Pharmacokinetic simulation of fatal carbamazepine intoxication in 23-month old child following phenytoin discontinuation
The antiepileptic, carbamazepine, is extensively metabolized via hepatic enzymes in the cytochrome P450 family and is therefore subject to a myriad of drug interactions. Concomitant administration with phenytoin enhances carbamazepine metabolism thus reducing serum concentrations and necessitating t...
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| Published in | Forensic science, medicine, and pathology Vol. 9; no. 1; pp. 73 - 76 |
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| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
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Springer US
01.03.2013
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| Abstract | The antiepileptic, carbamazepine, is extensively metabolized via hepatic enzymes in the cytochrome P450 family and is therefore subject to a myriad of drug interactions. Concomitant administration with phenytoin enhances carbamazepine metabolism thus reducing serum concentrations and necessitating the use of a higher maintenance dose. Removal of phenytoin therapy in the absence of anticipatory dose adjustments and careful monitoring of serum concentrations may result in catastrophic outcomes. Reported herein are the events leading to the death of a 23-month old child who suffered a fatal carbamazepine overdose following withdrawal of phenytoin therapy. |
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| AbstractList | The antiepileptic, carbamazepine, is extensively metabolized via hepatic enzymes in the cytochrome P450 family and is therefore subject to a myriad of drug interactions. Concomitant administration with phenytoin enhances carbamazepine metabolism thus reducing serum concentrations and necessitating the use of a higher maintenance dose. Removal of phenytoin therapy in the absence of anticipatory dose adjustments and careful monitoring of serum concentrations may result in catastrophic outcomes. Reported herein are the events leading to the death of a 23-month old child who suffered a fatal carbamazepine overdose following withdrawal of phenytoin therapy. The antiepileptic, carbamazepine, is extensively metabolized via hepatic enzymes in the cytochrome P450 family and is therefore subject to a myriad of drug interactions. Concomitant administration with phenytoin enhances carbamazepine metabolism thus reducing serum concentrations and necessitating the use of a higher maintenance dose. Removal of phenytoin therapy in the absence of anticipatory dose adjustments and careful monitoring of serum concentrations may result in catastrophic outcomes. Reported herein are the events leading to the death of a 23-month old child who suffered a fatal carbamazepine overdose following withdrawal of phenytoin therapy.The antiepileptic, carbamazepine, is extensively metabolized via hepatic enzymes in the cytochrome P450 family and is therefore subject to a myriad of drug interactions. Concomitant administration with phenytoin enhances carbamazepine metabolism thus reducing serum concentrations and necessitating the use of a higher maintenance dose. Removal of phenytoin therapy in the absence of anticipatory dose adjustments and careful monitoring of serum concentrations may result in catastrophic outcomes. Reported herein are the events leading to the death of a 23-month old child who suffered a fatal carbamazepine overdose following withdrawal of phenytoin therapy. |
| Audience | Academic |
| Author | Gengo, Fran M. Wollenberg, Lance Venci, Jineane V. Rainka, Michelle M. Rowcliffe, Meghan M. |
| Author_xml | – sequence: 1 givenname: Jineane V. surname: Venci fullname: Venci, Jineane V. email: jvenci3@gmail.com organization: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Dent Neurologic Institute – sequence: 2 givenname: Meghan M. surname: Rowcliffe fullname: Rowcliffe, Meghan M. organization: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York – sequence: 3 givenname: Lance surname: Wollenberg fullname: Wollenberg, Lance organization: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Dent Neurologic Institute – sequence: 4 givenname: Michelle M. surname: Rainka fullname: Rainka, Michelle M. organization: Dent Neurologic Institute – sequence: 5 givenname: Fran M. surname: Gengo fullname: Gengo, Fran M. organization: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Dent Neurologic Institute, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York |
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| Keywords | Toxicology Intoxication Forensics Pharmacokinetics Carbamazepine Phenytoin |
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Part I: phenobarbital, primidone, valproic acid, ethosuximide and mesuximideClin Pharmacokinet1995294257286854902710.2165/00003088-199529040-000051:CAS:528:DyaK2MXpslWju7c%3D ZielinskiJJHaidukewychDDuel effects of carbamazepine-phenytoin interactionTher Drug Monit198792123357665910.1097/00007691-198703000-000041:CAS:528:DyaL2sXhsVyqurY%3D SpillerHAKrenzelokEPCarbamazepine overdose: serum concentration less predictive in childrenJ Toxicol Clin Toxicol1993313459460835532110.3109/155636593090004131:STN:280:DyaK3szmtVehsw%3D%3D SpillerHAKrenzelokEPCooksonECarbamazepine overdose: a prospective study of serum levels and toxicityJ Toxicol Clin Toxicol1990284445458226999910.3109/155636590090385871:STN:280:DyaK3M7gtFagtQ%3D%3D MeWKoda-KimbleMACarbamazepineBasic clinical pharmacokentics19943VancouverApplied Therapeutics177184 SpillerHACarlisleRDTimely antemortem and postmortem concentrations in a fatal carbamazepine overdoseJ Forensic Sci200146615101512117141701:STN:280:DC%2BD3MnmvVCisw%3D%3D TibballsJAcute toxic reaction to carbamazepine: clinical effects and serum concentrationsJ Pediat19921212295299164030210.1016/S0022-3476(05)81208-91:STN:280:DyaK38zkvFWmtw%3D%3D StremskiESBradyWBPrasadKHennesHAPediatric carbamazepine intoxicationAnn Emerg Med1995255624630774133910.1016/S0196-0644(95)70175-31:STN:280:DyaK2M3lvF2juw%3D%3D ChapronDJLaPierreBAAbou-ElkairMUnmasking the significant enzyme inducing effects of phenytoin on serum carbamazepine concentrations during phenytoin withdrawalAnn Pharmacother19932770871183297871:STN:280:DyaK3szitVGhtw%3D%3D DuncanJSPatsalosPNShorvonSDEffects of discontinuation of phenytoin, carbamazepine, and valproate on concomitant antiepileptic medicationEpilepsia199131110111510.1111/j.1528-1157.1991.tb05620.x RivaRAlbaniFContinMBaruzziAPharmacokinetic interactions between antiepileptic drugs. Clinical considerationsClin Pharmacokinet1996316470493896865810.2165/00003088-199631060-000051:CAS:528:DyaK2sXjt12rtA%3D%3D SpinaEPisaniFPeruccaEClinically significant pharmacokinetic interactions with carbamazepine. An updateClin Pharmacokinet1996313198214887725010.2165/00003088-199631030-000041:CAS:528:DyaK28XlvVKjtrg%3D FaigleJWFeldmannFKWoodburyDMPippengerCECarbamazepine: biotransformationAntiepileptic drugs1982New YorkRaven Press483495 BonnetonJGentonPMesdjianEDistribution of carbamazepine and its epoxide in blood compartments in adolescent and adult epileptic patientsBiopharm Drug Dispos1992136411416139167910.1002/bdd.25101306041:STN:280:DyaK3s%2FgsVemtA%3D%3D MayTJurgensURambeckBSchnabelRComparison between premortem and postmortem serum concentrations of phenobarbital, phenytoin, carbamazepine and its 10, 11-epoxide metabolite in institutionalized patients with epilepsyEpilepsy Res199933157651002236610.1016/S0920-1211(98)00071-01:CAS:528:DyaK1cXotFWgsr8%3D BondarevaIBSokolovAVTischenkovaIFJelliffeRWPopulation pharmacokinetic modelling of carbamazepine by using the iterative Bayesian (IT2B) and the nonparametric EM (NPEM) algorithms: implications for dosageJ Clin Pharm Ther20012632132231142260610.1046/j.1365-2710.2001.00348.x1:CAS:528:DC%2BD3MXlt1yksbY%3D Product Information: EQUETRO(TM) oral extended release capsules, carbamazepine oral extended release capsules. In: Inc SU, editor. Wayne, PA; 2004. Product Information: TEGRETOL(R) chewable oral tablets, oral tablets, oral suspension, TEGRETOL(R) XR extended-release oral tablets, carbamazepine chewable oral tablets, oral tablets, oral suspension, extended-release oral tablets. In: Corporation NP, editor. East Hanover, NJ; 2003. AlbaniFRivaRBaruzziACarbamazepine clinical pharmacology: a reviewPharmacopsychiatry1995286235244877328910.1055/s-2007-9796091:STN:280:DyaK28zmvFarsQ%3D%3D D’ArgenioDZSchumitzkyAWangXADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software2009Los AngelesBiomedical Simulations Resource HanEKimEHongHJeongSKimJInSEvaluation of postmortem redistribution phenomena for commonly encountered drugsForensic Sci Int20122192652712228407310.1016/j.forsciint.2012.01.0161:CAS:528:DC%2BC38XnslSitr8%3D D Battino (9373_CR5) 1995; 29 J Tibballs (9373_CR20) 1992; 121 E Spina (9373_CR9) 1996; 31 HA Spiller (9373_CR16) 2001; 46 R Riva (9373_CR8) 1996; 31 JJ Zielinski (9373_CR10) 1987; 9 IB Bondareva (9373_CR12) 2001; 26 9373_CR2 JS Duncan (9373_CR7) 1991; 31 9373_CR1 HA Spiller (9373_CR19) 1990; 28 J Bonneton (9373_CR14) 1992; 13 E Han (9373_CR17) 2012; 219 DZ D’Argenio (9373_CR11) 2009 W Me (9373_CR3) 1994 HA Spiller (9373_CR18) 1993; 31 ES Stremski (9373_CR21) 1995; 25 F Albani (9373_CR4) 1995; 28 DJ Chapron (9373_CR6) 1993; 27 JW Faigle (9373_CR13) 1982 T May (9373_CR15) 1999; 33 8355321 - J Toxicol Clin Toxicol. 1993;31(3):459-60 11422606 - J Clin Pharm Ther. 2001 Jun;26(3):213-23 2269999 - J Toxicol Clin Toxicol. 1990;28(4):445-58 10022366 - Epilepsy Res. 1999 Jan;33(1):57-65 8877250 - Clin Pharmacokinet. 1996 Sep;31(3):198-214 7741339 - Ann Emerg Med. 1995 May;25(5):624-30 1985818 - Epilepsia. 1991 Jan-Feb;32(1):101-15 1391679 - Biopharm Drug Dispos. 1992 Aug;13(6):411-6 1640302 - J Pediatr. 1992 Aug;121(2):295-9 11714170 - J Forensic Sci. 2001 Nov;46(6):1510-2 8549027 - Clin Pharmacokinet. 1995 Oct;29(4):257-86 8773289 - Pharmacopsychiatry. 1995 Nov;28(6):235-44 3576659 - Ther Drug Monit. 1987;9(1):21-3 8329787 - Ann Pharmacother. 1993 Jun;27(6):708-11 8968658 - Clin Pharmacokinet. 1996 Dec;31(6):470-93 22284073 - Forensic Sci Int. 2012 Jun 10;219(1-3):265-71 |
| References_xml | – reference: MeWKoda-KimbleMACarbamazepineBasic clinical pharmacokentics19943VancouverApplied Therapeutics177184 – reference: BattinoDEstienneMAvanziniGClinical pharmacokinetics of antiepileptic drugs in paediatric patients. Part I: phenobarbital, primidone, valproic acid, ethosuximide and mesuximideClin Pharmacokinet1995294257286854902710.2165/00003088-199529040-000051:CAS:528:DyaK2MXpslWju7c%3D – reference: SpinaEPisaniFPeruccaEClinically significant pharmacokinetic interactions with carbamazepine. An updateClin Pharmacokinet1996313198214887725010.2165/00003088-199631030-000041:CAS:528:DyaK28XlvVKjtrg%3D – reference: FaigleJWFeldmannFKWoodburyDMPippengerCECarbamazepine: biotransformationAntiepileptic drugs1982New YorkRaven Press483495 – reference: SpillerHACarlisleRDTimely antemortem and postmortem concentrations in a fatal carbamazepine overdoseJ Forensic Sci200146615101512117141701:STN:280:DC%2BD3MnmvVCisw%3D%3D – reference: Product Information: TEGRETOL(R) chewable oral tablets, oral tablets, oral suspension, TEGRETOL(R) XR extended-release oral tablets, carbamazepine chewable oral tablets, oral tablets, oral suspension, extended-release oral tablets. In: Corporation NP, editor. East Hanover, NJ; 2003. – reference: RivaRAlbaniFContinMBaruzziAPharmacokinetic interactions between antiepileptic drugs. Clinical considerationsClin Pharmacokinet1996316470493896865810.2165/00003088-199631060-000051:CAS:528:DyaK2sXjt12rtA%3D%3D – reference: TibballsJAcute toxic reaction to carbamazepine: clinical effects and serum concentrationsJ Pediat19921212295299164030210.1016/S0022-3476(05)81208-91:STN:280:DyaK38zkvFWmtw%3D%3D – reference: ChapronDJLaPierreBAAbou-ElkairMUnmasking the significant enzyme inducing effects of phenytoin on serum carbamazepine concentrations during phenytoin withdrawalAnn Pharmacother19932770871183297871:STN:280:DyaK3szitVGhtw%3D%3D – reference: AlbaniFRivaRBaruzziACarbamazepine clinical pharmacology: a reviewPharmacopsychiatry1995286235244877328910.1055/s-2007-9796091:STN:280:DyaK28zmvFarsQ%3D%3D – reference: MayTJurgensURambeckBSchnabelRComparison between premortem and postmortem serum concentrations of phenobarbital, phenytoin, carbamazepine and its 10, 11-epoxide metabolite in institutionalized patients with epilepsyEpilepsy Res199933157651002236610.1016/S0920-1211(98)00071-01:CAS:528:DyaK1cXotFWgsr8%3D – reference: HanEKimEHongHJeongSKimJInSEvaluation of postmortem redistribution phenomena for commonly encountered drugsForensic Sci Int20122192652712228407310.1016/j.forsciint.2012.01.0161:CAS:528:DC%2BC38XnslSitr8%3D – reference: StremskiESBradyWBPrasadKHennesHAPediatric carbamazepine intoxicationAnn Emerg Med1995255624630774133910.1016/S0196-0644(95)70175-31:STN:280:DyaK2M3lvF2juw%3D%3D – reference: D’ArgenioDZSchumitzkyAWangXADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software2009Los AngelesBiomedical Simulations Resource – reference: SpillerHAKrenzelokEPCarbamazepine overdose: serum concentration less predictive in childrenJ Toxicol Clin Toxicol1993313459460835532110.3109/155636593090004131:STN:280:DyaK3szmtVehsw%3D%3D – reference: BondarevaIBSokolovAVTischenkovaIFJelliffeRWPopulation pharmacokinetic modelling of carbamazepine by using the iterative Bayesian (IT2B) and the nonparametric EM (NPEM) algorithms: implications for dosageJ Clin Pharm Ther20012632132231142260610.1046/j.1365-2710.2001.00348.x1:CAS:528:DC%2BD3MXlt1yksbY%3D – reference: BonnetonJGentonPMesdjianEDistribution of carbamazepine and its epoxide in blood compartments in adolescent and adult epileptic patientsBiopharm Drug Dispos1992136411416139167910.1002/bdd.25101306041:STN:280:DyaK3s%2FgsVemtA%3D%3D – reference: Product Information: EQUETRO(TM) oral extended release capsules, carbamazepine oral extended release capsules. 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| SubjectTerms | Anticonvulsants - administration & dosage Anticonvulsants - blood Anticonvulsants - pharmacokinetics Anticonvulsants - poisoning Autopsy Biotransformation Carbamazepine Carbamazepine - administration & dosage Carbamazepine - blood Carbamazepine - pharmacokinetics Carbamazepine - poisoning Case Report Computer Simulation Criminology and Criminal Justice Drug Administration Schedule Drug Interactions Drug Monitoring Drug Overdose - diagnosis Drug Overdose - etiology Drug Overdose - pathology Drug Therapy, Combination Drugs Fatal Outcome Forensic Medicine Forensic Toxicology Humans Infant Male Medical colleges Medicine Medicine & Public Health Models, Biological Monte Carlo Method Overdose Pathology Phenytoin Phenytoin - administration & dosage Phenytoin - blood Phenytoin - pharmacokinetics Physiological aspects Poisoning - diagnosis Poisoning - etiology Poisoning - pathology Seizures - drug therapy |
| Title | Pharmacokinetic simulation of fatal carbamazepine intoxication in 23-month old child following phenytoin discontinuation |
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