Pharmacokinetics and safety of lamotrigine (Lamictal®) in patients with epilepsy

Epilepsy Res., 10 (1991) 191-200

191

Elsevier EPIRES 00438

Pharmacokinetics and safety of lamotrigine (Lamictal ®) in patients with epilepsy R. E u g e n e R a m s a y a, J o h n M. PeUock b, William R. G a r n e t t c, R a m o n M. Sanchez a, A n t o n i a M. Valakas d, William A. W a r g i n d, A l l e n A. Lai d, J a m e s H u b b e l l d, W . H . C h e r n d, T h u r m a n Allsup d and Vicky O t t o d aDepartment of Neurology, Universityof Miami and Miami VeteransAdministration Medical Center, bDepartmentsof Neurology and Pediatrics, CDepartmentof Pharmacy and Pharmaceutics, MedicalCollegeof Virginia, Virginia Commonwealth Universityand dBurroughs WeUcomeCo., Research TrianglePark, NC (U.S.A.) (Received 17 January 1991; revision received 12 September 1991; accepted 13 September 1991)

Key words: Epilepsy; Experimental drug; Pharmacokinetics; Safety; Lamotri#one; Lamictal

In a double-blind parallel study, patients with epilepsy on stable regimen of antiepileptic drugs (AEDs) were #oven lamotri#one (8 pts) or placebo (3 pts). Patients were sequentially dosed with 100, 200 and 300 rag/day #oven as a b.i.d, regimen. After steady state was achieved, timed plasma lamotri#one levels were obtained post dose. No medical, psychogenic, neurolo#oc , or hematologic changes were observed and no subjective effects were detected as a result of treatment with lamotri#one. No changes in heart rhythm or blood pressure were observed related to lamotri#one. Pharmacokinetic parameters were calculated using 1-compartment and non-compartment models. The results were similar using both models. Area under the plasma concentration vs. time curves increased linearly with dose. Mean half life (13.5 h), volume of distribution (1.36 l/kg) and clearance (1.27 ml/min/kg) were similar to previously reported results and did not change with increasing dose. These findings indicate that lamotri#one pharmacokinetics can be described by the 1compartment model, has linear kinetics, and does not induce its own metabolism in patients on concomitant AEDs.

INTRODUCTION Lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)astriazine, LTG) is a chemically novel compound unrelated to any currently marketed antiepileptic drugs (AEDs). In vitro studies suggest lamotrigine (Lamictal®) stabilizes neuronal membranes and inhibits neurotransmitter release Correspondence to: R. Eugene Ramsay, M.D., Department of Neurology (127), Veterans Administration Medical Center, 1201 NW 16th Street, Miami, FL 33125, U.S.A. Tel.: (305) 324-3192.

through effects on voltage sensitive sodium channels16. It has an effect similar to carbamazepine (CBZ) and phenytoin (PHT) against maximal electroshock (MES) and pentylenetetrazol induced hindlimb extension. The EDs0 in single dose experiments ranged from 1.9 to 3.9 mg/kg in rats. Lamotrigine was more effective on a mg/kg basis than either PHT or CBZ and should be effective in tonic clonic and partial seizures19,2°. A significant reduction in interictal spike activity was found following a single dose of 240 mg and correlated with plasma levels of 2.2-2.7/zg/ml n. Chronic dose studies in humans suggest that the anticonvulsant

0920-1211/91/$03.50 ~) 1991 Elsevier Science Publishers B.V. All rights reserved

192 effect occurs with doses of 100-400 mg/day and plasma levels of 1-3 gg/ml 3-5'22. The pharmacokinetics of lamotrigine vary considerably among individuals and species. Plasma elimination half lives range from 2-4 h in beagle dogs to 12-52 h in cynomolgus monkeys22. In normal volunteers, mean peak lamotrigine plasma levels occurred 2-3 h after oral dosing. Protein binding, which is primarily to albumin, ranged from 40 to 60% in all animals tested (55% in man) and was not affected by other AEDs. The half life of elimination in man varied from 14 to 50 h when lamotrigine was administered alone 1°. AEDs which induce hepatic enzymes reduce the half life of lamotrigine by nearly 50%. The exception is valproic acid (VPA) which inhibits lamotrigine's metabolism, doubling its half life to 59 h 3. The enzyme inhibitory effect of VPA and the enzyme inducing effect of CBZ and PHT on the metabolism of lamotrigine are of similar magnitude. Therefore, the half life of lamotrigine during the co-administration of VPA and CBZ or PHT is essentially the same as that when LTG is administered alone. Trough levels of CBZ, PHT and VPA were not significantly affected by the co-administration of lamotrigine 13,17. Elimination is primarily by glucuronide conjugation in cynomolgus monkey and marmoset, metabolism to the 2-N-methyl metabolite in dog, and renal excretion of the unchanged parent drug in the rat (unpublished data, Burroughs Wellcome Co.). In beagle dogs, prolongation of the PR interval was found which was felt to be caused by the Nmethyl metabolite. Lamotrigine does not inhibit or induce hepatic enzymes involved in metabolism of other A E D s 13'17. In normal volunteers, approximately 70% of the oral dose was recovered in the urine of which 10% was lamotrigine and 90% was the 2-N-glucuronide metabolite 13. Trace amounts of the 2-N-methyl and the 5-N-glucuronide conjugate of lamotrigine have been isolated in urine of volunteers and patients (unpublished data, Burroughs Wellcome, Co.). In mice, ataxia was produced with doses 47 times the anticonvulsant ED50 against maximal electroshock (MES) while this ratio for PHT was 24. A dose 5 times the anticonvulsant dose (50 mg/kg) was necessary in marmosets to produce ataxia with

no adverse effects noted with lower doses 9. In mice, LTG has a wide margin between the MES EDs0 and the LDs019. The significant anticonvulsant effects in animals, good therapeutic index, and attractive pharmacokinetic profile of LTG led to the present study. The purposes were to evaluate, in patients with epilepsy concurrently taking AEDs, (1) the safety and chronic dose tolerance of lamotrigine up to 300 mg/day, (2) the pharmacokinetics of lamotrigine, and (3) whether the N-methylated metabolite of lamotrigine was present in plasma and urine. METHOD The study was conducted simultaneously at 2 centers (University of Miami and Virginia Commonwealth University, Medical College of Virginia) employing a double-blind, placebo-controlled, parallel design. Males or females of non-childbearing potential between the ages of 18 and 55 with either partial or generalized seizures were eligible to participate. Patients had to be on stable doses of marketed AEDs (excluding valproic acid) and have no more than 40 seizures per month. Patients with significant medical or psychiatric illnesses requiring treatment were excluded. Patients were randomly assigned (stratified by study center) in a ratio of 2:1 to receive lamotrigine or placebo. Protocols were reviewed and approved by institutional review boards and each patient signed an informed consent before inclusion in the study. Patients were admitted to a clinical pharmacology unit for the 28 days of the study. Doses of concurrent AEDs were kept constant. White capsules containing 50, 100 and 150 mg of lamotrigine and identically appearing placebo were formulated. Doses administered were 100 mg b.i.d, on day 1, 50 mg b.i.d, on days 2-5, 100 mg b.i.d, on days 6-12, 150 mg b.i.d, on days 13-25, 50 mg b.i.d, on days 26-27, and placebo on days 28-30. Experimental drug was given at 07.00 and 19.00 h. Concurrent AEDs were given 1 h or more before or after the dosing of lamotrigine. On days 5, 12 and 25 timed blood samples were obtained at 0, 1, 2, 4, 6, 8, 10 and 12 h after the morning lamotrigine dose. On days 1-4, 9, 13, 17 and 21, plasma lamotrigine

193 levels were drawn prior to and 4 h after the morning dose. During baseline and periodically during dosing, general physical and neurological examinations were done 2-3 h after the morning dose. On the same days, urinalysis, urine drug screen, serum chemistry and complete blood count were obtained and a 12 lead ECG was recorded. The patient completed the Visual Analog Scale6 at these times. Supine and standing blood pressures were obtained daily or every other day. At baseline and on study days 1-30, patients were questioned 12 h after the morning dose about any adverse events experienced during the day. ]'he investigators evaluated the intensity and severity of each report and assessed its relationship to the study drug. Lamotrigine plasma concentrations were determined using HPLC. 10 #1 of a solution containing 250 ng of internal standard (725C78) was added to 0.5 ml of plasma. Each sample was double extracted with 7.5 ml of methyl t-butyl ether:ethyl acetate (1:1). The organic layers were removed, combined and evaporated to dryness. The residue was dissolved in 200#1 of mobile phase (methylene chloride 1000 ml, methanol 50 ml, and 70% perchloric acid 100 gl). A normal phase silica column (5 #m Si-60 column from E.S. Industries) and UV detection at 265 nm were used. A calibration curve was generated by assaying plasma spiked with known lamotrigine concentrations ranging from 0.1 to 10.4 gg/ml. Plasma concentrations were calculated from regression parameters obtained from a least-squares regression of the log of the ratio of the lamotrigine peak area to the internal standard peak area versus the log of the spiking concentration. The peak area and concentration were linearly related. However, the calibration curve data were logarithmically transformed to normalize the variance and distribution of the residuals so that the data from high concentrations would not disproportionally affect the linear regression analysis. Total urinary concentration of LTG (unmetabolized drug and its 2-N-glucuronide metabolite) was determined following treatment of the urine with fl-glucuronidase. To a 0.1-ml sample of urine and 1 ml of pH 5.0 acetate buffer was added approximately 6 mg of fl-glucuronidase. Each sample was

placed in a 37°C water bath for 6 h. After 3 h, an additional 6 mg of ~-glucuronidase was added to each sample. After the incubation, 0.125 ml of 2 N sodium hydroxide was added, and each sample was extracted twice with t-butyl methyl ether/ethyl acetate (1:1). The organic layers were removed, combined, and evaporated to dryness. To each sample was added 1 ml of Tri-Sil/BSA in DMF and the samples were left at room temperature for 1 h. The samples were then diluted with toluene and analyzed by GC-EC. The injector and detector were set at 200°C and 300°C, respectively. The column (5 m DB 0.32 mm ID with a helium flow rate of 1.5 ml/min) temperature was set at 100°C for 1 rain, then programed to 220°C at 25°C/min. With the analysis of each set of urine samples was included a calibration curve consisting of urine spiked with LTG. To determine the urinary concentration of only metabolized LMG, a 0.1-ml sample of urine was used. To each sample was added 0.1 ml of 2 N sodium hydroxide. Then the samples were extracted, derivatized, and assayed using the procedure as outlined for LMT and its glucuronide metabolite. To determine the plasma concentration of 2-Nmethyl metabolite, a solid phase extraction procedure and analysis by HPLC with UV detection was used. To 0.5 mi of plasma was added 0.5 ml of phosphate buffer (pH 8). The buffered sample was then applied to a carboxylic acid (CBA) Bond Elut (1 ml). The extraction column was washed with 1 ml of phosphate buffer (pH 8) and 1 ml of acetonitrile. The eluant was evaporated to dryness; and then the residual reconstituted in 0.2 ml acetonitrile (ACN)/water/85% phosphoric acid (20:80:0.6). The samples were then assayed by HPLC with UV detection at 210 nm. A c-8 silica column (Dupont, 4.6 mm × 15 cm, 5 pro) with a flow rate of 2 ml/min. The mobile phase consisted of ACN/50 mM potassium phosphate dibasic and 5 mM octane sulfonic acid (30:70) adjusted to a pH of 5. For the analysis of urine, a 1.5-ml urine sample was added to 1.5 ml of 50 mM phosphate buffer (pH 8). The sample was then applied to 3 ml CBA Bond Elute. The extraction column was washed with 1 ml of phosphate buffer (pH 8) and 1 ml of 1 N sodium hydroxide/methanol (5:95). Except for these changes the assay procedure was the same as

194 used for the analysis of 2-N-methyl metabolite in plasma. With the analysis of each set of plasma or urine samples was included a calibration curve consisting of spiked samples of LTG, 2-N-methylLTG, 5-N-glucuronide LTG, or 2-N-glucuronide LTG. From regression parameters, the urine or plasma concentration was then estimated. Pharmacokinetic analysis was performed using compartmental and non-compartmental methods. Standard non-compartmental analysis involved calculating the area under the curve at steady state (AUCss) using the trapezoidal rule. As only oral dosing was used and the bioavailability (F) of lamotrigine could not be measured, the apparent total body clearance (CI/F) was calculated using Eq. 1. Cl

Dose

F

AUC

Equation i

Cmax and Tmax values were observed values from the plasma concentration-time curves. In addition, statistical moment theory was used to calculate non-compartmental pharmacokinetic parameters. This method was originally described by Yamaoka et al.2~ and later by Benet and Galeazzi 1 and applied to data obtained following a single intravenous dose of a drug. Subsequently, others have shown that statistical moment method is applicable to any route of administration and to steady state conditions if the mathematical model accurately describes the plasma level vs. time data 7'14'24-26. For our analysis, the plasma concentration vs. time curve for each patient was empirically fit to a 4-component polynomial equation without a weighting factor. The AUC and area under the moment curve (AUMC) were then computed and, from this, the CI/F and apparent volume of distribution (Vdss/F) were calculated. The half life was determined from the portion of the curve beyond "the maximum plasma concentration using an unweighted least squares fit. To test if the drug behaved in accordance with a 1-compartment model, data were preliminarily analyzed using a graphical curve stripping program (GSTRIP). Nonlinear regression analysis of individual plasma concentration vs. time data for

Q)

2.0

O

E (~

1.0

m

0.0 0

1 O0

200

,300

400

500

600

700

Time ( h o u r s ) Fig. 1. Typical plasma concentration versus time profile from compartimental modeling. Triangles represent the observed lamotrigine plasma concentrations for patient 203 over the 28 days of the study. Iterative analysis was used to find the solution to equation 2 which best fit the patient's data. The solution provided the values for the first order absorption and elimination constants, the half life, and volume of distribution. The continuous plot was then generated from equation 2. The same procedure was carried out for all eight patients that received lamotrigine.

each patient was subsequently performed using NONLIN TM with an appropriate DFUNC subroutine for multiple dosing. Equation 2 was used to describe the plasma concentration vs. time profile. C

kaxFxD

x ( e - r × L e -k~×t) Equation2

V x (ka-K)

where C is lamotrigine plasma concentration; ka, first-order absorption rate constant; K, first-order elimination rate constant; F, bio-availability; D, dose administered; V, volume of distribution and t, time after dosing. The method of superposition was applied to overlay subsequent doses given at any time interval after the initial dose (Fig. 1). All plasma concentration-time data were simultaneously fit to obtain estimates of V/F, ka and K. RESULTS Thirteen patients were originally screened for the study. Two patients were dropped for protocol non-compliance. Eight subjects were randomized to receive lamotrigine while 3 received placebo. All subjects were males with a mean age of 32.5 years and a mean duration of epilepsy of 19 years.

195 TABLE I

Plasma drug levels Patient number

Concurrent Plasmalevels (lag/ml) A E Ds Mean (range)

Lamotrigine treatment group 201 CBZ 10.9 MSM a 7.1 203 CBZ 7.4 PHT 10.6 204 CBZ 2.7 PHT 21.7 205 CBZ 10.2 MHT b 102 PHT 13.2 PB 13.3 103 CBZ 10.0 PB 20.4 104 PB 13.7 106 PHT 18.5 Placebo treatment group 202 PHT PB 101 CBZ PHT 105 PHT PRM PB

12.1 9.6 6.1 10.2 13.4 2.0 28.4

( 8.4-12.7) (5.4-8.8) (4.0-9.3) (8.5-12.9) (1.4-3.3) (15.2-31.8) (8.7-11.6) (11.0-15.0) (11.0-15.0) (8.0-12.0) (19.0-22.0) (13.0-15.0) (11.0-30.0)

t. r 6 half life,h)

10.3 11.7 23.1 11.8 7.5 11.3 18.1 14.1

(4.7-16.8) (5.1-12.5) (5.0-7.0) (9.0-11.0) (9.2-19.0) (1.4-2.4) (23.0-33.0)

a Values reported are the N-demethylated metabolite of methsuximide. b Plasma levelsof mephenytoin were not availableand thus are not reported.

Their weight varied from 63 to 106.9 kg (mean 86.6 kg) and at the highest dose (300 mg/day) the dosage ranged from 2.81 to 4.76 mg/kg/day. Patient demographics did not differ significantly between the 2 study sites nor between the lamotrigine and placebo treated groups. All patients were diagnosed as having partial epilepsy, 5 symptomatic and 6 idiopathic. Only 3 patients were seizure free at entry into the study. Patients were receiving 1 (2 pt), 2 (7 pt), or 3 (2 pt) AEDs at entry. Concurrent AEDs in the lamotrigine treated group consisted of CBZ (n = 5), PHT (n = 4), phenobarbital (PB, n = 3), methosuximide (MSM, n = 1) and mephenytoin (MHT, n = 1) (Table I). Plasma levels remained stable throughout the study for all concurrent AEDs except PHT. High plasma PHT levels (27-30/zg/ml)

were observed in 2 patients whose levels ranged from 8 to 13/zg/ml during baseline. PHT dosage was reduced from 500 to 400 mg/day in 1 patient because of ataxia and dizziness. The plasma level fell from 27 to 17/zg/ml following the dosage reduction. PHT dosage was not changed in the second patient as no subjective or objective toxicity was evident. No change in plasma levels of the other AEDs was noted with the co-administration of lamotrigine. Adverse experiences were reported in 5 (63%) patients receiving lamotrigine and 1 (33%) patient taking placebo. Symptoms reported were faintness, dyspepsia, agitation, drowsiness, and lethargy. These occurred randomly at all 3 dosage levels and were not dose dependent in any subject. Neurological findings included unsteady gait, mild tremor and nystagmus. Both adverse events and neurological findings occurred with equal frequency at different doses of lamotrigine and thus were felt to not likely be secondary to study drug. One patient reported ataxia and dizziness and, as noted previously, PHT concentration was found to be elevated (27/zg/ml). High PHT level was found in another patient without subjective symptoms. In the patient who reported ataxia and dizziness, lamotrigine was not tapered at the end of the study but abruptly discontinued in order to test for drug interactions. The PHT levels did not subsequently change and the high level was felt to have resulted TABLE II

Number of patients with abnormal laboratoryfindings The number of patients found to have abnormal serum chemistries or CBC values is fisted by treatment. Values were considered abnormal if they were outside the normal range for t h e laboratory. No serious or significant adverse effects were found and no patient was dropped from the study because of abnormal laboratory findings.

Laboratory test Platelet count Hgb/Hct WBC AlkPase SGOT CPK LDH

Lamotrigine

Placebo

(n = 8)

(n = 3)

1 2 1 3 1 6 1

0 2 2 0 1 2 0

196 #g/ml

had WBC counts between 3000 and 4000 while 1 patient had WBC counts of 3300 and 3600 when receiving 200 mg and 300 mg LTG per day respectively. High GGTP levels (141-171 U/l) were present in 1 patient at baseline which did not change during dosing with lamotrigine or at follow up. No CBC or chemistry values were more than twice the upper limit of normal. 24-h urine creatinine clearance was normal in all patients during the study and no change was noted in the lamotrigine treated patients. No systematic or clinically significant changes in supine, standing or postural vital signs were noted either within or between lamotrigine and placebo treatment groups. Sinus tachycardia, sinus bradycardia, and ectopic beats were noted in 7 (88%) of the subjects receiving lamotrigine. These were present randomly during both the 200 and 300 mg/ day treatment periods and were felt by ihe investigators to not be clinically significant. The PR interval ranged from 0.14 to 0.25 s in all patients and did not differ between treatment groups or with dosage of lamotrigine. The longest PR interval was observed in the placebo group. In the 4 patients in whom low levels of 2-N-methyl metabolite were detected in the urine (see below), no

O

m

0

2

4

6

8

10

2

Time After Dosing ( h o u r s ) Fig. 2. Plot of the mean lamotrigine plasma levels vs. time from the 8 patients. The 3 plots are the values for 100, 200 and 300 rag/day doses.

from improved compliance during the study. No additional physical or neurological findings were detected in any subject during treatment with lamotrigine. Sporadic changes in some serum chemistries and CBCs were noted in both groups (Table II) and no systematic or clinically significant abnormalities were seen. A platelet count of 104,000 was reported at the end of the study in 1 patient after LTG had been stopped. Two patients on placebo

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ro

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100

200

300

Daily Dose

(mg)

400

0

I

I

I

100

200

300

Daily Dose

(mg)

400

Fig. 3. Trend analysis for clearance and AUC. For each patient the clearance vs. dose and the AUC vs. dose is plotted. Although considerable interpatient variation exists (particularly for clearance), a similar trend is noted in most patient over the 3 doses used. Refer to Fig. 4 for listing of patient by symbol used to display data.

197 TABLE III Pharmacokinetics of lamotrigine, non-compartmental models

Mean pharmacokineticparameters of lamotriginecalculatedby the use of the trapezoid rule and the statisticalmoment method. The half llfe was determined by using least square curve fit of the data points after the Cmax. The values for the pharmacokineticparameters at each dose of lamotriginewere calculatedfrom the individualvaluesfor each patient. The valuesare the mean for the 8 subjects who received lamotrigine. (Cmax, maximumconcentrationpost dose; Tmax, time to maximumplasma concentration;CI, clearance; MRT, mean resident time; Vdss, volumeof distributionat steady state; F, bioavailability;Tt/2,half life). Daily dose (rag)

100

200 300 Mean

Trapezoid rule Cmax (#glml)

AUC (#g×hl ml)

0.96 1.98 3.00

8.68 17.34 26.16

Moment theory Tmax (h)

CIIF (mllmin/ kg)

AUC #gxhl rat

AUMC i~gxh21 rat

MRT (h)

Vdss (llkg)

CIIF (mllrainl kg)

T% (h)

1.92

1.25

1.47

1.75

1.23 1.20

8.85 17.46 25.92

48.10 94.69 143.95

5.30 5.37 5.46

1.35 1.25 1.47

1.27 1.27 1.27

13.42 12.25 15.08

1.71

1.23

5.38

1.36

1.27

13.58

changes in cardiovascular parameters were noted. The visual analog scale (VAS) consisted of 18 items which were combined and reported as measures of mental sedation, physical sedation, calming effect, and other feelings 15'21. No significant changes were noted in either treatment group compared to baseline. After day 25, lamotrigine was abruptly discontinued in 1 patient while it was reduced for 2 days and then discontinued in 7 patients. No subjective or objective adverse effects were noted nor were changes noted in the E C G or serum chemistries. VAS scores were unchanged after lamotrigine was stopped. The mean plasma l a m o t r i g i n e concentration versus time after morning dose profiles for the 3 doses are plotted in Fig. 2. The maximum concentration (Cmax) increased proportionally with the dose while the time to maximum concentration (Tmax) was not dose related and ranged from 0.75 to 4.02 h (mean 1.71 h) (Table III, Fig. 2). The steady state A U C s increased proportionally with dose (Table III). Although considerable intersubject variation was found, clearance did not change and A U C increased in a linear fashion with dose (Fig. 3). Dosage (mg/kg) and steady state through plasma concentrations were linearly related (Fig. 4). The slope of the regression line was 0.528 #g/ml/mg/kg (r = 0.651, P < 0.01). Mean residence time (MRT = A U M C / A U C ) 14 (5.38 h),

C1/F (1.35 ml/min/kg) and Vd/F (1.33 l/kg) were also independent of dose and plasma level (Table III, Fig. 3). Compartmental and non-compartmental analyses resulted in essentially the same values for all parameters (Table IV). The mean half life was 13.5 h, ranged from 7.5 to 23.1 h, and did not vary between the 3 dosages used or with chronic dosing. Analysis of lamotrigine and potential metabolite(s) was done on 24-h urine collections obtained on treatment day 25. This was the last day the patients received the highest allowable dose of 300 t~l/ml# Legend ,..-1

3

E 2 0

0

1 0

1

i 2

i 3

i 4

i 5

Dosage (mg/kg)

Fig. 4. Plot of the trough lamotrigineplasma vs. dosageadjusted to the patient's weight. The plasma level used was at time 0 of the pharmacokineticcurve whichwas done after the patient had achieved steady state conditions. Each patient is plotted usinga differentsymbol.

198 TABLE IV

Mean pharmacokinetics parameters of lamotrigine comparing I-compartment and statistical moment (non-compartmental) methods K, eliminaton rate constant; T1/z, half life; ka, absorption rate constant; Vd, volume of distribution; C1, clearance; F, bioavailability. For the 1-compartment model, iterative analysis was used to find the solution to equation 2 which best fit each patient's data. The solution provided the values for the first order absorption and elimination constants, the half life, and volume of distribution.

Pharmacokinetic model One-compartment mean (SD)/range K (h -1) 0.06 (0.02)/0.03-0.09 TI/2 (h) 13.5 (4.9)/7.5-23.1 ka 3.1 (2.5)/0.4-6.0 Vd/F (1/kg) 1.3 (0.3)/1.0-1.9 CI/F (ml/min/kg) 1.4 (0.4)/0.8-1.9

Non -compartment mean (SD)/range 0.06 (0.02)/0.02-0.09 13.6 (6.7)/8.0-35.4 N.A. 1.4 (0.1)/0.8-2.1 1.3 (0.4)/0.7-1.9

mg/day. No quantifiable amount of unchanged drug was found in the urine; however, the limit of quantitation was 5/~g/ml. The primary metabolite was the glucuronide of lamotrigine. The glucuronide metabolite was not detectable in plasma but in the urine accounted for a mean of 58% (+ 14%) of the daily LTG dose. A compound with identical chromatographic retention time as the 2-N-methyl metabolite was detected in the urine but not the plasma in 4 of the 8 patients receiving lamotrigine. The lower level of detection in plasma was 9.5 ng/ml. An average of 0.03 + 0.03% (maximum of 0.09%) of the total dose was detected in the urine as this N-methyl metabolite. No difference in subjective or objective findings was noted in the patients in whom the N-methyl metabolite was detected. DISCUSSION Some changes in serum chemistries (Table II) and subjective symptoms were reported during the study in both the LTG and placebo treated groups. Ataxia and dizziness in 1 patient were related to high levels of PHT and cleared when lower levels were achieved. The other findings did not corre-

late with dose or plasma level and were judged to be not related to LTG. The side effect profile was similar to that reported previously in normal volunteers and epileptic patients. In this study, all subjects received the same doses. The highest dose was 300 mg/day resulting in a maximum individual dosage of 4.76 mg/kg/day. In animal models, no adverse effects were found with dosages below 5 mg/kg/day. Mild dizziness and unsteadiness were transiently noted in some normal volunteers with doses up to 240 mg/day and in epileptic patients with doses up to 480 mg/day but no significant or persistent side effects were reported 11'23. From results in animals, the predicted effective anticonvulsant concentration should be 1-3 #g/ml. Acute 2'3'13'2° and chronic studies 4'5'17 in humans have also suggested that LTG levels of 1-3/~g/ml are effective in controlling seizures. To yield a minimally effective concentration, most patients taking other AEDs will require 200 mg/day or more. Only 50% of the patients achieve a steady state plasma level above 1 gg/ml with a dose of 100 mg/day (Table V). Binnie et al. 4 reported side effects only in patients with levels above 3 #g/ml. Patients tolerate plasma levels above that predicted to have anticonvulsant effect. Similar to the report by Loiseau et al.17, our results indicate that levels above 4 #g/ml can be attained without the patients experiencing side effects. Thus lamotrigine has a

TABLE V

Maximum plasma lamotrigine concentrations (l~g/ml) (Cmax) achieved at steady state Patient number

201 203 204 205 102 103 104 106 Mean (SO)

Weight (kg) 89.1 103.7 78.9 96.7 83.9 108.6 81.0 62.8

Daily dose 100 mg

200 mg

300 mg

0.77 0.52 1.38 0.77 0.83 1.00 1.38 1.02

1.31 1.60 2.69 1.80 1.59 1.91 2.89 2.10

1.85 2.32 4.65 2.39 2.25 2.62 4.14 2.75

0.96 (0.30)

1.98 (0.55)

3.00 (0.98)

199 good margin of safety and a favorable therapeutic index. Some rhythm changes were noted on the ECG in 5 of the patients who received LTG while none were noted in the placebo group. The findings were infrequent in those patients in whom they were encountered. They were commonly encountered in adult subjects and were considered not to be clinically significant. In beagle dogs, the 2-Nmethyl metabolite was found to prolong the PR interval in a dose dependent fashion. This metabolite was detected in the urine in very low amounts in only half of the patients exposed to lamotrigine and none was detected in the plasma. No changes in the PR interval were observed in these patients. Even if the metabolite has cardiotoxic properties, it appears unlikely to be a problem in humans as lamotrigine is primarily eliminated by glucuronidation. The pharmacokinetic parameters determined in this study are comparable to those previously reported. The half life (13.1 h) is similar to the 14-15 h reported in epileptic patients taking other A E D s 3'13. This is compared to the half life of at least 25 h seen in normal volunteers 1°'t3. The Vd/F in this study (1.36 l/kg) was slightly larger than the 1.2 1/kg reported previously in epileptic patients and normal subjects s'1°'11. The clearance, however, was greater (115 ml/min) than found in normal subjects (29 ml/min) 1°. These results suggest that the shorter half life and higher clearance have resuited primarily from induction of hepatic enzymes by the concurrent AEDs. The half life change is less than for clearance because of the increased Vd and the fact that the relationship between half life and clearance may not be linear.

REFERENCES 1 Benet, L.Z. and Galeazzi, R.L., Noncompartmental determination of the steady-state volume of distribution, J. Pharm. Sci., 68 (1979) 1071-1074. 2 Binnie, C.D., van Emde Boas, W., Land, W., Meijer, G.S., Overweg, J.W.A. and van Wieringen, A., Preliminary single-dose studies of a potential new anti-epileptic drug, lamotrigine (BW430C) in epileptic patients, Br..1. Clin. Pharmacol., 20 (1985) 285 (Abstract). 3 Binnie, C.D., van Emde Boas, A., Kasteleijn Nolst-Trenite, D.G.A., de Korte, R.A., Meijer, R.A., Meinardi,

The C1/F, MRT, half life and Vd/F did not change with chronic administration or with increasing dose. Thus lamotrigine does not appear to further induce its own metabolism in patients concurrently taking enzyme inducing AEDs. However all patients received the same ascending dose of LTG. Thus it is possible that a decrease in clearance with higher doses (non-linear metabolism) may have been counterbalanced by an increase in clearance with chronic dosing (autoinduction). The pharmacokinetic parameters calculated using a 1-compartment model and the 2 non-compartmental methods are very similar. This supports the hypothesis that lamotrigine obeys 1-compartment kinetics and justifies using this model to estimate its pharmacokinetic parameters. CONCLUSIONS In this placebo-controlled study, lamotrigine was given in doses up to 300 mg/day (dosage range 1.85-4.65 mg/kg). In doses which should produce an anticonvulsant effect, no adverse subjective effects, cardiovascular changes, or findings on examination were detected secondary to LTG. Thus, 300 mg/day is wel tolerated and does not appear to be the maximum tolerated dose for lamotrigine. Trace amounts of the 2-N-methyl metabolite were detected in the urine of only half of the subjects and no cardiovascular side effects were observed in these subjects. The pharmacokinetics of LTG can be described by a 1-compartment model and were similar to what has been previously reported in patients taking concurrent AEDs. The half life of 13.5 h and Tmax of 2 h suggest that b.i.d, dosing should be used in most patients.

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