QT time prolongation
Adverse drug events
|Upper respiratory infection|
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Cladribine is used intravenously to treat hairy cell leukemia and orally as a tablet for highly active, relapsing multiple sclerosis (MS). It is a chemotherapy drug and a selective immunosuppressant. Cladribine is a prodrug and is only phosphorylated in the cell to the active molecule CdATP (cladribine triphosphate). CdATP is incorporated into DNA as an adenosine analogue and causes strand breaks. This blocks the new synthesis of DNA in dividing cells and blocks the DNA repair mechanism with the consequence that DNA strand breaks accumulate and the concentration of NAD (nicotinamide adenine dinucleotide) and ATP also decreases in resting cells. Cell death occurs through lack of energy and apoptosis (programmed cell death). In the treatment of multiple sclerosis, cladribine acts as a so-called disease-modifying drug (DMD) and only needs to be taken at long intervals. Cladribine reduces the number of T and B lymphocytes, immune cells that play a key role in MS.
The warnings are checked for the combination of several active substances. For the individual substances, please consult the relevant specialist information.
Since only cladribine was entered without any further substances, no pharmacokinetic interaction can be detected.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Cladribine has a mean oral bioavailability [ F ] of 44%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The protein binding [ Pb ] is very weak at 25%. The metabolism does not take place via the common cytochromes and the active transport takes place in particular via MRP4.
|Serotonergic Effects a||0||Ø|
Rating: According to our knowledge, cladribine does not increase serotonergic activity.
|Kiesel & Durán b||0||Ø|
Rating: According to our knowledge, cladribine does not increase anticholinergic activity.
QT time prolongation
We do not know of any QT-prolonging potential for cladribine.
General adverse effects
|Side effects||∑ frequency||cla|
|Upper respiratory infection||38.0 %||38.0|
Thrombocytopenia (12%): cladribine
Hypersensitivity reaction (11%): cladribine
Heart failure: cladribine
Erythema multiforme: cladribine
Stevens johnson syndrome: cladribine
Toxic epidermal necrolysis: cladribine
Progressive multifocal leukoencephalopathy: cladribine
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: Cladribine is a new purine nucleoside analogue with promising activity in low-grade lymphoproliferative disorders, childhood acute myelogenous leukaemia and multiple sclerosis. Reversed phase high performance liquid chromatography and radioimmunoassay have been used for the analysis of the plasma pharmacokinetics of cladribine. The major (inactive) metabolite in plasma, chloroadenine, can only be detected by liquid chromatography. The oral bioavailability of cladribine is 37 to 51%, and that of subcutaneous administration is 100%. The terminal half-life varies from 5.7 to 19.7 hours and the apparent volume of distribution from 54 to 357 L/m2. The concentration in the cerebrospinal fluid is 25% of that in plasma in patients without central nervous system disease; in patients with meningeal disease, the cladribine concentration in the cerebrospinal fluid exceeds that in plasma. Cladribine is a prodrug and needs intracellular phosphorylation to active nucelotides. The intracellular concentration of these metabolites is several hundred-fold higher than that of cladribine in plasma and they are retained in leukaemia cells with half-lives between 9 and > 30 hours depending on diagnosis and sampling schedule. There is no correlation between the plasma concentration of cladribine and that of the intracellular metabolites. The renal clearance of cladribine is 51% of total clearance and 21 to 35% of an intravenously administered dose is excreted unchanged in the urine. Pretreatment with cladribine increases the intracellular accumulation of the active metabolite of cytarabine, cytosine arabinoside 5'-triphosphate, by 36 to 40%.
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.