The cytochrome P450 isoforms primarily involved in clobazam metabolism are CYP3A4 and 2C19. Drugs that modulate these enzymes would then be expected to alter the exposure of clobazam and its major metabolites. Etravirine, a second-generation non-nucleoside reverse transcriptase inhibitor has been shown to induce CYP3A4, while inhibiting CYP2C9 and CYP2C19. We report a case in which a potential drug interaction between clobazam and etravirine may have led to increased concentrations of clobazam and its pharmacologically active metabolite, N-desmethylclobazam, causing neurotoxic symptoms.
References
1.
Schöller-GyüreM., KakudaT., RaoofA., De SmedtG., HoetelmansR.Clinical Pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet2009; 48: 561–574.
2.
Scholler-GyureM., KakudaT.N., Van Solingen-RisteaR.Pharmacokinetic interaction between etravirine and fluconazole or voriconazole in HIV-negative volunteers.49th Interscience Conference on Antimicrobial Agents and Chemotherapy. 12–15 September 2009, San Francisco, CA, USA. Abstract A1-1299.
3.
LimM.L., MinS.S., EronJ.J.Coadministration of lopinavir/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction. J Acquir Immune Defic Syndr2004; 36: 1034–1040.
4.
JiP., DamleB., XieJ., UngerS., GraselaD., KaulS.Pharmacokinetic interaction between efavirenz and carbamazepine after multiple-dose administration in healthy subjects. J Clin Pharmacol2008; 48: 948–956.
5.
GiraudC., TranA., ReyE., VincentJ., TreluyerJ.M., PonsG.In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19. Drug Metab Dispos2004; 32: 1279–1286.
6.
SennouneS., MesdijianE., BonnetonJ., GentonP., DravetC., RogerJ.Interactions between clobazam and standard antiepileptic drugs in patients with epilepsy. Ther Drug Monit1992; 14: 269–274.
7.
Bentué-FerrerD., TributO., VerdierM.C., DebruyneD.Therapeutic drug monitoring of clobazam. Therapie2010; 65: 225–231.
8.
TheisJ.G., KorenG., DanemanR.Interactions of clobazam with conventional antiepileptics in children. J Child Neurol1997; 12: 208–213.
9.
ContinM., SangiorgiS., RivaR., ParmeggianiA., FiorenzoA., BaruzziA.Evidence of polymorphic CYP2C19 involvement in the human metabolism of N-desmethylclobazam. Ther Drug Monit2002; 24: 737–741.
10.
FoisyM.M., YakiwchukE.M., HughesC.A.Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother2008; 42: 1048–1059.
RemyC.Clobazam in the treatment of epilepsy: a review of the literature. Epilepsia1994; 35Suppl 5: S88–S91.
13.
SeoT., NagataR., IshitsuT., MurataT., TakaishiC., HoriM.Impact of CYP2C19 polymorphisms on the efficacy of clobazam therapy. Pharmacogenomics2008; 9: 527–537.
14.
PokP.R., MaurasM., De Saint LegerM.N., KuhlmannE., Charpenel-DuratC., NavaretteC.Blood concentrations of clobazam and norclobazam in a lethal case involving clobazam, meprobamate and clorazepate. Leg Med (Tokyo)2010; 12: 300–304.
15.
HornJ.R., HanstenP., ChanL.N.Proposal for a New Tool to Evaluate Drug Interaction Cases. Ann Pharmacother2007; 41: 674–680.
16.
KiangT.K., HoP.C., AnariM.R., TongV., AbbottF.S., ChangT.K.Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype. Toxicol Sci2006; 94: 261–271.
17.
FlemingJ., ChettyM.Psychotropic drug interactions with valproate. Clin Neuropharmacol2005; 28: 96–101.
18.
BowdenC.L., JanicakP.G., OrsulakP.Relation of serum valproate concentration to response in mania. Am J Psychiatry1996; 153: 765–770.