<<

References Table 1. Table based To different TdP the the A Materials the The Objective it are quality, that available classes should generated There Introduction Cummins Lancaster/ is literature Colatsky allow , CredibleMeds Champeroux compounds drugs Internet not Johannesen neither Antzelevich Haverkamp aim risk Lawrence 2006 the Redfern 2003 Mirams Kramer Camm Okada 2015 Guns 1 Reference Guo Yap Liu He on are . Original be 2016 (CIPA ) depending and consistent, 2012 2006 2004 2013 and 2012 predictive of 2004 than 2013 for 2011 mathematical . the 2001 2004 2014 Multiple 2005 the various Sobie 2016 surrogate the possible search the via prediction a and class 2016 TdP TdP end direct current Available the database which risk classes and results of resultsrisk and classes No re Category are3 drugs thosethat have a measurable incidenceof Category that includethose 2 drugs have beenwithdrawn orsuspendedfrom marketthe to due anunacceptable risk of pharmcacodynamic Category include1 drugs Intermediate Identifiedrisk: Compounds asIntermediate Risk for ManifestingHuman IdentifiedHigh risk:Compounds asHighRisk forManifesting Human propensity of TdP Their effecton repolarization becomesonly manifest overdose,during intoxication in thepresenceor ofsevere metabolicinh that Drugs prolongpotential action duration QTand interval at high doses/concentrationsare which clearly above thetherape C (lowClass However, prolongationrepolarization of is above theIC concurrent administration drug that inhibitmetabolismdrugs of (e.g. cytochromebythe inhibiting P450metabolism).Their IC which prolongDrugs myocardial repolarization (i.e. cardiac actionpotential duration and QT interval)at doses, at higher or high B (mediumClass concomitant therapy prolongingrepolarization and/or hypokalemia). prolongation has beendocumented at therapeutic doses/concentrations cases and of based onprolongationrepolarization of ortheIC early of induction which areDrugs potent blockerscurrentsof prolonging myocardial repolarization. Documentedaction potential prolongation an A (high Class Knownability to prolong with clinicalDrugs studies and/or case reportscausing of metabolisminhibiting a QTof as hypokalemia,conditionssuch or whentaken interactingwith OR bydrugs) creating conditionsthat facilitateinduce or Conditional recommended. Known Risk of Meyler’s Category 1 Group with numerousdrugs A: or several reports cases) (>2 of Equivocal resultsare reported, or thepositiveevents are observedonly inoverdose. Positive observations clinic.the in Category Drugs that have3: a measurable incidenceof risk of Category Drugs that have2: been withdrawn orsuspendedfrom marketthe at in least onemajorregulatory territory due to an QTmechanism,and prolongation asanintended, desirable effect). Category 1: Category a measurableDrugs with 3: incidenceof Category Drugs that have2: been withdrawn from marketthe (by at least onemajorregulatory duetoauthority) unacceptable Category Class 1: Category Drugs that have3: a measurable incidenceof risk of Category Drugs that have2: been withdrawn orsuspendedfrom marketthe at in least onemajorregulatory territory due to an QTmechanism,and prolongation asanintended, desirable effect). Category 1: propensity nonclinical descriptions on power point was an combinations Methods Google have been documented. However, in almostallso far available published cases, several factorsarewhich well known to increa to - markers scalingrequired. comparison TdP TdP the individual were SideEffects and Drugs, ofa list agentsof compiled by De . directly TdP work - algorithms, for theconditionbeing treated. for theconditionbeing treated. performed 3 according3 to Algorithms Repolarisation Repolarisation Risk ofRisk torsadogenic torsadogenic upon of TdP is usually associatedis usually with metabolicand/orinhibition presencethe risk ofother factors. TdP integrity of assumed , i.e. risk factors, were present. Ia afterdepolarizations search - primary TdP differently and III III and anti these drugs prolong drugs these QT the intervalare AND clearlyassociated with aknownof risk mechanism and QTand mechanism prolongation asanintended desirable effect). any is torsadogenic . were - and drugs associateddrugs with request QTc Neither repolarization to compare potency) CredibleMeds - - potency) prolonging (Class prolonging (Class given compound and/or induce classification - prolonging orby drug causing anelectrolyte disturbancethat induces - of . arrhythmics present all engine clinical excluded For using and which potency) relevant scale concern classifications . The . The aredrugs either antiarrhythmic antiarrhythmicthe whichof of drugs mechanisms actionis drug in prolonging (Class . (former categorized the IKr models ; generally; associated with alarge, acceptable,but risk of TdP the the Acknowledgement Ia Ia binarization 50 ) the TdP and Classand III) Classand III) were for thetherapeutic effect.Cases of can and in humans. in 50 are models inhibition ArizonaCERT TdP TdP for this effect samethe rangein is astheIC 50 for therapeuticthe action.Documented QT BUT only under certainBUT onlyunder circumstances excessivetheirof use(e.g. dose, patients in with is original predictive from keywords , foror whichnumerous case reports exist. in traditional TdP TdP model be sometimes compare available, TdP Ia risk used the specializing in humans, forhumans, in or whichnumerous case reports existliterature.in thepublished forhumans, in or whichnumerous case reports existliterature.in thepublished and Classand III) antiarrhythmics antiarrhythmics were identifiedas applied 2003) plus 2003) TdP the TdP available depending assessment . Ponti procedure cardiac with texts in humans or forin humans whichnumerous case reports exist. TdP TdP to nor depends analysis et al.2001. . + antiarrhythmics were TdP effectiveness search various (which have(which have(which tools and agents collectedfrom Micromedex, Drug Information Handbook, more . AP/QT to assigned TdP The safety TdP in +. assess applied, to . TdP various TdP . induced by alonehave drug the been documented. the on and not for . IKr IKr class (which have(which model, than assess induced by alone(inabsencethe drug the of classification prolongation block as anintegralblock as anintegralblock the the prediction assessment only publically the to B descriptions TdP of TdP two . these IKr classification W selected drug an TdP ). . proarrhythmic accurate block as an block integral as potential the . on , even whentaken as acknowledges opposing classes pharmacodynamic pharmacodynamic the models classifications included of available schemes . Category are scheme algorithm TdP TdP Multiple hERG no classification . cardiac ibi (e.g. by(e.g. and rmal doses withrmal were 50 uti TdP perfect tion. Cases of tion. una una d t for this c range. models nor class se he : cceptable cceptable risk. the the proarrhythmic inhibition, the potential . databases proposed classify re support classification depending risk utilized - and final scaled predictors, Category for5 includesdrugs therewhich have been published reportsno of Category are4 drugs thosefor whichthere have been isolated reports TdPof humans. in Very Identifiedlow Compounds orVeryrisk: asNo Low Risk forManifesting Human between eventthe is drug notclear. the and associationtreatment with may drug the with have been reported. However, causalthe relation human QT interval hasnotbeendemonstrated systematicin randomizedstudies. Casesof concentrations necessary for this effect were far above theclinicalconcentrations. Prolongation the of repolarization inother whichrepolarizing block Drugs ioncurrents D ( Class Established cardiacsafety in clinicalusage. at least30 years market of presence. used to Drugs treatdiabetes, commonas flu,diseases such hypertension, bacterial infection orventricular fibrillation which hadnoclinicalDrugs studies caseand reports of TdP Possible Risk of Information Handbook, Americanand Hospital (AHFS)FormularyService for agents. 243 Group without reportsdrugs C: of Group causingdrugs QT B: prolongation and/or Non Negative observationsin theclinic. Category Drugs for5: therewhich have been published reportsno of Category Drugs for4: therewhich have been isolated reports of Category Drugs for5: therewhich have been published reportsno of Category Drugs for4: therewhich have been isolated case reportsTdP. of havewhich beenassociatednot with cases of contains (e.g. ketoconazole) some drugs whichare associated interactions with drug leading to Category Drugs for5: therewhich have been published reportsno of Category Drugs for4: therewhich have been isolated reportsTdP of in humans. were Comparison of when taken as recommended. - of TdP TdP of the classification torsadogenic with noreported case of the type arrhythmia.type drugs from of the QT . for built in to models PubMed, TdP compound drugs , publicly prolongation on 1 compounds binary the - classification, FacultyPharmacy, of the these drugs can drugs these cause QT prolongation BUTcurrently lack evidencefor a riskof potential clear)not or schemes and in vitroin with the model drug Polish under developed models (e.g. papillary papillary muscle(e.g. models the chosen their classifications TdP TdP Google available after in humans; obtainedhumans; in from searchthe ofMicromedex, Drug candidates or QT prolongation. of ventricular development, for National development, in vitroin is interest use and binarization TdP TdP model, crucial etc categorizing scheme TdP when usedalone. Scholar, ) and had been used by hadbeen and alargeused ) patients.of number but whichhavebut sofar beenshownnot to prolong . 2 only, latterthe at a very lowfrequency cases). (≤2 to - Simcyp proarrhythmia scientific There TdP assess or similar symptomor similar (QT prolongation, . . Science fibres Jagiellonian . . Yet S drugs, proarrhythmia These This . TdP Proarrhythymia ebastian or isolated or the hearts) As is ScienceDirect LimitedCertara(a in humans. TdP TdP TdP it but are cardiac a sources a . on is in humans. category in humans.This also procedure drugs wide Center consequence, classifications torsadogenic TdP a also presented the well in humans. University Medical College, TdP endpoints Polak safety (into . range the basis and known (Grant TdP etc ( in data TdP TdP ) and and ) was and 2 list , but , but 1, of of of - in 5 2 ) , Company No Barbara . 2013 development classifications respectively ) mefloquine proarrhythmic compounds contradictory which one However, as identified to were 18 Results Both entities least character Table 2. mexiletine metronidazole mesoridazine mefloquine loperamide lapatinib ketoconazole ketanserin iloperidone hydroxyzine granisetron gemifloxacin gatifloxacin furosemide fosphenytoin foscarnet fluvoxamine fluoxetine fluconazole felbamate erythromycin donepezil dolasetron dobutamine clozapine clarithromycin ciprofloxacin chloroquine chloralhydrate azithromycin atazanavir amitryptiline amiodarone amantadine Compounds with torsadogenic binary different ), Sheffield,S2 4SU, U.K classification / groups some 11 Wiśniowska identified - phosphate were /D/NZ which Totalof models/classification number schemes for chemical entitieswith contradicting classification Classification Models . compounds) 398 ambiguous ) It and classification, Poland (spolak@cm ) of and . is are was classification of For 7 the worth results were were present out and / compounds in classification the 01583 presented Discussion 42 were indicated ( only compounds 110 16 the of 1 safe (e in not noting (e . . silico ) 552 g were were as equally For literature . . . was c Number g (e in used directly . 552 . . TdP schemes lassified as in 94 g fluvoxamine, compounds more predictive . that of of classification schemes where a compound at consistently found Table TdP - donepezil, 11 +) for 3 1 1 3 2 1 1 4 3 2 6 1 1 1 1 2 1 1 1 1 3 3 8 1 8 1 2 4 2 5 1 1 3 3 3 4 2 9 3 3 2 5 1 5 3 1 TdP uj.krakow.pl) compounds were compounds + least all search or often frequently the - . 2 used the differently . for safe 36 and in , models 2 moxifloxacin . above ( 646 silico 72 hydroxizine out olanzapine classified After ( indicated classifications) 340 ( TdP % 38 ( during . 4 5 3 1 2 1 1 3 2 1 4 1 1 1 1 1 2 1 3 3 2 1 1 2 1 1 1 1 2 2 1 1 5 6 1 3 1 3 4 3 1 1 1 3 2 1 1 TdP 85 - compounds ) of % models - of 6 mentioned appear % classified re as + of of various - the of scaling either TdP those these class and and and the the development, 94 as - in ) . between zolmitriptan ziprasidone zimeldine venlafaxine vardenafil troleandomycin trimipramine trimethoprim toremifene tizanidine tiapride tetrabenazine telithromycin tamoxifen tacrolimus sunitinib sultopride sulfamethoxazole spiramycin sparfloxacin sertindole saquinavir ritonavir risperidone quetiapine propafenone probucol pentamidine pazopanib papaverine paliperidone ondansetron olanzapine ofloxacin nilotinib nelfinavir nefazodone moxifloxacin moracizine moexipril mizolastine miconazole Compounds with models 100 150 200 250 50 Figure 0 ambiguous databases were 1. yet Redfern 2003 Resultsof developed classification their Mirams 2011

used Lancaster/Sobie 2016 categorization v was c Number Kramer 2013 sourcesarious for analysis thecontradictory results classifications for lassified as and

of of classification schemes where a compound Okada 2015 TdP model 11 1 3 2 2 1 1 1 2 1 1 1 1 1 1 3 4 1 1 1 8 1 1 5 2 3 5 2 4 1 8 1 3 3 4 1 1 2 3 1 2 1 8 1 1 2 1 + validated Guns 2012 Johannesen 2014 development differs

. Guo 1013 with TdP 1 1 1 1 2 1 1 1 1 1 1 1 1 5 2 1 1 1 1 2 1 4 1 5 5 3 4 1 1 1 1 1 1 1 1 5 1 1 1 2 1 1 4 1 1 1 1 depending Champeroux 2005 - the Yap 2004 . use

There CredibleMeds 2016 considered inhibition vitro neither development the studies wide include current It new manage framework changes knowledge dynamic quite proarrhythmic system standardized establishing point The of is

on Antzelevich 2004 different worth classification is presented the conducted He 2012 likely also out which range animal compounds information existing

classification Liu 2006 analysis but in . mentioning a of that to . group

datasets Haverkamp 2001 a could are studies nature propensity about having of In studies results new, the Camm 2004 ionic the conducted models and the classification TdP-

pre Colatsky 2016 (CIPA) from it help where need chemical scheme currents that general develop as - general

will Lawrence 2006 clinical . nor clearly . under drugs were work drug It not the the the for . be at to of in is . ,