Therapeutic drug monitoring of antiepileptic drugs by use of saliva

Therapeutic Drug Monitoring

Volumn 35, Issue 1, 2013, Pages 4-29

  Patsalos, Philip N ^a,b   Berry, Dave J ^b  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b EPILEPSY SOCIETY   (United Kingdom)

Author keywords

antiepileptic drugs; practical protocol for saliva antiepileptic drug monitoring; saliva; therapeutic drug monitoring

Indexed keywords

ANTICONVULSIVE AGENT; CARBAMAZEPINE; CLOBAZAM; CLONAZEPAM; ESLICARBAZEPINE ACETATE; ETHOSUXIMIDE; ETIRACETAM; FELBAMATE; GABAPENTIN; HARKOSERIDE; LAMOTRIGINE; OXCARBAZEPINE; PHENOBARBITAL; PHENYTOIN; PREGABALIN; PRIMIDONE; RETIGABINE; RUFINAMIDE; STIRIPENTOL; TIAGABINE; TOPIRAMATE; VALPROIC ACID; VIGABATRIN; ZONISAMIDE;

ACCURACY; ANTICONVULSANT THERAPY; ATONIC SEIZURE; BLOOD ANALYSIS; CLINICAL EFFECTIVENESS; CLINICAL PROTOCOL; CLONIC SEIZURE; DRIED BLOOD SPOT TESTING; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CEREBROSPINAL FLUID LEVEL; DRUG FORMULATION; DRUG MONITORING; DRUG SALIVA LEVEL; EPILEPSY; EPILEPTIC STATE; FOCAL EPILEPSY; GENERALIZED ANXIETY DISORDER; GENERALIZED EPILEPSY; HUMAN; HYPOALBUMINEMIA; INFANTILE SPASM; LACRIMAL FLUID; LENNOX GASTAUT SYNDROME; MICROCAPSULE; MONOTHERAPY; MYOCLONUS EPILEPSY; MYOCLONUS SEIZURE; PAIN; PARENTAL CONSENT; PATIENT PREFERENCE; PHYSICIAN; PRACTICE GUIDELINE; PREDICTIVE VALUE; PRIORITY JOURNAL; PROCESS OPTIMIZATION; PROTEIN BINDING; REVIEW; SALIVA ANALYSIS; SEIZURE; SUSPENSION; SWEAT; TABLET; TONIC CLONIC SEIZURE; TREATMENT INDICATION;

ANTICONVULSANTS; DRUG MONITORING; EPILEPSY; HUMANS; SALIVA;

EID: 84872839875     PISSN: 01634356     EISSN: 15363694     Source Type: Journal    
DOI: 10.1097/FTD.0b013e31827c11e7     Document Type: Review

References (253)

1. Patsalos PN, Berry DJ, Bourgeois BFD, et al. Antiepileptic drugs - best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49:1239-1276.
2. Johannessen SI, Battino D, Berry DJ, et al. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther Drug Monit. 2003;25:347-363.
3. Krasowski MD. Therapeutic drug monitoring of the newer anti-epilepsy medications. Pharmaceuticals (Basel). 2010;3:1909-1935.
4. Brandt C, May TW. Therapeutic drug monitoring of newer antiepileptic drugs. J Lab Med. 2011;35:161-169.
5. Hiemke C, Baumann P, Bergemann N, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44:195-235.
6. Patsalos PN. New antiepileptic drugs. Ann Clin Biochem. 1999;36: 10-19.
7. Kurz H, Trunk H, Weitz B. Evaluation of methods to determine proteinbinding of drugs: equilibrium dialysis, ultracentrifugation, gel filtration. Drug Res. 1977;27:1373-1380.
8. Oellerich M, Muller-Vahl H. The EMIT-ultrafiltration technique compared with equilibrium dialysis and ultra-centrifugation to determine protein binding of phenytoin. Clin Pharmacokinet. 1984;9(supp 1): 61-70.
9. Barre J, Chamouard JM, Houin G, et al. Equilibrium dialysis, ultrafiltration and ultracentrifugation compared for determining the plasma protein binding characteristics of valproic acid. Clin Chem. 1985;30: 60-64.
10. Edelbroek PM, van der Heijden J, Stolk LML. Dried blood spot methods in therapeutic drug monitoring: methods, assays, and pitfalls. Ther Drug Monit. 2009;31:327-336.
11. Coombes EJ, Gamlen TR, Batstone GF, et al. A phenytoin assay using dried blood spot samples suitable for domiciliary therapeutic drug monitoring. Ann Clin Biochem. 1984;21:519-522.
12. la Marca G, Malvagia S, Filippi L, et al. Rapid assay of topiramate in dried blood spots by a new liquid chromatography-tandem mass spectrometric method. J Pharm Biomed Anal. 2008;48:1392-1396.
13. la Marca G, Malvagia S, Filippi L, et al. A new rapid micromethod for the assay of phenobarbital from dried blood spots by LC-tandem mass spectrometry. Epilepsia. 2009;50:2658-2662.
14. la Marca G, Malvagia S, Filippi L, et al. Rapid assay of rufinamide in dried blood spots by a new liquid chromatography-tandem mass spectrometric method. J Pharm Biomed Anal. 2011;54:192-197.
15. Wegner I, Edelbroek P, de Haan GL, et al. Drug monitoring of lamotrigine and oxcarbazepine combination during pregnancy. Epilepsia. 2010;51:2500-2502.
16. Kolocouri F, Dotsikas Y, Loukas YL. Dried plasma spots as an alternative sample collection technique for the quantitative LC-MS/MS determination of gabapentin. Anal Bioanal Chem. 2010;398: 1339-1347.
17. Tondi M, Mutani R, Mastropaolo C, et al. Greater reliability of tear versus saliva anticonvulsant levels. Ann Neurol. 1978;4:154-155.
18. Monaco F, Mutani R, Mastropaolo C, et al. Tears as the best practical indicator of the unbound fraction of an anticonvulsant drug. Epilepsia. 1979;20:705-710.
19. Monaco F, Piredda S, Mastropaolo C, et al. Diphenylhydantoin and primidone in tears. Epilepsia. 1981;22:185-188.
20. Monaco F, Piredda S, Mutani R, et al. The free fraction of valproic acid in tears, saliva, and cerebrospinal fluid. Epilepsia. 1982;23:23-26.
21. Piredda S, Monaco F. Ethosuximide in tears, saliva and cerebral fluid. Ther Drug Monit. 1981;3:321-323.
22. Nakajima M, Yasmato S, Shimada K, et al. Assessment of drug concentration in tears in therapeutic drug monitoring I: determination of valproic acid in tears by gas chromatography/mass spectrometry with EC/NCI mode. Ther Drug Monit. 2000;22:716-722.
23. Parnas J, Flach H, Gram L, et al. Excretion of antiepileptic drugs in sweat. Acta Neurol Scand. 1978;58:197-204.
24. Kintz P, Tracqui A, Jamey C, et al. Detection of codeine and phenobarbital in sweat collected with a sweat patch. J Anal Toxicol. 1996;20: 197-201.
25. Troupin AS, Friel PN. Anticonvulsant levels in saliva, serum and cerebrospinal fluid. Epilepsia. 1975;16:223-227.
26. Schmidt D, Kupferberg H. Diphenylhydantoin, phenobarbital and primidone in saliva, plasma, and cerebrospinal fluid. Epilepsia. 1975;16: 735-741.
27. Johannessen SI, Gerna M, Bakke J, et al. CSF concentrations and serum protein binding of carbamazepine and carbamazepine-10,11-epoxide in epileptic patients. Br J Clin Pharmacol. 1976;3:575-582.
28. Weiser HG. Comparison of valproate concentrations in human plasma, CSF and brain tissue after administration of different formulations of valproate or valpromide. Epilepsy Res. 1991;9:154-159.
29. Riekkinen PJ, Ylinen A, Halonen T, et al. Cerebrospinal fluid GABA and seizure control with vigabatrin. Br J Clin Pharmacol. 1989;27: 87S-94S.
30. Ben-Menachem E, Perrsson LI, Hedner T. Selected CSF biochemistry and gabapentin concentrations in the CSF and plasma in patients with partial seizures after a single oral dose of gabapentin. Epilepsy Res. 1992;11:45-49.
31. Ben-Menachem E, Soderfelt B, Hamberger A, et al. Seizure frequency and CSF parameters in a double-blind placebo controlled trial of gabapentin in patients with intractable complex paryial seizures. Epilepsy Res. 1995;21:231-236.
32. Rambeck B, Jurgens UH, May TW, et al. Comparison of brain extracellular fluid, brain tissue, cerebral fluid, and serum concentrations of antiepileptic drugs measured intraoperatively in patients with intractable epilepsy. Epilepsia. 2006;47:681-694.
33. Buvanendran A, Kroin JS, Kari M, et al. Can a single dose of 300 mg of pregabalin reach acute antihyperalgesic levels in the central nervous system? Reg Anesth Pain Med. 2010;35:535-538.
34. Nunes T, Rocha JF, Falcao A, et al. Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine and oxcarbazepine in healthy volunteers. Epilepsia. In press.
35. Kintz P, Marescaux C, Mangin P. Testing human hair for carbamazepine in epileptic patients: is hair investigation suitable for drug monitoring? Hum Exp Toxicol. 1995;14:812-815.
36. Psillakis T, Tsatsakis AM, Christodoulou P, et al. Carbamazepine levels in head hair of patients under long-term treatment: a method to evaluate the history of drug use. J Clin Pharm. 1999;39:55-67.
37. Mieczkowski T, Tsatsakis AM, Kruer M, et al. The concentration of three anti-seizure medications in hair: the effects of hair color, controlling of dose and age. BMC Clin Pharmacol. 2001;1:2.
38. Williams J, Myson V, Steward S, et al. Self-discontinuation of antiepileptic medication in pregnancy: detection by hair analysis. Epilepsia. 2002;43:824-831.
39. Klys M, Rojek S, Bolechala F. Determination of oxcarbazepine and its metabolites in postmortem blood and hair by means of liquid chromatography with mass detection (HPLC/APCI/MS). J Chromatogr B Analyt Technol Biomed Life Sci. 2005;825:38-46.
40. Williams, Patsalos PN, Wilson JF. Hair analysis as a potential index of therapeutic compliance in the treatment of epilepsy. Forensic Sci Int. 1997;84:113-122.
41. Williams J, Patsalos PN, Mei Z, et al. Relationship between dosage of carbamazepine and concentration in hair and plasma samples from a compliant inpatient epileptic population. Ther Drug Monit. 2001;23:15-20.
42. Mantzouranis EC, Bertsias GK, Pallis EG, et al. Hair analysis differentiates chronic from acute carbamazepine intoxication. Pediatr Neurol. 2004;31:73-75.
43. Danhof M, Breimer DD. Therapeutic drug monitoring in saliva. Clin Pharmacokinet. 1978;3:39-57.
44. Mucklow JC. The use of saliva in therapeutic drug monitoring. Ther Drug Monit. 1982;4:229-247.
45. Drobitch RK, Svenson CK. Therapeutic drug monitoring in saliva. An update. Clin Pharmacokinet. 1992;23:365-379.
46. Liu H, Delgado MR. Therapeutic drug concentration monitoring using saliva samples: focus on anticonvulsants. Clin Pharmacokin. 1999;36:453-470.
47. Baumann RJ. Salivary monitoring of antiepileptic drugs. J Pharm Pract. 2007;20:147-157.
48. Moreland TA, Priestman DA, Rylance GW. Saliva carbamazepine levels in children before and during multiple dosing. Br J Clin Pharmacol. 1982;13:647-651.
49. Van HG. Comparative study of the levels of anticonvulsants and their free fractions in venous blood, saliva and capillary blood in man. J Pharmacol. 1984;15:27-35.
50. Knott C, Reynolds F. The place of saliva in antiepileptic drug monitoring. Ther Drug Monit. 1984;6:35-41.
51. Tomlin PI, McKinlay I, Smith I. A study on carbamazepine levels, including estimation of 10-11 epoxy-carbamazepine and levels in free plasma and saliva. Dev Med Child Neurol. 1986;28:713-718.
52. Eeg-Olofsson O, Nilsson HL, Tonnby B, et al. Diurnal variation of carbamazepine and carbamazepine-10,11-epoxide in plasma and saliva in children with epilepsy: a comparison between conventional and slowrelease formulations. J Child Neurol. 1990;5:159-165.
53. Miles MV, Tennison MB, Greenwood RS, et al. Evaluation of the Ames Seralyzer for the determination of carbamazepine, phenobarbital, and phenytoin in saliva. Ther Drug Monit. 1990;12:452-460.
54. Gorodischer R, Burtin P, Verjee Z, et al. Is saliva suitable for therapeutic monitoring of anticonvulsants in children: an evaluation in the routine clinical setting. Ther Drug Monit. 1997;19:637-642.
55. Bardy AH, Seppälä T, Salokorpi T, et al. Monitoring of concentrations of clobazam and norclobazam in serum and saliva of children with epilepsy. Brain Dev. 1991;13:174-179.
56. McAuliffe JJ, Sherwin AL, Leppik IE, et al. Salivary levels of anticonvulsants: a practical approach to drug monitoring. Neurology. 1977;27: 409-413.
57. Horning MG, Brown L, Nowlin J, et al. Use of saliva for therapeutic drug monitoring. Clin Chem. 1977;23:157-164.
58. Bachmann K, Schwartz J, Sullivan T, et al. Single sample estimate of ethosuximide clearance. Int J Clin Ther Toxicol. 1986;24:546-550.
59. Benetello P, Furlanut M, Fortunato M, et al. Oral gabapentin disposition in patients with epilepsy after a high-protein diet. Epilepsia. 1997;38: 1140-1142.
60. Berry DJ, Beran RG, Plunkett MJ, et al. The absorption of gabapentin following high dose escalation. Seizure. 2003;12:28-36.
61. Greenaway C, Ratnaraj N, Sander JW, et al. Saliva and serum lacosamide concentrations in patients with epilepsy. Epilepsia. 2011;52: 258-263.
62. Tsiropoulos I, Kristensen O, Klitgaard NA. Saliva and serum concentration of lamotrigine in patients with epilepsy. Ther Drug Monit. 2000; 22:517-521.
63. Ryan M, Grim SA, Miles MV, et al. Correlation of lamotrigine concentrations between serum and saliva. Pharmacotherapy. 2003;23: 1550-1557.
64. Malone SA, Eadie MJ, Addison RS, et al. Monitoring salivary lamotrigine concentrations. J Clin Neurosci. 2006;13:902-907.
65. Grim SA, Ryan M, Miles MV, et al. Correlation of levetiracetam concentrations between serum and saliva. Ther Drug Monit. 2003;25: 61-66.
66. Lins RL, Otoul C, De Smedy F, et al. Comparison of plasma and saliva concentrations of levetiracetam following administration orally as a tablet and as a solution in healthy adult volunteers. Int J Clin Pharmacol Ther. 2007;45:47-54.
67. Mecarelli O, Li Voti P, Pro S, et al. Saliva and serum levetiracetam concentrations in patients with epilepsy. Ther Drug Monit. 2007;29: 313-318.
68. Thiesohn M, Heimann G. Disposition of the anti-epileptic oxcarbazepine and its metabolites in healthy volunteers. Eur J Clin Pharmacol. 1982;22:545-551.
69. Kristensen O, Klitgaard NA, Jonsson B, et al. Pharmacokinetics of 10-OH-carbazepine, the main metabolite of the antiepileptic oxcarbazepine from serum and saliva concentrations. Acta Neurol Scand. 1983; 68:145-150.
70. Klitgaard NA, Kristensen O. Use of saliva for monitoring oxcarbazepine therapy in epileptic patients. Eur J Clin Pharmacol. 1986;31: 91-94.
71. Cardot JM, Degan F, Flesch G, et al. Comparison of plasma and saliva concentrations of the active monohydroxy metabolite of oxcarbazepine in patients at steady state. Biopharm Drug Dispos. 1995;16:603-614.
72. Miles MV, Tang PH, Ryan MA, et al. Feasibility and limitations of oxcarbazepine monitoring using salivary monohydroxycarbamazepine (MHD). Ther Drug Monit. 2004;26:300-304.
73. Goldsmith RF, Ouvrier RA. Salivary anticonvulsant levels in children: a comparison of methods. Ther Drug Monit. 1981;3:151-157.
74. Luoma PV, Heikkinen JE, Ylostalo PR. Phenobarbital pharmacokinetics and salivary and serum concentrations in pregnancy. Ther Drug Monit. 1982;4:65-68.
75. Tokugawa K, Ueada K, Fujito H, et al. Correlation between the saliva and free serum concentration of phenobarbitone in epileptic children. Eur J Pediatr. 1986;145:401-402.
76. Tsanaclis LM, Allen J, Perucca E, et al. Effect of valproate on free plasma phenytoin concentrations. Br J Clin Pharmacol. 1984;18:17-20.
77. Mazzucchelli I, Rapetti M, Fattore C, et al. Development and validation of an HPLC-UV detection assay for the determination of rufinamide in human plasma and saliva. Anal Bioanal Chem. 2011;401:1013-1021.
78. Miles MV, Tang PH, Glauser TA, et al. Topiramate concentration in saliva: an alternative to serum monitoring. Pediatr Neurol. 2003;29: 143-147.
79. Durham SL, Hoke JF, Chen TM. Pharmacokinetics and metabolism of vigabatrin following a single oral dose of [14C]vigabatrin in healthy male volunteers. Drug Metab Dispos. 1993;21:480-484.
80. Kumagai N, Seki T, Yamada T, et al. Concentrations of zonisamide in serum, free fraction, mixed saliva and cerebrospinal fluid in epileptic children treated with monotherapy. Jpn J Psychiatry Neurol. 1993;47: 291-292.
81. Rawlins MD, Collste P, Bertilsson L, et al. Distribution and elimination kinetics of carbamazepine in man. Eur J Clin Pharmacol. 1975;8: 91-96.
82. Kudriakova TB, Sirota LA, Rpzova GI, et al. Autoinduction and steadystate pharmacokinetics of carbamazepine and its major metabolites. Br J Clin Pharmacol. 1992;33:611-615.
83. Eichelbaum M, Tomson T, Tybnring G, et al. Carbamazepine metabolism in man: induction and pharmacogenetic aspects. Clin Pharmacokinet. 1985;10:80-90.
84. Chambers RE, Homeida M, Hunter KR, et al. Salivary carbamazepine concentrations. Lancet. 1977;1:656-657.
85. Bartels H, Oldigs HD, Gunther E. Use of saliva in monitoring carbamazepine medication in epileptic children. Eur J Pediat. 1977;126: 37-44.
86. Westenberg HGM, van der Kleijn E, Oei TT. Kinetics of carbamazepine and carbamazepine-epoxide, determined by use of plasma and saliva. Clin Pharmacol Ther. 1978;23:320-328.
87. Paxton JW, Donald RA. Concentrations and kinetics of carbamazepine in whole saliva, parotid saliva, serum ultrafiltrate, and serum. Clin Pharmacol Ther. 1980;28:695-702.
88. Kristensen O, Larsen HF. Value of saliva samples in monitoring carbamazepine concentrations in epileptic patients. Acta Neurol Scand. 1980; 61:344-350.
89. MacKichan JJ, Duffner PK, Cohen ME. Salivary concentration and plasma protein binding of carbamazepine and carbamazepine- 10,11-epoxide in epileptic patients. Br J Clin Pharmacol. 1981;12: 31-37.
90. Rylance GW, Moreland TA. Saliva carbamazepine and phenytoin level monitoring. Arch Dis Child. 1981;56:637-640.
91. Miles MV, Tennison MB, Greenwood RS. Interindividual variability of carbamazepine, phenobarbital, and phenytoin concentrations in saliva. Ther Drug Monit. 1991;13:166-171.
92. Chee KY, Lee D, Byron D, et al. A simple collection method for saliva in children: potential for home monitoring of carbamazepine therapy. Br J Clin Pharmacol. 1995;35:311-313.
93. Rosenthal E, Hoffer E, Ben-Aryeh H, et al. Use of saliva in home monitoring of carbamazepine levels. Epilepsia. 1995;36:72-74.
94. Vasudev A, Tripathi KD, Puri V. Correlation of serum and salivary carbamazepine concentration in epileptic patients: implications for therapeutic drug monitoring. Neurol India. 2002;50:60-62.
95. Al Za'abi M, Deleu D, Batchelor C. Salivary free concentrations of antiepileptic drugs: an evaluation in routine clinical setting. Acta Neurol Belg. 2003;103:19-23.
96. Aucamp AK. Aspects of the pharmacokinetics and pharmacodynamics of benzodiazepines with particular reference to clobazam. Drug Dev Res. 1982;2(suppl 1):117-126.
97. Kaplan SA, Alexander K, Jack ML, et al. Pharmacokinetic profile of clonazepam in dog and humans and of flunitrazepam in dog. J Pharm Sci. 1974;63:527-532.
98. Berlin A, Dahlstrom H. Pharmacokinetics of the anticonvulsant drug clonazepam evaluated from single oral and intravenous doses and repeated oral administration. Eur J Clin Pharmacol. 1975;9:155-159.
99. Walson PD, Edge JH. Clonazepam disposition in pediatric patients. Ther Drug Monit. 1996;18:1-5.
100. Hart BJ, Wilting J, de Gier JJ. The stability of benzodiazepines in saliva. Methods Find Exp Clin Pharmacol. 1988;10:21-26.
101. Almeida L, Soares-da-Silva P. Safety, tolerability, and pharmacokinetics profile of BIA 2-093, a novel putative antiepileptic, in a rising multiple-dose study in young healthy humans. J Clin Pharmacol. 2004;44:906-918.
102. Patsalos PN, Berry DJ. Pharmacotherapy of the third-generation AEDs: lacosamide, retigabine and eslicarbazepine acetate. Exp Opin Pharmacother. 2012;13:699-715.
103. Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev Neurother. 2010;10:119-140.
104. Buchanan RA, Kinkel AW, Smith TC. The absorption and excretion of ethosuximide. Int J Clin Pharmacol. 1973;7:213-218.
105. Eadie MJ, Tyrer JH, Smith GA, et al. Pharmacokinetics of drugs used for petit mal 'absence' epilepsy. Clin Exp Neurol. 1977;14:172-183.
106. Shumaker RC, Fantel C, Kelton E, et al. Evaluation of the elimination of (14C) felbamate in healthy men. Epilepsia. 1990;31:642.
107. Thompson CD, Barthen MT, Hopper DW, et al. Quantification in patient urine samples of felbamate and three metabolites: acid carbamate and two mercapturic acids. Epilepsia. 1999;40:769-776.
108. Wagner ML, Graves NM, Marineau K, et al. Discontinuation of phenytoin and carbamazepine in patients receiving felbamate. Epilepsia. 1991;32:398-406.
109. Howard JR, Dix RK, Shumaker RC, et al. Effect of felbamate on carbamazepine pharmacokinetics. Epilepsia. 1992;33(suppl 3):84-85.
110. Ward DL, Wagner ML, Perhach JL, et al. Felbamate steady-state pharmaco- kinetics during co-administration of valproate. Epilepsia. 1991;32 (suppl 3):8.
111. Gidal BE, Radulovic LL, Krugar S, et al. Inter- and intra-subject variability in gabapentin absorption and absolute bioavailability. Epilepsy Res. 2000;40:123-127.
112. Vollmer KO, von Hodenberg A, Kolle EU. Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Azneimittelforschung. 1986;36:830-839.
113. Besag FMC, Berry DJ, Aylett SA, et al. Serum gabapentin levels continue to increase with dose in the high-range in children and teenagers. Epilepsia. 2000;41(suppl florence):147.
114. Tennison MB, Miles MV, Ali I, et al. Salivary monitoring of lamotrigine and gabapentin. Epilepsia. 1999;40(suppl 7):144.
115. Doty P, Rudd GD, Stohr T, et al. Lacosamide. Neurotherapeutics. 2007; 5:145-148.
116. Vimpat, SPC. Slough, United Kingdom: UCB Pharma. Available at: http://www.medicines.org.uk/emc/medicines/21158. Accessed April 23, 2012.
117. Rambeck B, Wolf P. Lamotrigine clinical pharmacokinetics. Clin Pharmacokinet. 1993;5:433-443.
118. Biton V. Pharmacokinetics, toxicology and safety of lamotrigine in epilepsy. Expert Opin Drug Metab Toxicol. 2006;2:1009-1018.
119. Trnavska Z, Krejcova H, Ykaczykovam Z, et al. Pharmacokinetics of lamotrigine (Lamictal) in plasma and saliva. Eur J Drug Metab Pharmacokinet. 1991;3:211-215.
120. Cohen AF, Ashby L, Crowley D, et al. Lamotrigine (BW430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam. Br J Clin Pharmacol. 1985; 20:619-629.
121. Incecayir T, Agabeyoglu I, Gucuyener K, Comparison of plasma and saliva concentrations of lamotrigine in healthy volunteers. Arzneimittelforschung. 2007;57:517-521.
122. Mallayasamy SR, Arumugamn K, Jain T, et al. A sensitive and selective HPLC method for estimation of lamotrigine in human plasma and saliva: application to plasma-saliva correlation in epileptic patients. Arzneimittelforschung. 2010;60:599-606.
123. Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther. 2000;85:77-85.
124. Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet. 2004;43:707-724.
125. Patsalos PN. Levetiracetam: pharmacology and therapeutics in the treatment of epilepsy and other neurological conditions. Rev Contemp Pharmacother. 2004;13:1-168.
126. Patsalos PN, Ghattaura S, Ratnaraj N, et al. In situ metabolism of levetiracetam in blood of patients with epilepsy. Epilepsia. 2006;47: 1818-1821.
127. Volosov A, Xiaodong S, Perucca E, et al. Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects. Clin Pharmacol Ther. 1999;66: 547-553.
128. Wellington K, Goa KL. Oxcarbazepine-an update of its efficacy in the management of epilepsy. CNS Drugs. 2001;15:137-163.
129. Patsalos PN, Elyas AA, Zakrzewska JM. Protein binding of oxcarbazepine and its primary active metabolite, 10-hydroxycarbazepine, in patients with trigeminal neuralgia. Eur J Clin Pharmacol. 1990;39: 413-415.
130. McKee PJ, Blacklaw J, Forrest G, et al. A double-blind, placebocontrolled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients. Br J Clin Pharmacol. 1994;37:27-32.
131. May TW, Korn-Merker E, Rambeck B. Clinical pharmacokinetics of oxcarbazepine. Clin Pharmacokinet. 2003;42:1023-1042.
132. Nelson E, Powell JR, Conrad K, et al. Phenobarbital pharmacokinetics and bioavailability in adults. J Clin Pharmacol. 1982;22:141-148.
133. Wilensky AJ, Friel PN, Levy RH, et al. Kinetics of phenobarbital in normal subjects and epileptic patients. Eur J Clin Pharmacol. 1982;23: 87-92.
134. Cook C, Amerson E, Pool W, et al. Phenytoin and phenobarbital concentrations in saliva and plasma measured by radioimmunoassay. Clin Pharmacol Ther. 1975;18:742-747.
135. Mucklow JC, Bending MR, Kahn GC, et al. Drug concentration in saliva. Clin Pharmacol Ther. 1978;24:563-570.
136. Nishihara K, Katsuyoski U, Saitoh Y, et al. Estimation of plasma unbound phenobarbital concentration by using mixed saliva. Epilepsia. 1979;20:37-45.
137. Friedman IM, Litt IF, Henson R, et al. Saliva phenobarbital and phenytoin concentrations in epileptic adolescents. J Pediatr. 1981;98: 645-647.
138. Herkes GK, Eadie MJ. Possible roles for frequent salivary antiepileptic drug monitoring in the management of epilepsy. Epilepsy Res. 1990;6: 146-154.
139. Neurvonen PJ. Bioavailability of phenytoin: clinical pharmacokinetic and therapeutic implications. Clin Pharmacokinet. 1979;4:91-103.
140. Richens A. Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet. 1979;4:153-169.
141. Nakajima M, Sakata N, Ohashi N, et al. Involvement of multiple UDP-glucuronosyltransferase 1A isoforms in glucuronidation of 5-(4'-hydroxyphenyl)-5-phenylhydantoin in human liver microsomes. Drug Metab Dispos. 2002;30:1250-1256.
142. Reynolds F, Ziroyanis PN, Jones NF, et al. Salivary phenytoin concentrations in epilepsy and in chronic renal failure. Lancet. 1976;II: 384-386.
143. Bachmann K, Forney RBJ, Voeller K. Monitoring phenytoin salivary and plasma utrafiltrates of pediatric patients. Ther Drug Monit. 1983;5: 325-329.
144. Knott C, Williams CP, Reynolds F. Phenytoin kinetics during pregnancy and the puerperium. Br J Obstet Gynaecol. 1986;93:1030-1037.
145. Lifshitz M, Ben-Zvi Z, Gorodischer R. Monitoring phenytoin therapy using citric acid-stimulated saliva in infants and children. Ther Drug Monit. 1990;12:334-338.
146. Liamsuwan S, Jaiweerawattana U. Correlation between serum and salivary phenytoin concentrations in Thai epileptic children. J Med Assoc Thai. 2011;94(suppl 3):S172-S177.
147. Kamali F, Thomas SHL. Effect of saliva flow rate on saliva phenytoin concentrations: implications for therapeutic monitoring. Eur J Clin Pharmacol. 1994;46:565-567.
148. Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia. 2004;45:13-18.
149. Wood DM, Berry DJ, Glover G, et al. Significant pregabalin toxicity managed with supportive care alone. J Med Toxicol. 2010;6:435-437.
150. Gallagher BB, Baumel IP, Mattson RH. Metabolic disposition of primidone and its metabolites in epileptic subjects after single and repeated administration. Neurology. 1972;22:1186-1192.
151. Bartels H, Gunther E, Wallis S. Flow-dependent salivary primidone levels in epileptic children. Epilepsia. 1979;20:431-436.
152. Hermann R, Ferron GM, Erb K, et al. Effects of age and sex on the disposition of retigabine. Clin Pharmacol Ther. 2003;73:61-70.
153. Ferron GM, Paul J, Fruncillo R, et al. Multiple-dose, linear, doseproportional pharmacokinetics of retigabine in healthy volunteers. J Clin Pharmacol. 2002;42:175-182.
154. Perucca E, Cloyd J, Critchley D, et al. Rufinamide: clinical pharmacokinetics and concentration-response relationships in patients with epilepsy. Epilepsia. 2008;49:1123-1141.
155. Wheless JW, Vazquez B. Rufinamide: a novel broad-spectrum antiepileptic drug. Epilepsy Curr. 2010;10:1-6.
156. Cardot JM, Lecaillon JB, Czendlik C, et al. The influence of food on the disposition of the antiepileptic rufinamide in healthy volunteers. Biopharm Drug Dispos. 1998;19:259-262.
157. Arroyo S. Rufinamide. Neurotherapeutics. 2007;4:155-162.
158. Sachdeo RC, Rosenfeld WE, Choi L, et al. Pharmacokinetics and safety of adjunctive rufinamide therapy in pediatric patients with epilepsy. Epilepsia. 1998;39(suppl 6):166-167.
159. Chiron C. Stiripentol. Neurotherapeutics. 2007;4:123-125.
160. Levy RH, Loiseau P, Guyot M, et al. Stiripentol kinetics in epilepsy: nonlinearity and interactions. Clin Pharmacol Ther. 1984;36:661-669.
161. Levy RH, Lin HS, Blehaut HM, et al. Pharmacokinetics of stiripentol in normal man: evidence of nonlinearity. J Clin Pharmacol. 1983;23:523-533.
162. Moreland TA, Astoin J, Lepage F. The metabolic fate of stiripentol in man. Drug Metab Dispos. 1986;14:654-662.
163. Farwell JR, Anderson GD, Kerr BM, et al. Stiripentol in atypical absence seizures in children: an open trial. Epilepsia. 1993;34:305-311.
164. Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomized placebo-controlled syndrome-dedicated trial. Lancet. 2000;356:1638-1642.
165. Gustavson LE, Mengel HB. Pharmacokinetics of tiagabine, a g-amino butyric acid-uptake inhibitor, in healthy subjects after single and multiple doses. Epilepsia. 1995;36:605-611.
166. Wang X, Patsalos PN. The pharmacokinetic profile of tiagabine. Rev Contemp Pharmacother. 2002;12:225-233.
167. Uthman BM, Rowan J, Ahmann PA, et al. Tiagabine for complex partial seizures. A randomized, add-on, dose-response trial. Arch Neurol. 1998;55:56-62.
168. Patsalos PN. The pharmacokinetic profile of topiramate. Rev Contemp Pharmacother. 1999;10:155-162.
169. Sachdeo RC, Sachdeo SK, Walker SA, et al. Steady-state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy during monotherapy and concomitant therapy. Epilepsia. 1996;37:774-780.
170. Britzi M, Perucca E, Soback S, et al. Pharmacokinetic and metabolic investigation of topiramate disposition in healthy subjects in the absence and in the presence of enzyme induction by carbamazepine. Epilepsia. 2005;46:378-384.
171. Cramer JA, Mattson RH, Bennett DM, et al. Variable free and total valproic acid concentrations in sole- and multi-drug therapy. Ther Drug Monit. 1986;8:411-415.
172. Perucca E, Gatti G, Frigo GM, et al. Disposition of sodium valproate in epileptic patients. Br J Clin Pharmacol. 1978;5:495-499.
173. Gorodischer R, Koren G. Salivary excretion of drugs in children: theoretical and practical issues in therapeutic drug monitoring. Dev Pharmacol Ther. 1992;19:161-177.
174. Abbott FS, Burton R, Orr J, et al. Valproic acid analysis in saliva and serum using selected monitoring (electron ionization) of the tertbutyldimethylsilyl derivatives. J Chromatogr. 1982;227:433-444.
175. Fung K, Ueda K. Saliva and serum valproic acid levels in epileptic children [letter]. J Pediatr. 1982;100:512.
176. Nitsche V, Mascher H. The pharmacokinetics of valproic acid after oral and parenteral administration in healthy volunteers. Epilepsia. 1982;23:153-162.
177. Richens A. Pharmacology and clinical pharmacology of vigabatrin. J Child Neurolol. 1991;6:2S7-2S10.
178. Haegele KD, Huebert ND, Ebel M, et al. Pharmacokinetics of vigabatrin: implications of creatinine clearance. Clin Pharmacol Ther. 1988; 44:558-565.
179. Patsalos PN, Duncan JS. The pharmacology and pharmacokinetics of vigabatrin. Rev Contemp Pharmacother. 1995;6:447-456.
180. Arteaga R, Herranz JL, Valdizen EM, et al. Gamma-vinyl-GABA (vigabatrin): relationship between dosage, plasma concentrations, platelet GABA-transaminase inhibition, and seizure reduction in children. Epilepsia. 1992;33:923-931.
181. Ito T, Yamaguchi T, Miyizaki H, et al. Pharmacokinetic studies of AD-810, a new antiepileptic compound. Arzneimittelforschung. 1982; 32:1581-1586.
182. Matsumoto K, Miyazaki H, Fujii T, et al. Absorption, distribution and excretion of 3-(sulfamoyl[14C]methyl)-1,2-benziosoxazole (AD-810) in rats, dogs and monkeys and of AD-810 in men. Arzneimittelfoeschung. 1983;33:961-968.
183. Buchanan RA, Bockbrader HN, Chang T, et al. Single- and multipledose pharmacokinetics of zonisamide. Epilepsia. 1996;37(suppl 5):172.
184. Kochak GM, Page JG, Buchanan RA, et al. Steady-state pharmacokinetics of zonisamide, an antiepileptic agent for treatment of refractory complex partial seizures. J Clin Pharmacol. 1998;38:166-171.
185. Mimaki T. Clinical pharmacology and therapeutic drug monitoring of zonisamide. Ther Drug Monit. 1998;20:593-597.
186. Jones MD, Ryan M, Miles MV, et al. Stability of salivary concentrations of the newer antiepileptic drugs in the postal system. Ther Drug Monit. 2005;27:576-579.
187. Mucklow JC, Dollery CT. Compliance with anticonvulsant therapy in a hospital clinic and community. Br J Clin Pharmacol. 1978;6:75-79.
188. Stanaway L, Lambie DG, Johnson RH. Non-compliance with anticonvulsant therapy as a cause of seizures. N Z Med J. 1985;98:150-152.
189. Zysset T, Rudeberg A, Vassella F, et al. Phenytoin therapy for epileptic children: evaluation of salivary and plasma concentrations and methods of assessing compliance. Dev Med Child Neurol. 1981;23:66-75.
190. Hamilton MJ, Cohen AF, Yuen AW, et al. Carbamazepine and lamotrigine in healthy volunteers: relevance to early tolerance and clinical trial dosage. Epilepsia. 1993;34:166-173.
191. Ball DE, McLaughlin WS, Seymour RA, et al. Plasma and saliva concentrations of phenytoin and 5-(4-hydroxyphenyl)-5-phenylhydantoin in relation to the incidence and severity of phenytoin-induced gingival overgrowth in epileptic patients. J Periodontol. 1996;67:597-602.
192. Aman MG, Werry JS, Paxton JW, et al. Effects of carbamazepine on psychomotor performance in children as a function of drug concentration, seizure type, and time of medication. Epilepsia. 1990;31:51-60.
193. Aman MG, Paxton JW, Field CJ, et al. Prevalence of toxic anticonvulsant drug concentrations in mentally retarded persons with epilepsy. Am J Ment Defic. 1986;90:643-650.
194. Djordjevic S, Kilibarda V, Vucinic S, et al. Toxicokinetics and correlation of carbamazepine salivary and serum concentrations in acute poisoning. Vosjnosanit Pregl. 2012;69:389-393.
195. Perucca E. Clinical pharmacokinetics of new generation antiepileptic drugs at the extremes of age. Clin Pharmacokinet. 2006;45:351-363.
196. Walson PD. Role of therapeutic drug monitoring (TDM) in pediatric anti-convulsant drug dosing. Brain Dev. 1994;16:23-26.
197. Hadjiloizou SM, Bourgeois BF. Antiepileptic drug treatment in children. Exp Rev Neurother. 2007;7:179-193.
198. Mucklow JC, Bacon CJ, Hierons AM, et al. Monitoring of phenobarbitone and phenytoin therapy in small children by salivary samples. Ther Drug Monit. 1981;3:275-277.
199. Cai WM, Zhu GZ, Chen G. Free phenytoin monitoring in serum and saliva of patients in China. Ther Drug Monit. 1993;15:31-34.
200. de Wildt SN, Kerkvliet KTM, Wazenberg MGA, et al. Use of saliva in therapeutic drug monitoring of caffeine in preterm infants. Ther Drug Monit. 2001;23:250-254.
201. Anderson GD. Pregnancy-related changes in pharmacokinetics: a mechanistic- based approach. Clin Pharmacokinet. 2005;44:989-1008.
202. Perucca E. Drug metabolism in pregnancy, infancy and childhood. Pharmacol Ther. 1987;34:129-143.
203. Pennell PB. Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology. 2003;61(suppl 2):S35-S42.
204. Knott C, Reynolds F. Value of saliva anticonvulsant monitoring in pregnancy and the newborn. J Clin Chem Clin Biochem. 1989;27: 227-228.
205. Cloyd JC, Lackner TE, Leppik IE. Antiepileptics in the elderly. Pharmacoepidemiology and pharmacokinetics. Arch Fam Med. 1994; 3:589-598.
206. Crooks J, Stevenson IH. Drug response in the elderly: sensitivity and pharmacokinetic considerations. Age Ageing. 1981;10:73-80.
207. Wallace SM, Verbeeck RK. Plasma protein binding of drugs in the elderly. Clin Pharmacokinet. 1987;12:41-72.
208. Hockings N, Pall A, Moody J, et al. The effect of age on carbamazepine pharmacokinetics and adverse effects. Br J Clin Pharmacol. 1986;22: 725-728.
209. Umstead GS, Morales M, McKercher PL. Comparison of total, free, and salivary phenytoin concentrations in geriatric patients. Clin Pharm. 1986;5:59-62.
210. Umstead GS, McKernan TM. Salivary phenytoin concentrations in geriatric patients. Clin Pharm. 1982;1:54-58.
211. Aronsen KF, Ekelund G, Kindmark CO, et al. Sequential changes of plasma proteins after surgical trauma. Scand J Clin Lab Invest Suppl. 1972;29:127-136.
212. Bowdle IA, Neal GD, Levy RH, et al. Phenytoin pharmacokinetics in burned rats and plasma protein binding of phenytoin in burned patients. J Pharmacol Exp Ther. 1980;213:97-99.
213. Martyn JAJ, Abernethy DR, Greenblatt DJ. Plasma protein binding of drugs after severe burn injury. Clin Pharmacol Ther. 1984;35:535-539.
214. Burger D, Meenhorst PL, Mulder JW, et al. Therapeutic drug monitoring of phenytoin in patients with acquired immunodeficiency syndrome. Ther Drug Monit. 1994;16:616-620.
215. Boggs JG. Elderly patients with systemic disease. Epilepsia. 2001;42 (suppl 8):18-23.
216. Perucca E. Free level monitoring of antiepileptic drugs. Clinical usefulness and case studies. Clin Pharmacokinet. 1984;9(suppl 1):71-78.
217. Asconape JJ, Penry JK. Use of antiepileptic drugs in the presence of liver and kidney diseases: a review. Epilepsia. 1982;23(suppl 1): S65-S79.
218. Al-Obaidy SS, Li Wan Po A, McKiernan PJ, et al. Assay of paracetamol and its metabolites in urine, plasma and saliva of children with chronic liver disease. J Pharm Biomed Anal. 1995;13:1033-1039.
219. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol. 2003;2:347-356.
220. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol. 2003;2:473-481.
221. Patsalos PN, Froscher W, Pisani F, et al. The importance of drug interactions in epilepsy therapy. Epilepsia. 2002;43:365-385.
222. Paxton JW. Effects of aspirin on salivary and serum phenytoin kinetics in healthy subjects. Clin Pharmacol Ther. 1980;27:170-178.
223. Perucca E, Hebdige S, Frigo GM, et al. Interaction between phenytoin and valproic acid: plasma protein binding and metabolic effects. Clin Pharmacol Ther. 1980;28:779-789.
224. Pisani FD, Di Perri RG. Intravenous valproate: effects on plasma and saliva phenytoin levels. Neurology. 1981;31:467-470.
225. Leonard RF, Knott PJ, Rankin GO, et al. Phenytoin-salicylate interaction. Clin Pharmacol Ther. 1981;29:56-60.
226. Knott C, Hamshaw-Thomas A, Reynolds F. Phenytoin-valproate interaction: importance of saliva monitoring in epilepsy. Br Med J. 1982; 284:13-16.
227. Geaney DP, Carver JG, Davies CL, et al. Pharmacokinetic investigation of the interaction of azapropazone with phenytoin. Br J Clin Pharmacol. 1983;15:727-734.
228. Bachmann K, Schwartz J, Forney R, et al. Single dose phenytoin clearance during erythromycin treatment. Res Commun Chem Pathol Pharmacol. 1984;46:207-217.
229. Perucca E, Albani F, Capovilla G, et al. Recommendations of the Italian League against Epilepsy working group on generic products of antiepileptic drugs. Epilepsia. 2006;47(suppl 5):16-20.
230. Berg MJ, Gross RA, Tomaszewski KJ. Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures. Neurology. 2008;71:525-530.
231. Fitzgerald CL, Jacobson MP. Generic substitution of levetiracetam resulting in increased breakthrough seizures. Ann Pharmacother. 2011;45:e27.
232. Backman E, Dahlstrom G, Eeg-Olofsson O, et al. The 24 hour variation of salivary carbamazepine and carbamazepine-10,11-epoxide concentrations in children with epilepsy. Pediatr Neurol. 1987;3:327-330.
233. Bachmann K, Schwartz J, Forney R, et al. Phenytoin as a probe of drug metabolism. Predicting clearance with a salivary sample. Pharmacology. 1985;30:145-152.
234. Cawello W, Boekens H, Nickel B, et al. Tolerability, pharmacokinetics, and bioequivalence of the tablet and syrup formulations of lacosamide in plasma, saliva, and urine: saliva as a surrogate of pharmacokinetics in the central compartment. Epilepsia. 2012. In press.
235. Hirji MR, Measuria H, Kuhn S, et al. A comparative study of the bioavailability of five different phenytoin preparations. J Pharm Pharmacol. 1985;37:570-572.
236. Ruiz ME, Conforti P, Fagiolino P, et al. The use of saliva as a biological fluid in relative bioavailability studies: comparison and correlation with plasma results. Biopharm Drug Dispos. 2010;31:476-485.
237. Kankirawatana P. Salivary antiepileptic drug levels in Thai children. J Med Assoc Thai. 1999;82:80-88.
238. Thieme T, Fitchen J, Bartos F, et al. Therapeutic drug monitoring using oral samples collected with the OraSure device. Ann N Y Acad Sci. 1993;694;337-339.
239. Schramm W, Annesley TM, Siegel GJ, et al. Measurement of phenytoin and carbamazepine in an ultrafiltrate of saliva. Ther Drug Monit. 1991; 13:452-460.
240. Schramm W, Smith RH. An ultrafiltrate of saliva collected in situ as a biological sample for diagnostic evaluation. Clin Chem. 1991;37:114-115.
241. O'Neal CL, Crouch DJ, Rollins DE, et al. Correlation of saliva codeine concentrations with plasma concentrations after oral codeine administration. J Anal Toxicol. 1999;23:452-459.
242. Crouch DJ. Oral fluid collection: the neglected variable in oral fluid testing. Forensic Sci Int. 2005;150:165-173.
243. Dickinson RG, Hooper WD, King AR, et al. Fallacious results from measuring salivary carbamazepine concentrations. Ther Drug Monit. 1985;7:41-45.
244. Ayers GJ, Burnett D. Drug formulation and salivary phenytoin measurements. Lancet. 1977;1:656.
245. Tennison M, Ali I, Miles MV, et al. Feasibility and acceptance of salivary monitoring of antiepileptic drugs via the US Postal Service. Ther Drug Monit. 2004;26:295-299.
246. Gorodischer R, Burtin P, Hwang P, et al. Saliva versus blood sampling for therapeutic drug monitoring in children: patient and parental preferences and economic analysis. Ther Drug Monit. 1994;16:437-443.
247. Baumann RJ, Ryan M, Yelowitz A. Physicians preference for antiepileptic drug concentration testing. Pediatr Neurol. 2004;30:29-32.
248. Bienvenu OJ, Eaton WW. The epidemiology of blood-injection-injury phobia. Psychol Med. 1998;28:1129-1136.
249. Liu H, Delgado M, Forman LJ, et al. Simultaneous determination of carbamazepine, phenytoin, phenobarbital, primidone and their principal metabolites by high performance liquid chromatography with photodiode- array detection. J Chromatogr. 1993;616:105-115.
250. Guo T, Oswald LM, Mendu DR, et al. Determination of levetiracetam in human plasma/serum/saliva by liquid chromatography-electrospray tandem mass spectrometry. Clin Chim Acta. 2007;375:115-118.
251. Saracino MA, Tallarico K, Raggi MA. Liquid chromatographic analysis of oxcarbazepine and its metabolites in plasma and saliva after a novel microextraction by packed sorbent procedure. Anal Chim Acta. 2010; 661:222-228.
252. Tonic-Ribarrska J, Haxhiu A, Sterjev Z, et al. Development and validation of bioanalytical LC-UV method with solid-phase extraction for determination of valproic acid in saliva. Acta Pharm. 2012;62:211-220.
253. Lenn JN, RobertsonM. Clinical utility of unbound antiepileptic drug blood levels in the management of epilepsy. Neurology. 1992;42:988-990.