December 1‘15“, Vol. 25, N0. 6 (pp. 425-532}
`ISSN: “312-5963
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`LEADING ARTICLE
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`Once—Daily Aminoglycosides
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`REVIEW ARTICLES
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`Lamotrigine Kinetics
`Interactions with Antimicrobials
`
`Antirheumatic Drugs in Pregnancy
`
`ORIGINAL RESEARCH ARTICLES
`
`Time and Theophylline
`Theopliylline Target Concentrations
`Salicylates in Malnomished Children
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`Clinical
`Pharmacokinetics
`
`Page 1
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`all
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`In
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`IPR2015-00410
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`

`

`V91...2_5_,sz-6,_1993
`
`Clinical
`_ maCOkImE—FHCS
`
`425-426
`
`From the Editor
`
`LEADING ARTICLE
`
`427-432
`
`Atninoglycoside Dosage Regimens: Is Once a Day Enough?
`Hasn'nx WMN. Hometown l'M
`
`433-443
`
`444-449
`
`REVIEW ARTICLES
`
`pkuo DlSEOSITION
`Lamotrigine Clinical Pharmacokinetics
`Rambeck B, Wolf P
`
`CLINICAL PHARMACOKINETICS AND DISEASE PROCESSES
`
`Clinical Pharmacokinetics in the Treatment of Rheumatoid Arthritis
`in Pregnancy
`Witter FR
`
`Pi-IARMACOKIN ETIC DRUG INTER ACTIONS
`
`450-432
`
`Pharmacokinetic Drug Interactions with Antimicrobial Agents
`Gt‘flnm JG, Israel 05. Polk RE
`
`ORIGINAL RESEARCH ARTICLES
`
`483-494
`
`495-505
`
`506-515
`
`Disposition of Salicylic Acid in Malnourished Ethiopian Children
`after Single Oral Dose
`Ashton M, Botme R Zerilmn G, Hofmberg K. Paalzow [K
`
`Theophylline Target Concentration in Severe Airways Obstruction —
`10 or 20 mgt’L'?
`Hotford N. Block P. Conch R. Kennedy .1. Brian: R
`
`Time and Theophylline Concentration Help Explain the Recovery
`of Peak Flow Following Acute Airways Obstruction
`Holfi'trd N3 Hashimoto I; Sheiner LB
`
`516-518
`
`Cumulated Contents
`
`519-532
`
`Subject Index I993
`
`Clinical Pitarmnookt'nen'cs is indexed in Current Contents'. ‘lndex Medicus‘ and 'Excerpla Medica‘.
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`I
`
`IPR2015—00410
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`

`International Editorial Board:
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`IPR2015-00410
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`DRUG DISPOSITION
`
`Clin. Phannacokinet. 25 (6): 433-443, 1993
`0312-5963/93/00 12-0433/$05 .50/0
`© Adis International Limited. All rights reserved.
`
`Lamotrigine Clinical Pharmacokinetics
`
`Bernhard Rambeck and Peter Wolf
`
`Epilepsy-Centre Bethel and Department of Biochemistry, Gesellschaft fUr Epilepsieforschung,
`Bielefeld, Federal Republic of Germany
`
`Contents
`433
`434
`434
`434
`435
`435
`435
`435
`436
`437
`437
`437
`438
`438
`438
`438
`439
`439
`440
`440
`441
`
`Summary
`
`Summary
`1. Physicochemical Properties of Lamotrigine
`2. Analytical Methods
`2.1 High Performance Liquid Chromatography
`2.2 Immunoassays
`3. Pharmacokinetic Properties
`3.1 Absorption
`3.2 Distribution
`3.3 Elimination
`3.4 Autoinduction
`4. Pharmacokinetics in Special Groups
`4.1 Healthy Volunteers and Nonepileptic Patients
`4.2 Adults with Epilepsy
`4.3 Children with Epilepsy
`5. Drug Interactions
`5.1 Effect of Other Drugs on Lamotrigine
`5.2 Effect of Lamotrigine on Other Drugs
`5.3 Pharmacodynamic Interactions
`6. Drug Monitoring
`7. Safety and Adverse Events
`8. Therapeutic Implications
`
`Lamotrigine is a new antiepileptic agent chemically unrelated to any established drugs in use.
`The drug can be estimated in biological fluids by high performance liquid chromatography and
`immunoassays. It is rapidly absorbed, reaching peak: concentrations within about 3 hours postdose.
`The bioavailability of the oral formulation is about 98%. The area under the plasma concentra(cid:173)
`tion-time curve indicates dose-linear pharmacokinetics. The degree of plasma protein binding is
`56%. Saliva concentrations are 46% of the plasma concentration. The concentration oflamotrigine
`in the brain is similar to the total concentration in the plasma.
`Lamotrigine exhibits first-order linear kinetics during long term administration. 43 to 87% of
`a dose is recovered in the urine, predominantly as glucuronide metabolites. Mean half-lives of
`lamotrigine in healthy volunteers (single and multiple doses) as well as in epileptic patients
`receiving lamotrigine monotherapy range from 22.8 to 37.4 hours. Enzyme-inducing antiepileptic
`drugs such as phenytoin, phenobarbital (phenobarbitone) or carbamazepine reduce the half-life
`
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`434
`
`c/in. Pharmacokinet. 25 (6) 1993
`
`of lamotrigine (to mean values of 13.5 to 15 hours), whereas valproic acid increases the half-life
`of the drug (to mean values of 48.3 to 59 hours). Lamotrigine itself does not influence the plasma
`concentrations of concomitant antiepiJeptic drugs, except for causing an increase in concentrations
`of carbamazepine-lO, II-epoxide, the main metabolite of carbamazepine. Other observations in(cid:173)
`dicate that the interaction of carbamazepine and lamotrigine may be primarily pharmacodynamic
`rather than pharmacokinetic.
`Usual dosages of lamotrigine range from 50 to 400 mg/day depending on an enzyme-inducing
`or -inhibiting comedication. Therapeutic plasma concentrations of the drug are not known, but a
`putative therapeutic range of I to 4 mglL has been proposed. Some patients have tolerated con(cid:173)
`centrations > I 0 mglL with benefit and without clinical toxicity. The value of measuring the con(cid:173)
`centrations of lamotrigine in helping to optimise the dosage or reduce the likelihood of adverse
`effects has not been established. Safety data from several large studies indicate that the incidence
`of adverse effects of the drug is low and that unwanted effects are reversible.
`
`Lamotrigine (BW 430C, Well come Research
`Laboratories) is a new antiepileptic drug. It is a
`phenyItriazine unrelated to any established antiepi(cid:173)
`leptic drug (fig. 1). Its discovery was due to the
`hypothesis that the disturbances of folate metabo(cid:173)
`lism produced by antiepileptic drugs such as
`phenytoin or phenobarbital (phenobarbitone)
`could be related to their anticonvulsant properties.
`Studying a series of folate antagonists for possible
`anticonvulsant effects a group of phenyltriazines
`was investigated. Some substances with clear anti(cid:173)
`convulsant actions in experimental models but
`with only weak antifolate properties were found.
`From this group of phenyltriazines lamotrigine was
`further developed.
`Lamotrigine seems to act by a phenytoin-like
`membrane-stabilising mechanism, namely block(cid:173)
`ade of voltage-sensitive sodium channels and inhi(cid:173)
`bition of glutamate release (Cheung et al. 1992;
`Leach et al. 1986).
`The efficacy of lamotrigine as add-on therapy
`(added to existing therapy) against focal and
`
`generalised tonic-clonic seizures has been demon(cid:173)
`strated in a series of double-blind, placebo-control(cid:173)
`led, crossover trials (Binnie et al. 1986; Jawad et
`al. 1989; Loiseau et al. 1990; Risner 1990; Sander
`et al. 1990) in 283 people with refractory epilepsy
`(Brodie 1992). Daily doses of lamotrigine in these
`trials varied from 120 to 240mg (Binnie et al.
`1986), 75 to 400mg (Jawad et al. 1989), 100 to
`300mg (Sander et al. 1990), 150 to 300mg (Loiseau
`et al. 1990) and 100 to 400mg (Risner 1990). For
`a review of lamotrigine pharmacology and thera(cid:173)
`peutic use, see Goa et al. (1993).
`
`1. Physicochemical Properties
`of Lamotrigine
`
`Lamotrigine is a white, chemically stable pow(cid:173)
`der that is poorly soluble in both water and ethanol.
`The solubility in water is 1 giL and in ethanol is "" 1
`giL. The molecular weight is 256.09D, and the
`drug has a pKa of 5.5. The conversion factor is
`3.90; i.e. concentrations in mg/L, when multiplied
`by 3.90 give the concentration in IlmoleslL.
`
`CI
`
`2. Analytical Methods
`
`In biological fluids lamotrigine can be esti(cid:173)
`mated by high performance liquid chromatography
`(HPLC) and immunoassays.
`
`2.1 High Performance Liquid Chromatography
`
`Fig. 1. Structure of iamotrigine.
`
`One of the first HPLC methods for the analysis
`
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`Lamotrigine Clinical Pharmacokinetics
`
`435
`
`of lamotrigine in serum samples was developed by
`Land and co-workers, using an ethyl acetate extrac(cid:173)
`tion of the alkalinised samples and separation on a
`silica gel column (Cohen et al. 1987). The sample
`pretreatment methods and HPLC separation were
`modified by Juergens et al. (1987), who used re(cid:173)
`versed phase HPLC columns for the separation of
`the analytes and solid phase extraction on C-18
`cartridges, or liquid-liquid extraction with Ex(cid:173)
`trelut® cartridges. The separation of lamotrigine
`from other antiepileptic drugs by reversed-phase
`chromatography with a basic phosphate buffer (pH
`9) containing triethylamine or n-butylamine was
`performed by Juergens (1988).
`Cociglio et al. (1991) describe a reversed-phase
`column liquid chromatographic assay for lamotri(cid:173)
`gine. The drug and an internal standard were ex(cid:173)
`tracted from plasma into acetonitrile, separated on
`a LiChrospher® 100CN column and measured by
`ultraviolet absorption at 280nm.
`Fazio et al. (1992) developed a sensitive, spe(cid:173)
`cific and rapid HPLC method for the determination
`of lamotrigine. The drug and an internal standard
`were extracted with ethyl acetate after alkalinisa(cid:173)
`tion, and analysed using a high-speed column. The
`detector wavelength was 313nm.
`Sinz and Remmel (1991a) described the analy(cid:173)
`sis of lamotrigine and lamotrigine 2-N-glucuronide
`in guinea-pig blood and urine by reversed phase
`ion-pairing liquid chromatography. The extraction
`procedure and reversed-phase HPLC assay em(cid:173)
`ployed sodium dodecylsulphate as an ion-pairing
`reagent to selectively separate lamotrigine and
`lamotrigine-2-N-glucuronide from endogenous
`blood components, and from other antiepileptic
`drugs and their metabolites. The same assay sys(cid:173)
`tem has also been applied to human urine, blood
`and brain tissue.
`
`2.2 Immunoassays
`
`Sailstadt and Findlay (1991) developed an im(cid:173)
`munofluorometric assay for
`the analysis of
`lamotrigine in plasma samples collected during
`clinical trials. The assay involves competition, for
`a limited amount of lamotrigine antisera, between
`
`lamotrigine free in solution and bound to a bovine
`thyroglobulin conjugate on the surface of micro(cid:173)
`titre strip wells.
`A radioimmunoassay to determine human
`plasma lamotrigine is described by Biddlecombe
`et al. (1990). The method is a direct double anti(cid:173)
`body procedure employing a rabbit polyc1onal first
`antibody raised to a bovine serum albumin conju(cid:173)
`gate of lamotrigine, and an iodinated tyrosine
`methyl ester of lamotrigine as the tracer.
`
`3. Pharmacokinetic Properties
`3.1 Absorption
`
`In healthy volunteers, single and multiple doses
`of lamotrigine of up to 240 mg/day have shown
`rapid absorption, with a mean ± SD time of peak
`concentration 2.8 ± 1.3 hours postdose (Cohen et
`al. 1987).
`The absolute bioavailability of lamotrigine was
`examined in a combined intravenous and oral
`study in 8 volunteers (Yuen & Peck 1988).
`Lamotrigine 75mg administered orally was com(cid:173)
`pared with 67 .8mg intravenously given by infusion
`over 30 minutes. The absolute bioavailability of
`the oral formulation was 0.98 ± 0.05.
`
`3.2 Distribution
`
`The plasma protein binding of lamotrigine and
`its possible perturbation by phenobarbital,
`phenytoin and valproic acid have been studied in
`vitro by equilibrium analysis (Miller et al. 1986).
`The degree of plasma protein binding was 56%,
`constant over a concentration range which encom(cid:173)
`passes the anticipated therapeutic range of 1 to 4
`mg/L, and unaffected by therapeutic concentra(cid:173)
`tions of phenytoin, phenobarbital or valproic acid.
`Remmel et al. (1992) assessed the ability of
`lamotrigine and its glucuronide to penetrate the
`blood-brain barrier in a 10-year-old epileptic pa(cid:173)
`tient who underwent a frontal topectomy to remove
`seizure-causing foci in the cerebral cortex approx(cid:173)
`imately 4 hours after the last lamotrigine dose. The
`concentration oflamotrigine in the brain (4.2Ilg/g)
`was higher than the unbound concentration in
`
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`436
`
`Clin. Pharmacokinet. 25 (6) 1993
`
`Table I. Mean (± SO) elimination half-life (t.,,;) of lamotrigine
`
`Reference
`
`Study participants
`
`No.
`
`Binnie et al. (1986)
`
`Epileptic patients
`
`Cohen et al. (1987)
`
`Healthy volunteers
`
`Depot et al. (1990)
`
`Healthy volunteers
`
`Jawad et al. (1987)
`
`Epileptic patients
`
`Posner et al. (1989)
`
`Volunteers with
`Gilbert's syndrome
`
`Controls
`
`Posner et al. (1991a)
`
`Healthy volunteers
`
`mean age 71y
`
`mean age 31y
`
`Ramsay et al. (1991)
`
`Epileptic patients
`
`Yuen et al. (1992)
`
`Healthy volunteers
`
`9
`
`4
`
`10
`
`10
`
`8
`
`8
`
`9
`
`13
`
`7
`
`9
`
`12
`
`12
`
`8
`
`6
`
`8
`
`Comedication
`
`CBlor PT
`
`VPA
`
`Paracetamol (acetaminophen)
`
`CBl, PTorPB
`
`CBl, PT or PB + VPA
`
`Single/multiple
`dose
`
`Single dose
`
`Single dose
`
`Single dose
`
`Multiple doses
`
`Single dose
`
`Single dose
`
`Single dose
`
`Single dose
`
`Single dose
`
`Single dose
`
`Single dose
`
`Single dose
`
`Multiple doses
`
`CBl, PTorPB
`
`t.,,;
`(h)
`
`15.0 (7.8-33.3)
`
`59.0 (30.5-88.8)
`
`24.1±5.7
`
`25.5± 10.2
`
`35.7 ± 9.3
`
`30.2 ± 7.3
`
`14.3 ± 6.5
`
`29.6 ± 10.0
`
`31.2±7.4
`
`22.8 ± 4.4
`
`31.2±5.4
`
`24.9 ± 9.3
`
`13.5 ± 4.9
`
`37.4 ± 15.7
`
`Single dose
`
`Single dose
`
`Paracetamol (acetaminophen)
`
`30.2± 7.3
`
`Abbreviations: y = years; CBl = carbamazepine; PT = phenyloin; PB = phenobarbital (phenobarbitone); VPA = valproic acid.
`
`plasma (2.64 mglL). Concentrations oflamotrigine
`glucuronide were very low in the brain (0.05 I1g/g).
`
`3.3 Elimination
`
`Mikati et al. (1989) performed a pharmacoki(cid:173)
`netic study of lamotrigine with 4 adult males with
`resistant focal seizures. The drug appeared to ex(cid:173)
`hibit first-order linear kinetics during long term ad(cid:173)
`ministration. 43 to 87% of the dose was recovered
`in the urine, predominantly as the glucuronide me(cid:173)
`tabolite.
`Sinz and Remmel (1991b) isolated and charac(cid:173)
`terised a quaternary ammonium-linked glucuron(cid:173)
`ide of lamotrigine from human urine. The structure
`of the compound was proven as lamotrigine 2-N(cid:173)
`glucuronide by mass spectroscopy and nuclear
`magnetic resonance spectrometry, along with
`chemical and enzymatic hydrolysis studies.
`Doig and Clare (1991) used thermos pray liquid
`chromatography-mass spectrometry and HPLC
`
`with radiochemical detection to allow the struc(cid:173)
`tural elucidation of a number of urinary metabo(cid:173)
`lites of lamotrigine. In human 24-hour urine sam(cid:173)
`ples the percentage of radioactivity found as
`lamotrigine was 7 to 30%, as the 2-N-glucuronide
`was 80 to 90%, as (probably) 5-N-glucuronide was
`10%, 2-N-oxide was 0 to 5%, and as a 2-N-meth(cid:173)
`ylated metabolite was 0 to 5%.
`The metabolism of lamotrigine was further
`characterised in human liver microsomes by Mag(cid:173)
`dalou et al. (1992). The glucuronidation on the N-2
`atom of the triazine ring, leading to a quaternary
`ammonium-linked glucuronide, proceeded with an
`apparent minimum rate of metabolism (V max) of
`0.65 nmol/min/mg and a Michaelis-Menten con(cid:173)
`stant (Km) of 2.56 mmollL. The average value of
`lamotrigine glucuronidation in 4 human samples of
`transplantable liver was 0.43 ± 0.14 nmol/minlmg,
`thus indicating a large interindividual variation.
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`Lamotrigine Clinical Pharmacokinetics
`
`437
`
`3.4 Autoinduction
`
`Richens (1992) described indications of au(cid:173)
`toinduction of the metabolism of lamotrigine. This
`occurred, however, in the early stages of treatment,
`when the plasma concentrations are rising to
`steady-state. It was thus concluded that such an
`effect was without clinical relevance.
`Pharmacokinetic data, which are further dis(cid:173)
`cussed in sections 4 and 5, are summarised in tables
`I and II.
`
`4. Pharmacokinetics in Special Groups
`4.1 Healthy Volunteers and
`Nonepileptic Patients
`
`Cohen et al. (1987) investigated the pharmaco(cid:173)
`kinetics of lamotrigine in 3 studies in healthy vol(cid:173)
`unteers. In the first study, 5 volunteers received
`oral doses of lamotrigine up to 240mg. A linear
`relationship was observed between the adminis(cid:173)
`tered dose and both the peak concentration (C max )
`and the area under the plasma concentration-time
`
`Table II. Mean (± SD) pharmacokinetic properties of lamotrigine
`
`Parameter
`
`Value
`
`Reference
`
`Time to peak
`concentration
`
`Bioavailability
`
`Volume of
`distribution
`
`Plasma protein
`binding
`
`Saliva/plasma
`concentration ratio
`
`Oral clearance
`
`Elimination half-life
`
`Excretion
`
`Percentage of dose
`in urine
`
`Tentative
`therapeutic plasma
`concentration
`
`2.8 ± 1.3 hours
`
`Cohen et al. (1987)
`
`0.98 ± 0.05
`
`Yuen et al. (1988)
`
`1.2±0.12Ukg
`
`Cohen et al. (1987)
`
`56%
`
`0.46
`
`Miller et al. (1986)
`
`Cohen et al. (1987)
`
`41 .7 ± 10.3 ml/min Cohen et al. (1987)
`(2.5 ± 0.62 Uh)
`
`22.8-59.0 hours
`depending on
`comedication
`
`First-order linear
`pharmacokinetics
`
`Various authors -
`see table I
`
`Mikati et al. (1989)
`
`43-87%
`
`Mikati et al. (1989)
`
`1-4 mglL
`
`Various authors
`
`curve (AVC). In a second study, 10 volunteers re(cid:173)
`ceived lamotrigine 120mg. The mean ± SD elimi(cid:173)
`nation half-life (V/2) was 24.1 ± 5.7 hours, the mean
`volume of distribution adjusted for bioavailability
`was 1.2 ± 0.12 Llkg, and mean oral clearance was
`41.7 ± 10.3 ml/min (2.5 ± 0.62 Llh). Saliva con(cid:173)
`centrations were 46% of the plasma concentration
`for the samples taken during the single-dose study.
`Total urinary recovery of drug over 144 hours was
`70.5% of the oral dose. A glucuronide conjugate
`accounted for 89.4% of the urinary recovery. In a
`third study the pharmacokinetics of repeated ad(cid:173)
`ministration was studied. 15 volunteers were
`randomised to lamotrigine (n = 10) or placebo (n =
`5) and received multiple doses over 7 days. The
`overall plasma elimination t1;2 calculated from data
`during the 7 days was 25.5 ± 10.2 hours. Observed
`pharmacokinetics on multiple administration
`obeyed closely those predicted from the single(cid:173)
`dose experiment, suggesting the absence of au(cid:173)
`toinduction of metabolism. Subsequent studies
`showed that the linear relationship between dose
`and both AVC and Cmax extended to 450mg in vol(cid:173)
`unteers and 700mg at steady-state in patients (Peck
`1991).
`Posner et al. (l991a) compared the pharmaco(cid:173)
`kinetics of lamotrigine in 2 groups of healthy vol(cid:173)
`unteers; 12 volunteers with a mean age of 71 years
`and 12 with a mean age of 31 years. Mean values
`of Cmax and AVC were 27 and 55% higher, respec(cid:173)
`tively, in the elderly than in the young. Mean ap(cid:173)
`parent clearance was 37% lower and apparent vol(cid:173)
`ume of distribution 12% lower in the elderly. Mean
`elimination t1;2 was 6.3 hours longer, at 31.2 ± 5.4
`hours, in the elderly individuals. The age-related
`differences were thought to be due to diminished
`glucuronidation in the elderly.
`Posner et al. (1989) studied the pharmacokinet(cid:173)
`ics of lamotrigine in volunteers with unconjugated
`hyperbilirubinaemia (Gilbert's syndrome). In
`those with Gilbert's syndrome, mean oral clear(cid:173)
`ance was 32% lower and the plasma t1;2 was 37%
`higher than in healthy controls [30.2 ± 7.7 vs 44.2
`± 7.5 ml/min (1.81 ± 0.46 vs 2.65 ± 0.45 L/h), and
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`Clin. Pharmacokinet. 25 (6) 1993
`
`31.2 ± 7.4 vs 22.8 ± 4.4 hours, respectively). The
`amount of unchanged lamotrigine excreted in the
`urine was 30% higher in the volunteers with Gil(cid:173)
`bert's syndrome. It is unlikely that this impairment
`of lamotrigine elimination is clinically important.
`
`4.2 Adults with Epilepsy
`
`Ramsay et al. (1991) studied pharmacokinetics
`of lamotrigine in patients receiving stable re(cid:173)
`gimens of antiepileptic drugs. AUC values in(cid:173)
`creased linearly with dose. Mean tV2 (13.5 hours),
`volume of distribution (1.36 L/kg) and clearance
`(1.27 mllmin/kg) did not change with increasing
`dose. The findings indicate that lamotrigine phar(cid:173)
`macokinetics can be described by a I-compartment
`model and that the drug has linear kinetics. Unlike
`the findings of Richens (1992), it seemed that the
`drug did not to induce its own metabolism in pa(cid:173)
`tients receiving concomitant antiepileptic drugs.
`Further pharmacokinetic data in epileptic pa(cid:173)
`tients are discussed in connection with drug inter(cid:173)
`actions (section 5).
`
`4.3 Children with Epilepsy
`
`Since there is insufficient experience in chil(cid:173)
`dren, the use of lamotrigine is not yet recom(cid:173)
`mended in this population, even in the UK and Ire(cid:173)
`land, where lamotrigine is already licensed (Brodie
`1992). Correspondingly, data on pharmacokinetics
`in children are not available.
`
`5. Drug Interactions
`5.1 Effect of Other Drugs on Lamotrigine
`
`Binnie et al. (1986) reported on short term ef-
`fects of a single dose of lamotrigine in 16 persons
`with epilepsy. Comedication with carbamazepine
`and/or phenytoin reduced the tV2 to a mean of 15
`hours (range 7.8 to 33.3 hours) and comedication
`with valproic acid prolonged the tl/2 to a mean of 59
`hours (range 30.5 to 88.8 hours).
`Jawad et al. (1987) performed an open study of
`4 weeks' duration with 23 residential patients of an
`epilepsy centre receiving long term antiepileptic
`drugs. Patients receiving lamotrigine together with
`
`liver enzyme-inducing anti epileptic drugs showed
`a mean lamotrigine plasma elimination tV2 of 14 ±
`7 hours. Those receiving lamotrigine plus an in(cid:173)
`ducing antiepileptic drug plus valproic acid exhib(cid:173)
`ited a mean lamotrigine tl/2 of 30 ± lO hours.
`As a consequence of the shortened half-life of
`lamotrigine in patients comedicated with enzyme(cid:173)
`inducing drugs, higher circadian fluctuations of
`lamotrigine serum concentrations might be ex(cid:173)
`pected. Wolf (1992) determined the lamotrigine
`pharmacokinetic profiles of 7 patients receiving
`enzyme-inducing comedication, and of 1 patient
`receiving valproic acid plus carbamazepine com(cid:173)
`edication. High fluctuations were observed in all
`patients receiving enzyme-inducing drugs; the
`peak: trough concentration ratios ranging from 1.6
`to 2.3. In the only patient receiving valproic acid
`plus lamotrigine and carbamazepine the fluctua(cid:173)
`tions were low (ratio 1.26 with lamotrigine 150
`mg/dayand 1.13 with lamotrigine 300 mg/day).
`To examine the inhibition of the lamotrigine
`metabolism by valproic acid, Yuen et al. (1992)
`studied 6 healthy volunteers who received lamo(cid:173)
`trigine as a single dose alone or together with
`valproic acid. Concomitant administration of
`valproic acid reduced lamotrigine total clearance
`by approximately 21 % and increased the elimina(cid:173)
`tion tl/2 and AUe. Renal elimination of lamotrigine
`was not impaired. The investigators explained this
`effect by hepatic competition for glucuronidation
`between valproic acid and lamotrigine.
`These interactions with lamotrigine are re(cid:173)
`flected in dosage patterns. Betts et al. (1991) re(cid:173)
`viewed the major completed trials with lamotri(cid:173)
`gine, showing that most patients (68%, n = 389)
`received lamotrigine dosages in the range of 200
`to 400 mg/day, with most of the remainder (30%,
`n = 174) receiving only 50 to 150 mg/day. In their
`opinion, this pattern reflects 2 major patient
`groups, i.e. those receiving liver enzyme-inducing
`antiepileptic drugs without valproic acid and those
`receiving inducing drugs plus valproic acid.
`Depot et al. (1990) studied the pharmacokinetic
`effects of multiple oral doses of the analgesic and
`antipyretic drug paracetamol (acetaminophen) on
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`Lamotrigine Clinical Pharmacokinetics
`
`439
`
`a single oral dose of lamotrigine in healthy volun(cid:173)
`teers. AVC and t'l2 values of lamotrigine were de(cid:173)
`creased by 20% (p < 0.01) and 15% (p < 0.01),
`respectively, when concurrently administered with
`paracetamol. There was no significant difference
`in the Cmax or the time to reach Cmax . The percent(cid:173)
`age of the lamotrigine dose recovered in the urine
`was significantly higher during paracetamol treat(cid:173)
`ment (65.9 ± 12.3% vs 72.5 ± 5.7%). Thus,
`paracetamol
`increases
`lamotrigine clearance
`through a yet to be determined mechanism.
`
`5.2 Effect of Lamotrigine on Other Drugs
`
`The plasma concentrations of concomitant
`valproic acid, phenytoin, carbamazepine, pheno(cid:173)
`barbital or primidone were unaltered by I week of
`lamotrigine administration in 23 patients examined
`by Jawad et al. (1987).
`Loiseau et al. (1990) reported a randomised
`double-blind placebo-controlled add-on trial of
`lamotrigine in 23 patients with treatment-resistant
`focal seizures. Plasma concentrations of concomi(cid:173)
`tant antiepileptic drugs (phenytoin, carbamaze(cid:173)
`pine, phenobarbital) remained unchanged. Sander
`et al. (1990) performed a randomised double-blind
`placebo-controlled add-on trial of lamotrigine in
`21 patients with severe epilepsy. Concomitant se(cid:173)
`rum antiepileptic drug concentrations (carbamaze(cid:173)
`pine, phenytoin, valproic acid and phenobarbital)
`were unaffected by lamotrigine treatment.
`Jawad et al. (1989) assessed the antiepileptic
`effects of lamotrigine in a double-blind, placebo(cid:173)
`controlled crossover trial in 24 adult patients with
`refractory focal seizures. No statistically signifi(cid:173)
`cant changes
`in plasma concentrations of
`phenytoin, carbamazepine, primidone or pheno(cid:173)
`barbital were found between the 2 treatment peri(cid:173)
`ods.
`These results are confirmed by an investigatio