To evaluate the clinical significance of interactions between anticonvulsant and antiretroviral agents and provide recommendations regarding their concurrent use.
DATA SOURCES
A PubMed search (1966 to April 2003) was conducted using individual anticonvulsant and antiretroviral drug names and the following key search terms: anticonvulsant, antiepileptic, antiretroviral, protease inhibitor, and pharmacokinetic. Abstracts from scientific meetings that pertained to drug interactions were manually reviewed.
STUDY SELECTION AND DATA EXTRACTION
All articles identified by the PubMed search were examined. Articles and abstracts from scientific meetings with relevant information were included.
DATA SYNTHESIS
Six case reports were identified that describe interactions between anticonvulsant agents and protease inhibitors. In several reports, carbamazepine serum concentrations increased by approximately two- to threefold with concurrent ritonavir, resulting in carbamazepine-related toxicity. Carbamazepine was also associated with loss of viral suppression when combined with indinavir. Phenytoin serum concentrations were decreased with nelfinavir in a patient who developed recurrent seizures. The effect of ritonavir on phenytoin was variable; a 30% reduction in phenytoin serum concentration occurred in one patient, while no apparent change was observed in another. Interactions with nonnucleoside reverse-transcriptase inhibitors are poorly characterized because existing data involve concurrent protease inhibitor therapy. The utility of newer anticonvulsant agents is explored. Experience with newer anticonvulsant agents in 2 patients at our site is also described.
CONCLUSION
Limited data exist regarding interactions between anticonvulsant and antiretroviral agents. Valproic acid and newer anticonvulsant agents may provide useful alternatives to first-generation agents. Clinicians need to be diligent when monitoring for anticonvulsant–antiretroviral interactions because of the potential for toxicity, loss of seizure control, and incomplete viral suppression.
. HoltzmanDKakuDASoY.New-onset seizures associated with human immunodeficiency virus infection: causation and clinical features in 100 cases. Am J Med1989;87:173–7.
2.
. WongMSuiteNLabarD.Seizures in human immunodeficiency virus infection. Arch Neurol1990;47:640–2.
3.
. WongMSuiteNLabarD.Seizures in HIV infection (abstract 3). Neurology1989;39(suppl 1):362.
4.
. SniderWSimpsonDNielsenSGoldJMetrokaCPosnerJ.Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol1983;14:403–18.
. KumarGRodriguesABukoADenissenJ.Cytochrome P450–mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther1996;277:423–31.
7.
. HesseLvon MoltkeLShaderRGreenblattD.Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion. Drug Metab Dispos2001;29:100–2.
8.
. SheltonMCloenDBeckerMHsyuPWiltonJHewittR.Evaluation of the pharmacokinetic interactions between phenytoin and nelfinavir in healthy volunteers at steady state (abstract 426). Presented at: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, September 17–20, 2000.
9.
. HondaMYasuokaAAokiMOkaS.A generalized seizure following initiation of nelfinavir in a patient with human immunodeficiency virus type I infection, suspected due to interaction between nelfinavir and phenytoin. Intern Med1999;38:302–3.
10.
. von MoltkeLGreenblattDGrandaBGiancarloGDuanSDailyJInhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol2001;41:85–91.
11.
. HeelonMMeadeL.Methadone withdrawal when starting an antiretroviral regimen including nevirapine. Pharmacotherapy1999;19:471–2.
12.
. MoulySLownKKornhauserDJosephJFiskeWBenedekIHepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans. Clin Pharmacol Ther2002;72:1–9.
13.
. BurmanWOrrL.Carbamazepine toxicity after starting combination antiretroviral therapy including ritonavir and efavirenz. AIDS2000;14:2793–4.
14.
. DatoYFujiiTMizoguchiNTakataNUedaKFeldmanMPotential interaction between ritonavir and carbamazepine. Pharmacotherapy2000;20:851–4.
15.
. IribarneCBerthouFCarlhantDDreanoYPicartDLohezicFInhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors. Drug Metab Dispos1998;26:257–60.
. BajpaiMRoskosLShenDLevyR.Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Dispos1996;24:1401–3.
21.
. LimMMinSEronJBertzRRobinsonMGaedigkAA two-way drug interaction between lopinavir/ritonavir and phenytoin (abstract 535). Presented at: 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 10–14, 2003.
22.
. ButlerTC.The metabolic hydroxylation of phenobarbital. J Pharmacol Exp Ther1956;116:326–36.
23.
. XiaWJun-ShengWKivistoKNeuvonenPBackmanJ.In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9). Br J Clin Pharmacol2001;52:547–53.
. LertoraJRegeAGreenspanDAkulaSGeorgeWHyslopNPharmacokinetic interaction between zidovudine and valproic acid in patients with human immunodeficiency virus. Clin Pharmacol Ther1994;56:272–8.
26.
. MoogCKuntz-SimonGCaussin-SchwemlingCObertG.Sodium valproate, an anticonvulsant drug, stimulates human immunodeficiency virus type 1 replication independently of glutathione levels. J Gen Virol1996;77:1993–9.
27.
. WitvrouwMSchmitJ-CVanremoortelBDaelemansDEsteJVandammeA-MCell type–dependent effect of sodium valproate on human immunodeficiency virus type 1 replication in vitro. AIDS Res Hum Retroviruses1997;13:187–92.
. JedrzejczakJDlawichowskaEOwczarekKMajkowskiJ.Effect of vigabatrin addition on carbamazepine blood serum levels in patients with epilepsy. Epilepsy Res2000;39:115–20.
36.
. RimmerEMRichensA.Interaction between vigabatrin and phenytoin. Br J Clin Pharmacol1989;27(suppl 1):27S–33S.
37.
. GrantSMHeelRC.Vigabatrin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs1991;41:889–926.
38.
. Product information. Zonegran (zonisamide). San Diego, CA: Elan Pharmaceuticals, June2002.
39.
. Ben-MenachemEFalterU, for the European Levetiracetam Study Group. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia2000;41:1276–83.
40.
. NicholasJ-MCollartPGerinBMatherGTragerWLevyRIn vitro evaluation of potential drug interaction with levetiracetam, a new antiepileptic agent. Drug Metab Dispos1999;27:250–4.
41.
. JawadSYuenWPeckAHamiltonMOxleyJRichensA.Lamotrigine: single-dose pharmacokinetics and initial 1 week experience in refractory epilepsy. Epilepsy Res1987;1:194–201.
42.
. BinnieCvan Emde BoasWKasteleijn-Nolste-TreniteDde KorteRMeijerJMeinardiHAcute effects of lamotrigine (BW430C) in persons with epilepsy. Epilepsia1986;27:248–54.
43.
. SimpsonDMcArthurJOlneyRCliffordDSoYRossDLamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology2003;60:1508–14.
44.
. MatherGCarlsonSTragerWBuchananRLevyR.Prediction of zonisamide interactions based on metabolic isozymes (abstract 3.078). Epilepsia1997;38(suppl 8):108.
45.
. LevyRBishopFStreeterATragerWKunzeKThummelKExplanation and prediction of drug interactions with topiramate using a CYP450 inhibition spectrum (abstract 2.52). Epilepsia1995;36(suppl 4):47.
. SaanoVGluePBanfieldCReidenbergPColucciRMeehanJEffects of felbamate on pharmacokinetics of low-dose combination oral contraceptive. Clin Pharmacol Ther1995;58:523–31.
48.
. LevyRTragerWKunzeKThummelKWienkersLBishopFPrediction of phenytoin interactions based on cytochrome P450 isoforms (abstract). Epilepsia1994;35(suppl 8):143.
49.
. SachdeoRSachdeoSWagnerMReitzJShumakerRPerhachJSteady-state pharmacokinetics of felbamate (Felbatol) when coadministered with phenytoin (abstract). Epilepsia1992;33(suppl 3):84.
50.
. FuerstRGravesNLeppikIBrundageRHolmesGRemmelR.Felbamate increases phenytoin but decreases carbamazepine concentrations. Epilepsia1988;29:488–91.
51.
. NightingaleS.From the Food and Drug Administration. JAMA1994;272:995.
52.
. AarnoutseREVerweij-van WissenCVan Ewijk-Beneken KolmerEWuisEWKoopmansPPHeksterYAInternational interlaboratory quality control program for measurement of antiretroviral drugs in plasma. Antimicrob Agents Chemother2002;46:884–6.
53.
. DrosteJAAarnoutseREKoopmansPPHeksterYABurgerDM.Evaluation of antiretroviral drug measurements by an interlaboratory quality control program. J Acquir Immune Defic Syndr2003;32:287–91.
54.
. PiscitelliSBechtelCSadlerBFalloonJ, and the Intramural AIDS Program. The addition of a 2nd protease inhibitor eliminates amprenavir–efavirenz drug interactions and increases amprenavir plasma concentrations (abstract 78). Presented at: 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, January 30-February 2, 2000.
55.
. BertzRLamWHsuARynkiewiczKFoitCBryanPAssessment of pharmacokinetic interaction between ABT-378/ritonavir (ABT-378/r) and efavirenz (EFV) in healthy volunteers and in HIV+ subjects (abstract 424). Presented at: 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, September 17–20, 2000.
56.
. FaughtE.Pharmacokinetic considerations in prescribing antiepileptic drugs. Epilepsia2001;42(suppl 4):19–23.
