Summary

Original Research Article

Clinical Phannacokinetics 12: 433-439 (1987) 0312-5963/87/0006-0433/$03.50/0 © ADIS Press Limited All rights reserved.

Pharmacokinetics of Nafimidone in Patients with Chronic Intractable Epilepsy

David M. Treiman and Sonny Gunawan Neurology and Research Services, VA West Los Angeles Medical Center, and Department of Neurology, UCLA School of Medicine, Los Angeles

Nafimidone is a new antiepileptic drug which may be effective in partial onset seizures. We studied the pharmacokinetics of nafimidone and its metabolite. nafimidone alcohol. in 12 patients already taking phenytoin and/or carbamazepine. The half-life of nafimidone was 1.34 ± 0.48 hours after a 100mg single dose and 1.69 ± 0.91 hours after a 300mg single dose. However. the half-life of nafimidone alcohol increased from 2.84 ± 0.72 hours after a 100mg single dose to 4.22 ± 1.09 hours after a 300mg single dose (p < 0.02). The clearance of nafimidone was 43.56 ± 22.11 L/h/kg after a 100mg single dose and 35.51 ± 28.93 L/h/kg after the 300mg single dose. The respective apparent volumes of distri­bution of nafimidol'!e after single 100 and 300mg doses were 80.78 ± 46.11 L/kg and 71.01 ± 36.86 L/kg. After short term (9 to 10 weeks) and long term (127 to 152 weeks) maintenance therapy on nafimidone 600mg per day the half-life of nafimidone alcohol was 2.23 ± 0.36 hours and 2.16 ± 0.60 hours. respectively. No nafimidone could be detected in urine but from 4 to 7% of the daily nafimidone dose was recovered as nafim­idone alcohol. Thus. it appears that over 90% of the administered dose of nafimidone is metabolised by pathways other than glucuronidation of nafimidone alcohol and urinary excretion.

Nafimidone [1-(2-naphthoylmethyl) imidazole 1 is a new antiepileptic drug which may be effective in the treatment of partial onset seizures and which is rapidly converted to nafimidone alcohol, an ac­tive metabolite. We recently reported the results of the first pilot efficacy study in patients with epi­lepsy (Treiman et al. 1985b), during which a sig­nificant inhibitory effect on the clearance on carb­amazepine and phenytoin (diphenylhydantoin) was also observed (Treiman et al. 1987). In this paper we report our observations on the pharmacokinetic behaviour of nafimidone and nafimidone alcohol in patients with chronic intractable epilepsy.

Methods

Patient Selection

Following approval by the local Ethical Com­mittee, pharmacokinetic data were collected from 12 patients (table I), 6 of whom had participated in a pilot study of the efficacy of nafimidone given as an add-on drug to patients who were already taking both phenytoin and carbamazepine (Trei­man et al. 1985b). These patients were males be­tween the ages of 19 and 59 years and between 59 and 80kg in weight. All 6 patients participated in

Pharmacokinetics of Nafimidone in Chronic Intractable Epilepsy 434

Table I. Clinical profile of the 12 patients, with partial onset seizures, who participated in the study

Patient Sex Age

(years)

DH M 20

GS M 35

JS M 19

SM M 23

AH M 30

WB M 59 DA M 32

WR M 25

KP M 27

LS F 37

CB F 49

KJ M 36

Abbreviations: CBZ = carbamazepine; PHT = phenytoin.

the first 14 weeks of the efficacy trial; 5 of the 6 continued into long term follow-up.

The other 6 patients had participated in a study designed to assess the inhibitory effect of nafimi­done on phenytoin and carbamazepine metabol­ism (Treiman et al. 1985a). Five of these patients were taking only carbamazepine at the time of en­try into the study and 1 was taking only phenytoin. Four were men and 2 were women. One of the women was surgically sterile. The other was post­menopausal. Ages ranged from 25 to 49 years and bodyweights ranged from 67 to 90kg. None of the 12 patients used either alcohol or tobacco during the study period.

Antiepileptic Drug Assays

Phenytoin and carbamazepine concentrations were determined using the Syva EMIT® assay sys­tem or the Abbott TOX® fluorescence polarisation immunoassay system. Plasma and urine concen­trations of nafimidone [1-(2-naphthoylmethyl) im­idazole] and its metabolite, nafimidone alcohol (1-[2-hydroxy-2-(2-naphthyl)-ethyl]imidazole), were determined using a high pressure liquid chroma­tography (HPLC) assay developed in our labora-

Weight CBZ dose PHT dose

(kg) (mg/day) (mg/day)

69

80

67

59

69

71

68

90

71

67

73

72

1200 500

1000 500

800 230

700 400

800 400

1000 450

2200

2400

2200

1000

1000

300

tory (Gunawan & Treiman 1987). The chromato­graphic system comprises two Model 110A pumps, a Model 421 controller and a C-RIA integrator. Two detection methods (UV and fluorescence detec­tion) were employed for the quantification of na­fimidone and the metabolite, nafimidone alcohol. For the parent drug nafimidone, a Kratos FS 970 fluorometer operated at Aex 245nm and Aem 456nm was used. For the metabolite, nafimidone alcohol, a Schoeffel SF 770 variable-wavelength detector set at 225nm was used. Separation was carried out in a reverse-phase system with Whatman Partisil 10 OOS-3 as the stationary phase (250mm X 4.6mm 1.0.; particle size lO~m) and methanol-SOS buffer (64: 36, v/v) as the mobile phase. The flow rate of the mobile phase was 1.5 ml/min for nafimidone and 1.7 ml/min for the nafimidone alcohol assay. A Rheodyne 7125 injection valve with a 20~1100p was used. The column was heated to 3rC by a Bio Rad column heater. Standard curves for nafimi­done and nafimidone alcohol were generated using drug-free plasma and urine to which known amounts of nafimidone and nafimidone alcohol were added. Concentrations of nafimidone and na­fimidone alcohol were determined by the ratio of the peak areas of each compound to the peak area

Pharmacokinetics of Nafimidone in Chronic Intractable Epilepsy 435

of the internal standard plotted against the known concentrations of the standards. The detection lim­its for nafimidone and nafimidone .alcohol were 5.0 and 12.5 ILg/L, respectively. The coefficient ofvari­ation for within day and between day determina­tions was less than 7.0% in all cases.

Single Dose Pharmacokinetics

Single dose pharmacokinetic studies were car­ried out in 6 patients. Five were taking carbam­azepine with daily dosages ranging from 1000 to 2400mg. One was taking 300 mg/day of phenytoin. All were at steady-state at the time of the study. The patients were admitted to the Clinical Re­search Center at VCLA. On the morning after ad­mission they were given a single 100mg oral dose of nafimidone at 8.00am with their regular carba­mazepine or phenytoin dose. Blood samples for de­termination of plasma concentration of nafimi­done and its metabolite, nafimidone alcohol, were drawn via an indwelling catheter at 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours after the na­fimidone dose. The patients were given a single 300mg oral dose of nafimidone at 8.00am on the third morning after hospitalisation and blood sam­ples were drawn according to the same schedule. On the fifth hospital day the patients commenced maintenance therapy with nafimidone and the dose was rapidly increased to 200mg three times daily.

Elimination of Nafimidone after Maintenance Therapy

The half-life of nafimidone after maintenance therapy was determined in 4 patients on stable doses of carbamazepine and in 6 patients on stable doses of carbamazepine and phenytoin after 6 to 16 weeks of treatment with nafimidone. Patients came to the outpatient clinic early in the morning. At 8.00am they took their routine morning dose of nafimidone and concomitant antiepileptic drug, and simultaneously had a blood sample drawn for de­termination of the plasma concentration of nafim­idone alcohol. Blood samples were also drawn 5 to 7 times over the next 7 to 8 hours.

Pharmacokinetic Calculations

The pharmacokinetic parameters of nafimidone and nafimidone alcohol given as a single oral dose of nafimidone were calculated assuming a I-com­partment model and assuming that oral bioavail­ability is complete. Peak absorption time for each compound was determined by taking the time at which the concentration was maximum. Log con­centration versus time curves were plotted for each experiment and the half-life was calculated by the method of least squares regression analysis of the terminal log linear slope. The area under the curve (AVC) was determined using the trapezoidal rule and extrapolated to infinity. Clearance was deter­mined by dividing the administered dose by the AVe. The apparent volume of distribution was de­termined by dividing the clearance by the elimin­ation rate constant. Statistical significance was de­termined through the use of the 2-tailed Student's t-test for paired data.

Excretion of Nafimidone and Nafimidone Alcohol

The percentage of the daily dose of nafimidone excreted as nafimidone alcohol was determined by measuring the total amount of the 2 compounds excreted during 24 hours in at least 3 different samples from each of the patients while at steady­state. Vrine samples were incubated with ~-glu­curonidase at 37°C for 17 hours before HPLC an-

Table II. Nafimidone alcohol serum half-life (tv.) following nafim­idone 200mg oral (550 or 600 mg/day for 6 to 16 weeks)

Patient tv, (h) R Im>x (h)

DH 3.14 0.99 1.5

GS 2.43 0.95

JS 5.26 0.99

SM 3.29 0.99

AH 3.08 0.99

WB 2.76 0.83

Mean ± SD 3.33 ± 1.00

Abbreviation: tmax = time to peak concentration.

Pharmacokinetics of Nafimidone in Chronic Intractable Epilepsy 436

Table III. Nafimidone alcohol half-life (tv.) after short and long term maintenance therapy with nafimidone 600 mg/day

Patient

OA KP WB

WR Mean ± SO

t'h (h)

9-10 weeks

2.01 2.00 2.76 2.16

2.23 ± 0.36

127-152 weeks

2.89 1.63 2.41 1.70 2.16 ± 0.60

alysis in order to measure both free and conjugated nafimidone alcohol (Gunawan & Treiman 1987). Prior experiments had shown that this incubation period did not significantly alter formation of na­fimidone alcohol. Without enzymatic hydrolysis the concentration of nafimidone alcohol detected in the urine samples was much less than after hydrolysis.

Results

Half-Life of Nafimidone Alcohol after Maintenance Therapy

Table II shows the plasma half-life of nafimi­done alcohol in 6 patients treated with phenytoin and carbamazepine, after 6 to 16 weeks following the addition of 550 or 600mg of nafimidone per day. The mean serum half-life was 3.33 ± 1.00

hours whereas a half-life of 8 hours had been pre­viously reported in normal volunteers (Buhles et al. 1986). In 4 other patients, the nafimidone al­cohol serum half-life was determined after short term maintenance therapy (9 to 10 weeks) and again after 127 to 152 weeks of treatment. These results are shown in table III. There was no significiant difference in the mean half-life after short term (2.23 ± 0.36 hours) and long term (2.16 ± 0.60 hours) treatment with nafimidone 600mg per day.

Single Oral Dose of Nafimidone

To determine whether the difference in half-life between volunteers and epileptic patients was due to autoinduction of nafimidone metabolism or in­duction of the metabolising enzymes by phenytoin and carbamazepine, the elimination half-lives of nafimidone and nafimidone alcohol were deter­mined after a single dose in nafimidone-naive patients who were taking stable doses of either carbamazepine or phenytoin. Table IV shows that there was no significant difference between the mean half-life of 1.34 hours after nafimidone lOOmg and 1.69 hours after 300mg. However, when the elimination half-life was determined for nafimi­done alcohol the mean elimination half-life was 2.84 hours after a 100mg dose of nafimidone and 4.22 hours after a 300mg dose of nafimidone [p < 0.02 (table V)]. There was no statistically significant dif-

Table IV. Pharmacokinetic parameters of nafimidone after single doses of 100mg and 300mg administered 2 days apart

Patient 100mg 300mg

t'h CL Vd tv. CL Vd (h) (L/h/kg) (L/kg) (h) (L/h/kg) (L/kg)

OA 1.55 28.37 63.05 2.23 33.76 108.92 WR 0.63 35.60 32.36 1.15 28.40 47.33 KP 1.48 34.24 72.86 2.41 26.20 90.34 LS 1.98 22.95 65.56 2.84 11.98 49.94

CB 0.96 59.38 82.47 0.71 20.19 20.60 KJ 1.44 80.82 168.39 0.82 92.58 108.92

Mean ± SO 1.34 ± 0.48 43.56 ± 22.11 80.78 ± 46.11 1.69 ± 0.91 35.51 ± 28.93 71.01 ± 36.86

Abbreviations: t'h = plasma half-life, CL = clearance; Vd = apparent volume of distribution.

Table V. Plasma concentration and half-life of nafimidone alcohol after a single dose of nafimidone l00mg or 300mg

Patient Plasma nafimidone-alcohol concentration (l'g/L)

0 0.5h lh 2h 3h 4h 6h 8h 12h

100mg DA 124.6 1224.3 957.0 652.3 543.1 349.9 184.0 45.5 WR 818.7 755.2 500.6 333.4 189.0 89.3 KP 21 .5 505.0 699.4 537.0 389.6 247.7 147.2 LS 828.4 1733.0 1152.7 1048.7 904.4 706.4 540.9 208.8 CB 222.9 849.6 1015.3 835.5 670.5 520.1 322.0 167.1 KJ 384.5 957.5 739.5 579.8 357.7 127.0

Mean 299.4 919.2 750.0 718.9 570.1 395.1 235.1 140.5 ±SD ±363.2 ±495.5 ±335.0 ± 203.9 ±205.6 ± 189.8 ± 169.9 ±84.8

300mg DA 27.9 1842.8 3211.1 3088.3 2381 .3 1900.8 1298.9 745.1 WR 20.7 3282.5 2421.7 1872.0 1682.3 1233.7 861.6 300.9 KP 15.5 45.2 1585.6 2530.2 2164.3 1945.6 1391 .9 925.8 354.2 LS 307.0 267.2 421 .9 760.5 2923.4 3091 .3 2356.3 CB 47.3 1878.6 3160.9 3338.9 2965.0 2412.3 1758.7 1283.2 KJ 140.7 2340.4 3089.6 2839.5 2362.2 1795.7 1296.3 694.0

Mean 31.4 422.6 2086.5 2476.4 2225.2 1924.0 1834.0 1459.5 890.1 ±SD ± 22.5 ±815.3 ± 1106.9 ± 1144.2 ± 1005.0 ±640.7 ±592.3 ±823.2 ±843.1

16h 24h 36h

69.7 89.2 32.2

79.3 32.2 ±13.6 ±O.O

230.3 19.1 24.7 75.6

1240.9 572.8 18.3 313.0 74.7 67.1 300.0

364.0 222.2 42.7 ±445.4 ±304.9 ±34.5

tV2

(h)

2.37 2.12 2.69 3.48 3.97 2.43

2.84 ±0.72

3.81 3.40 3.54 6.35 4.00 4.19

4.22 ±1 .09

'" ::>" ~ .., 3 ~ ("> 0 1r. ::s '" g. en 0 .., Z ~ ::tl 3 5: 0 ::s '" S· (j ::>" a ::. (">

5' ~ ; ~ tr1 'S. Ii" '0 en '<

""" W -..l

Pharmacokinetics of Nafimidone in Chronic Intractable Epilepsy 438

Table VI. Excretion of nafimidone (NAF) as nafimidone alcohol

(NAF-OH)

Patient Total 24h Total24h Percentage of

dose of urine daily dose

NAF NAF-OH excreted as

(mg) (mg) NAF alcohol

DA 300 13.68 4.56

WR 600 25.93 4.32 KP 600 28.84 4.81

LS 600 44.04 7.34

ference in the mean clearance of nafimidone for the 6 patients at the two doses, which is consistent with the observation that the half-life did not change (table IV). Table IV also shows the appar­ent volume of distribution for nafimidone. The measured plasma concentrations of nafimidone al­cohol after the 100mg and 300mg doses of nafim­idone are also shown in table V for each time point for each patient.

Excretion of Nafimidone as Nafimidone Alcohol in Urine

The percentage of the daily dose of nafimidone excreted as nafimidone alcohol in urine of 4 patients studied at steady-state is shown in table VI. The results reflect the total of both free and conjugated nafimidone alcohol. No nafimidone could be de­tected in the urine either before or after incubation of the urine sample with iJ-glucuronidase.

Discussion

Our studies indicate that nafimidone is rapidly absorbed and very rapidly converted to nafimi­done alcohol in patients with chronic epilepsy being treated with other antiepileptic drugs. Nafimidone alcohol is also rapidly metabolised with a half-life of 2 to 4 hours, which is less than half that ob­served in healthy volunteers (Buhles et al. 1986). The half-life of nafimidone alcohol is similar in na­fimidone-naive, short and long term chronically treated patients. This suggests that the apparent de­crease in the half-life in chronic epileptic patients

compared with healthy volunteers is principally due to induction of the enzyme system responsible for nafimidone metabolism by carbamazepine and/or phenytoin, rather than auto induction by nafi!lli­done itself It is known that phenytoin and carb­amazepine interact with other drugs and may alter their plasma concentration. Phenytoin is a potent inducer of carbamazepine (Lander et al. 1977), and primidone (Fincham & Schottelius 1982) biotrans­formation. Additionally, the concentration of a pharmacologically active metabolite of methsux­imide has been reported to be elevated by pheny­toin (Rambeck 1979). Carbamazepine may lower the plasma concentration of valproic acid (Reu­nanen et al. 1980) and to a lesser extent may lower the plasma concentration of ethosuximide (Warren et al. 1980).

Nafimidone, as the parent compound, is rapidly metabolised to nafimidone alcohol, and there is no apparent effect of drug dose or blood concentration on the rate of metabolism of nafimidone. In con­trast, the half-life of nafimidone alcohol is signifi­cantly longer after a single 300mg dose of the par­ent drug than after a single 100mg dose. As the fraction of nafimidone metabolised to nafimidone alcohol was unknown, it was not possible to cal­culate the clearance and apparent volume of dis­tribution of the metabolite. However, the differ­ence in the half-life of nafimidone alcohol after a 100mg and 300mg dose of nafimidone appears to be due to slower elimination of nafimidone alcohol after the larger dose. Further studies are needed to fully elucidate the details of the apparent dose-de­pendent kinetics exhibited by nafimidone alcohol. Such studies would best be done by directly ad­ministering nafimidone alcohol rather than the parent compound, in order to eliminate the pos­sibility that dose effects on the rate of conversion of nafimidone to nafimidone alcohol may account for part of the observed differences in the rate of elimination of nafimidone alcohol.

A substantial presystemic metabolic clearance of nafimidone might occur after oral administra­tion. This could complicate the determination of the pharmacokinetic parameters. We have as­sumed complete oral bioavailability of nafimidone

Pharmacokinetics of Nafimidone in Chronic Intractable Epilepsy 439

in our calculations, and no attempt was made to

correct for possible first-pass metabolism.

No nafimidone could be detected in the urine

and only 4 to 7% of the dose of nafimidone could

be accounted for by the nafimidone alcohol which

appeared in the urine. Thus over 90% of the ad­

ministered dose of nafimidone must be eliminated

by pathways other than glucuronidation of nafim­

idone alcohol and urinary excretion. Several other

metabolites have been detected in rats after ad­

ministeration of nafimidone (Buhles et al. 1986);

no other metabolites have thus far been identified

in human.

Therapeutic Implications

The very short half-life of both the parent com­

pound and of the pharmacologically active metab­

olite, nafimidone alcohol, which we have observed

in patients already being treated with other anti­

epileptic drugs could result in several difficulties in

the use of this drug as an anticonvulsant. The rapid

absorption of nafimidone, and the rapid metab­

olism of both parent drug and the active metabo­

lite may result in a large fluctuation between peak

and trough concentrations and thus increase the

risk of dose-related side effects. Symptoms of toxic

psychosis have been observed in some patients at high blood concentrations (Treiman et al. 1985b).

Frequent small doses of nafimidone could be given

to reduce the peak-trough variation but may cause

problems with patient compliance. However, al­

though further investigations are required, these

problems may be overcome by the use of a sus­

tained release formulation administered once or

twice daily.

The increase in half-life of nafimidone alcohol

after a 300mg single dose compared with the 100mg

dose suggests the possibility that elimination ofna­

fimidone alcohol could follow mixed-order or zero­

order kinetics at higher concentrations. Under such

circumstances, as with phenytoin (Ram beck et al.

1980), small increases in dose may result in large

increases in blood concentrations. However, even

at nafimidone doses of 600 mg/day there was no

evidence of accumulation of the metabolite, nafim­

idone alcohol, so the possibility of saturation ki­

netics may not be relevant at the dosages which

have thus far been used clinically.

Acknowledgements

Supported in part by Contract NOI-NS-81-2377, T.O. I from the Epilepsy Branch, National Institute of Neu­rological and Communicative Disorders and Stroke, by USPHS CRC Grant RR00865, and by a Grant from Syn­tex Research. We thank Dr J Massey ofSyntex, Palo Alto, California, for supplying nafimidone and nafimidone al­cohol used in this study.

References

Buhles W, Wallach M, Chaplin M, Treiman DM. Nafimidone -a novel imidazole anticonvulsant. In Porter & Meldrum (Eds) Current problems in epilepsy IV, New anticonvulsant drugs pp. 203-214, John Libbey, London, 1986

Fincham RW, Schottelius DD. Primidone: interactions with other drugs. In Woodburry et al. (Eds) Antiepileptic drugs, 2nd ed., pp. 421-429, Raven Press, New York, 1982

Gunawan S, Treiman DM. HPLC determination of nafimidone and its major metabolite, nafimidone alcohol, in human plasma and urine. Journal of Chromatography 414: 389-398, 1987

Lander CM, Eadie MJ, Tyrer JH. Factors influencing plasma carbamazepine concentrations. Clinical and Experimental Neurology 14: 184-93, 1977

Rambeck B. Pharmacological interactions of methsuximide with phenobarbital and phenytoin in hospitalized epileptic patients. Epilepsia 20: 147-56, 1979

Rambeck B, Boenigbk HE, Dunlop A, Mullen PW, Wadsworth J, et a!. Predicting phenytoin dose: a revised nomogram. Ther­apeutic Drug Monitoring I: 325, 1980

Reunanen MI, Luoma P, Myllya VV, Hokkanen E. Low serum valproic acid concentrations in epileptic patients on combin­ation therapy. Current Therapy Research 28: 456-462, 1980

Treiman DM, Ben-Menachem E, Barber KO. Inhibition of carb­amazepine and phenytoin elimination by nafimidone, a new antiepileptic drug. Submitted for publication, 1987

Treiman DM, Kupferberg HJ, Ben-Menachem E, Barber KO, Chelberg R, et al. Inhibition of the metabolism of carbamaz­epine and its metabolites by nafimidone, a new antiepileptic drug. Neurology 35 (Supp!.): 285, 1985a

Treiman DM, Wilensky AJ, Ben-Menachem E, Ojemann L, Yerby M, et al. Efficacy of nafimidone in the treatment of intractable partial seizures: report of a two-center pilot study. Epilepsia 26: 607, 1985b

Warren JW, Benmaman JD, Wannamaker BB, Levy RH. Kinet­ics of carbamazepine-ethosuximide interaction. Clinical Pharmacology and Therapeutics 28: 646-651, 1980

Author's address: Dr David M. Treiman, Department of Neur­ology, Reed Neurological Research Center, UCLA School of Medicine, Los Angeles, CA 90024 (USA).