage interval. However, the concentrations and in vitro activity of 14-hydroxyclarithromycin must be considered for pathogens such as Haemophilus influenzae. In addition, clarithromycin achieves significantly higher drug concentrations in the epithelial lining fluid and alveolar macrophages, the potential sites of extracellular and intracellular respiratory tract pathogens, respectively. Further studies are needed to determine the importance of these concentrations of clarithromycin at the site of infection. Clarithromycin can increase the steady-state concentrations of drugs that are primarily depend upon CYP3A metabolism (e.g., astemidole, cisapride, pimozide, midazolam and triazolam). This can be clinically important for drugs that have a narrow therapeutic index, such as carbamazepine, cyclosporin, digoxin, theophylline and warfarin. Potent inhibitors of CYP3A (e.g., omeprazole and ritonavir) may also alter the metabolism of clarithromycin and its metabolites. Rifampicin (rifampin) and rifabutin are potent enzyme inducers and several small studies have suggested that these agents may significantly decrease serum clarithromycin concentrations. Overall, the pharmacokinetic and pharmacodynamic studies suggest that fewer serious drug interactions occur with clarithromycin compared with older macrolides such as erythromycin and troleandomycin.
Abstract: Two cases of QT prolongation and torsades de pointes (TdP) are presented. The patients had been taking clarithromycin (400 mg/day) for respiratory disease. Although erythromycin is reportedly associated with TdP, this is the first report of clarithromycin associated with TdP in the absence of other drugs already known to produce QT prolongation.
Abstract: No Abstract available
Abstract: The involvement of intestinal permeability in the oral absorption of clarithromycin (CAM), a macrolide antibiotic, and telithromycin (TEL), a ketolide antibiotic, in the presence of efflux transporters was examined. In order independently to examine the intestinal and hepatic availability, CAM and TEL (10 mg/kg) were administered orally, intraportally and intravenously to rats. The intestinal and hepatic availability was calculated from the area under the plasma concentration-time curve (AUC) after administration of CAM and TEL via different routes. The intestinal availabilities of CAM and TEL were lower than their hepatic availabilities. The intestinal availability after oral administration of CAM and TEL increased by 1.3- and 1.6-fold, respectively, after concomitant oral administration of verapamil as a P-glycoprotein (P-gp) inhibitor. Further, an in vitro transport experiment was performed using Caco-2 cell monolayers as a model of intestinal epithelial cells. The apical-to-basolateral transport of CAM and TEL through the Caco-2 cell monolayers was lower than their basolateral-to-apical transport. Verapamil and bromosulfophthalein as a multidrug resistance-associated proteins (MRPs) inhibitor significantly increased the apical-to-basolateral transport of CAM and TEL. Thus, the results suggest that oral absorption of CAM and TEL is dependent on intestinal permeability that may be limited by P-gp and MRPs on the intestinal epithelial cells.
Abstract: Crizotinib (Xalkori®) is an orally administered, selective, small-molecule, ATP-competitive inhibitor of the anaplastic lymphoma kinase (ALK) and mesenchymal epithelial transition factor/hepatocyte growth factor receptor tyrosine kinases, and has recently been approved for the treatment of ALK-positive non-small cell lung cancer. The absolute bioavailability of crizotinib, effect of a high-fat meal on crizotinib pharmacokinetics (PK), and bioequivalence of several oral formulations (powder in capsule [PIC], immediate-release tablet [IRT], and commercial formulated capsule [FC]) were evaluated in two phase I clinical studies involving healthy volunteers who received single doses of crizotinib. PK parameters for crizotinib and its metabolite, PF-06260182, were determined using non-compartmental methods. The absolute oral bioavailability of crizotinib was approximately 43%, with a slight decrease in crizotinib exposures (area under the plasma concentration-time profile and maximum plasma concentration) following a high-fat meal that was not considered clinically meaningful. The FC was bioequivalent to the clinical development IRT and PIC formulations. No serious adverse events were observed during either study and the majority of adverse events were mild, the most common being diarrhea. Single-dose crizotinib could be safely administered to healthy subjects.
Abstract: Crizotinib (Xalkori®) and nilotinib (Tasigna®) are tyrosine kinase inhibitors approved for the treatment of non-small cell lung cancer and chronic myeloid leukemia, respectively. Both have been shown to result in electrocardiogram rate-corrected Q-wave T-wave interval (QTc) prolongation in humans and animals. Liposomes have been shown to ameliorate drug-induced effects on the cardiac-delayed rectifier K(+) current (IKr, KV11.1), coded by the human ether-a-go-go-related gene (hERG). This study was undertaken to determine if liposomes would also decrease the effect of crizotinib and nilotinib on the IKr channel. Crizotinib and nilotinib were tested in an in vitro IKr assay using human embryonic kidney (HEK) 293 cells stably transfected with the hERG. Dose-responses were determined and the 50% inhibitory concentrations (IC50s) were calculated. When the HEK 293 cells were treated with crizotinib or nilotinib that were mixed with liposomes, there was a significant decrease in the IKr channel inhibitory effects of these two drugs. When isolated, rabbit hearts were exposed to crizotinib or nilotinib, there were significant increases in QTc prolongation. Mixing either of the drugs with liposomes ameliorated the effects of the drugs. Rabbits dosed intravenously (IV) with crizotinib or nilotinib showed QTc prolongation. When liposomes were injected prior to crizotinib or nilotinib, the liposomes decreased the effects on the QTc interval. The use of liposomal encapsulated QT-prolongation agents, or giving liposomes in combination with drugs, may decrease their cardiac liability.
Abstract: With the widespread availability of biological antitumor drugs, the current scene of chemotherapies is changing. New chemotherapy agents, such as crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK) and ROS1, usually used in pretreated advanced ALK-positive non-small-cell lung carcinoma, are more often used, and a description of the onset of side effects with suggestions for their management could be of interest for physicians. We describe a case of diffuse and aggressive renal polycystosis induced by crizotinib, which regressed after therapy, which could be of interest considering its wide extension and disappearance after the end of treatment. We also suggest some considerations from the literature and from the case reported that could be helpful in the management of this condition, which is known to be caused by crizotinib treatment.
Abstract: We report the case of a woman with an ALK positive lung adenocarcinoma, who developed bilateral complex renal cysts 17 months after the introduction of treatment with crizotinib. Clinical investigation led to the conclusion that the cysts were due to anticancer drug. Regression of the renal cysts was observed one month after cessation of the crizotinib. This case illustrates that specific and little known toxicities can occur with these novel molecules which have entered use for the management of lung cancer.
Abstract: Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. In clinical practice, three small molecule inhibitors of ALK-1 are used, namely crizotinib, ceritinib and alectinib. Several more agents are in active pre-clinical and clinical studies. Crizotinib is approved for the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). According to the package insert and published literature, treatment with crizotinib appears to be associated with kidney failure as well as an increased risk for the development and progression of renal cysts. In addition, this agent is associated with development of peripheral edema and rare electrolyte disorders. This review focuses on the adverse renal effects of Crizotinib in clinical practice.
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.
Abstract: An increasing number of tyrosine kinase inhibitors (TKIs) are available for the treatment of non-small cell lung cancer (NSCLC). QT prolongation is one of the known, but relatively rare, adverse events of several TKIs (e.g. osimertinib, crizotinib, ceritinib). Screening for QT prolongation in (high risk) patients is advised for these TKIs. When a QT prolongation develops, the physician is challenged with the question whether to (permanently) discontinue the TKI. In this perspective, we report on a patient who developed a grade III QT prolongation during osimertinib (a third-generation epidermal growth factor receptor [EGFR]-TKI) treatment. On discontinuation of osimertinib, she developed a symptomatic disease flare, not responding to subsequent systemic treatment. The main aim of this perspective is to describe the management of QT prolongation in stage IV EGFR driver mutation NSCLC patients. We also discuss the ethical question of how to weigh the risk of a disease flare due to therapy cessation against the risk of sudden cardiac death. A family history of sudden death and a prolonged QT interval might indicate a familiar long QT syndrome. We have summarised the current monitoring advice for TKIs used in the treatment of lung cancer and the most common drug-TKI interactions to consider and to optimise TKI treatment in lung cancer patients.