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Efficacy and safety evaluation of loreclezole as add-on treatment in therapy-resistant epilepsy patients
Epi@sy Res., 8 (1991) 166 169 Elsevier
166 EPIRES 00369
Efficacy and safety evaluation of loreclezole as add-on treatment in therapy-resistant epilepsy patients
T. Rentme~ster and J, Hulsman Epilepsy Centre Kempenhaeghe,
Heeze (The Netherlands)
(Received 7 June 1990; revision received 20 July 1990; accepted 27 July 1990) Key words: ~erapy-resistant
epilepsy; Add-on; Loreclezole
Thirteen drug-resistant epilepsy patients received loreclezole as add-on therapy. The trial lasted 6 months. Loreclezole was dosed to reach a target plasma concentration between 1 and 3 mg/i. The seizure frequency in the total group decreased by 23%. A reduction of 50% or more was observed in four patients. These effects are most likely related to Ioreclezole, as doses and plasma levels of the associated anti-epileptic drugs remained unch~ged during the study. Loreclezole was tolerated well and no changes in haematologicai or biochemical parameters were observed.
INTRODUCTION Loreclezole (R 72063) is a triazole derivative (Fig. 1) with potent anticonvulsive properties, as demonstrated in several animal models of epilepsy. It antagonizes both chemically and electrically induced convulsions and is active in models of genetic epilepsy. In dogs, loreclezole concentrations from 1 mg/l are efficacious and side-effects (ataxia and drowsiness) appear at doses of 10 times the effective dose. Loreclezole’s activity profile is comparable to that of well-known broad-spectrum antiepileptics such as diazepam, phenobarbital and sodium valproate’,‘-‘. In principle, it would therefore be expected to be clinically useful in both generalized and partial epilepsy. Correspondence
Kempenhaeghe, lands.
roe: T. Rentmeester M.D., Epilepsy Centre P.O. Box 61, 5590 AB Heeze, The Nether-
0920-1211/91/$03.SO~ 1991 Elsevier Science Publishers B.V.
Administration of single and multiple doses of loreclezole to volunteers is well tolerated. The test drug is rapidly absorbed, with peak plasma concentrations appearing l-2 h after oral administration Initial volunteer trials established that the terminal half-life is 3-4 weeks2-4. It was decided to assess the clinical usefulness of this novel compound by observing its effect as an add-on therapy in patients with refractory epilepsy. PATIENTS AND METHODS Thirteen drug-resistant patients (7 male and 6 female) with a minimum of 4 seizures per month were included in the trial. Twelve patients had partial epilepsy with complex symptomatology. Three of them also had secondary generalization. The rem~ning patient had generalized epilepsy with mixed seizure types (Table I). The age of the patients ranged from 20 to 52 (mean 37) years and
167 TABLE I Individualpatientdata Patient number
Sex @f/Q
Age tYr1
Age at orlset(yr)
Anti-epilepticdrugsb fmgiday~
W
I 1 2 3 4 5 6 7 8 9 10 11 12 13
Duration of Typeof therapyresistance seizurefl
M F M F M M F M F M M F F
37 38 26 20 52 36 30 37 44 41 42 31 31
8 10 20 11 45 16 14 11 8 25 8 25 12
29 27 6 9 7 20 16 17 36 10 34 18 19
CP, PSG CP, PSG CP CP, PSG CP CP CP CP CP A, TC, T, At CP CP CP
CBZ CBZ PHT CBZ CBZ CBZ oxc PHT PHT VPA CBZ CBZ CBZ
(WO), VPA (2700), CL2 (20) (500), VPA (1500), AZA (750) (400), VPA (2000) (400), AZA (750) (1000) (1600), PRI (1000) (1200), PRI (250) (350), AZA (500) (400) (2000) (lloa), CLB (40) (800), PHT (350) (700), CLN (5), AZA (500)
a CP, complex partial; PSG, partial secondary generalizing; A, absence; TC, tonic-clonic; T, tonic; At, atonic. b CBZ, carbamazepine; VPA, valproate; PHT, phenytoin; AZA, acetazolamide; PRI, primidone; OXC, oxcarbazepine; CLZ, clora- ezepate; CLB, clobazam; CLN, clonazepam.
the duration of therapy resistance from 6 to 36 (mean 19) years. Patients were excluded if they presented hepatic or renal disorders or progressive neurological anomalies. In addition, noncompliance, mental retardation, pregnancy, pregnancy potential and the use of co-medication (other than anti-epileptics or ~ntraceptives) were grounds for exclusion. The trial was run on an open basis. At the start of the study, all patients were using anti-epileptics, the dose of which was maintained throughout the trial. Two were on monotherapy, 7 were taking 2 anti-epileptics and 4 were using 3 anti-epileptic drugs. The most frequently prescribed anti-epileptics were carbamazepine (9 patients) and phenytoin and valproate (4 patients each) (Table I). The seizure frequency over the 12 weeks preceding the add-on administration of loreclezole was adopted as a baseline for the efficacy evaluation. The total treatment period lasted 6 months, and at the end of the trial the patient was given the option of continuing on the experimental drug. Initially, the investigator dosed loreclezole so as to reach a target plasma level of 1 mg/l. The loreclezole dose could be increased up to a m~imum of 3 mg/l as a function of the currently attained plasma levels
(measured regularly) and clinical need. The protocol allowed the dose to be lowered to that previously tolerated in the event of adverse experiences occurring. For safety analysis, the following haematological and biochemical variables were monitored monthly: haemoglobin, RBC, haematocrit, WBC, leucocyte differential count, platelet count, calcium, chloride, phosphorus, potassium, sodium, total protein, glucose, total cholesterol, total bilirubin, alkaline phosphatase, SGGT, LDH, ASAT, ALAT, creatinine, BUN and uric acid. Plasma concentrations of the anti-epileptic drugs and loreclezole were determined, by HPLC method, at the laboratory of the Kempenhaeghe epilepsy centre in Heeze (The Netherlands).
Fig. 1. Two-d~ension~
representation of the molecular structure of loreclezole.
168 TABLE II Mean (range) serum concentrations (mgll) of anti-epileptic drugs before and during treatment with loreclezole -Anti-epileptic drug
N
Basefine
At 2 months
At 4 months
Carbamazepine Valproate Phenytoin
9 4 4
6.9 (4.5-10.2) 59 (55-67) 16.7 (10.3-27.3)
7.4 (4.1-12.0) 56 (41-77) 16.7 (10.8-27.1)
6.3 (3.6-9.6)” 55 (42-67) 16.8 (12.2-25.3)
At 6 months __~_______.
6.9(4.0-11.3)a 57 (41-76) 18.4 (13.1-28.6)
a N = 8; one patient withdrawn because of change in carbamazepine dosage.
RESULTS Loreclezole add-on therapy was initiated at 40 mgiday in 4 patients and at 50 mglday in 9 patients. The doses were increased throughout the trial, and varied between 50 and 120 mglday at the end of treatment. The total daily dose was always administered as a single intake in the morning, During the trial, the mean plasma concentrations increased from 0.9 mg/l after 2 months to 1.7 and 2.1 mg/l after 4 and 6 months of treatment with loreclezole . The median seizure frequency before add-on therapy with loreclezole was 0.61 per day (range 0.20-2.23). At 2,4 and 6 months of treatment, the median frequencies were 0.34 (range 0.06-2.32) 0.27 (range 0.02-2.97) and 0.33 (range 0.07-2.69). All 3 decreases from baseline are sig% change +4n
~_
____~.
..--
r
nificant (Ztailed Wilcoxon test for intragroup comparisons: P = 0.001, P = 0.003 and P = 0.05). In addition to a substantial response at the initial dose, three patients presented further gains in the course of the dose increase. An overall reduction in seizure frequency of 23% was observed. A clinically relevant reduction (of 50% or more) in seizure frequency was observed in four patients (Fig. 2). One patient who had experienced only slight reduction in seizure frequency reported an appreciable diminution of seizure duration; whereas he had had sequences of seizures lasting on average 2 h before treatment, these lasted 10 min at the end of the study. Loreclezole was tolerated very well by most of the patients. One patient reported nausea and vomiting immediately after intake of the trial medication. This patient turned out to be intolerant of capsules (the dosage formulation of loreclezole in the study). Drowsiness and fatigue were reported by one patient. These adverse effects are, however, unlikely to be related to loreclezole, as they disappeared after reducing the dose of carbamazepine. No clinically significant changes were observed in haematological or biochemical variables. There were no systematic trends in changes in the serum levels of the concomitant antiepileptic drugs (Table II). The observed changes were minor and considered normal fluctuations, unrelated to the add-on therapy with loreclezole. DISCUSSION AND CONCLUSIONS
10
5. 12
7
3
8.- 8 --9 -.b lj
2
1
13
patient number Fig. 2. Individual % change in seizure frequency during the add-on treatment with loreclezole with respect to baseline.
Although results from an open trial should be interpreted with caution, it is tempting to conclude that the findings of this trial bear out the predic-
169
tion, based on animal models of epilepsy, that loreclezole has anticonvulsant properties. This trial clearly demonstrated that add-on therapy with loreclezole is useful for more than one-third of the patients. Given that these patients had been refractory to all commercially available antiepileptic drugs for several years, this result can be seen as being of particular clinical significance. The effects observed in this trial relate to loreclezole plasma concentrations in the range of l-3 mg/l. The plasma concentrations in the patients who did not respond were of the same order. For these patients, the question remains whether higher concentrations would be efficacious.
Loreclezole add-on treatment did not significantly interfere with the plasma levels of the concurrent anti-epileptic drugs. The reported effects cannot, therefore, be attributed to metabolic interaction with these substances. Finally, loreclezole was very well tolerated.
REFERENCES
4 Van de Velde, V. , Van Peer, A., De Beukelaar, F., Van Rooy, P., Woestenborghs, R., Heykants, J. and Vanden Bussche, G., Pharmacokinetics of R 72063 after single oral administration of a 100 mg dose to a healthy volunteer, Junssen Research Foundation, Clinical Research Report, January (1988) R 7206314(N 59724). 5 Wauquier, A., Fransen, J., Melis, W., Ashton, D., Gillardin, J.M. and Van Clemen, G., R 72063: a broad spectrum anticonvulsant, Janssen Research Foundation, Preclinical Research Report, February (1988) R 7206312(N 56239). 6 Wauquier, A., Melis, W. and Van den Broeck, W., R 72063 increases the threshold to generalized EEG seizures in dogs induced by metrazol infusion, Janssen Research Foundation, Preclinical Research Report, March (1988) R 7206316 (N 59941). 7 Wauquier, A., Smeyers, F., Melis, W. and Woestenborghs, R., R 72063 protects against metrazol-induced convulsions in dogs. Relationship to plasma levels, Junssen Research Foundation, Preclinical Research Report, March (1988) R 72063l7 (N 59942).
1 Jenkins, S.A., Edmonds, Jr., Paloheimo, M. and Zhang, Y.P., Anticonvulsant testing of R 72063 in a rat model of postischemic sound-induced convulsions, Janssen Research Foundation, Preclinical Reseach Report, December (1987) R 72063/g (N 62089). 2 Van de Velde, V., De Beukelaar, F., Van Rooy, P., Van Peer, A., Woestenborghs, R., Heykants, J. and Vanden Bussche, G., Multiple dose pharmacokinetics of R 72063 in healthy volunteers after oral administration of 50 mg o.d. for 7 days, followed by 10 mg/day for 14 days, Janssen Research Foundation, Clinical Research Report, April (1988) R 7206315(N 62347). 3 Van de Velde, V., De Beukelaar, F., Van Rooy, P., Van Peer, A., Woestenborghs, R., Vanden Bussche, G. and Heykants, J., Oral pharmacokinetics and bioavailability of R 72063 in healthy volunteers, Janssen Research Foundation, Clinical Research Report, September (1987) R 7206312 (N 56899).
ACKNOWLEDGEMENTS The authors thank F. de Beukelaar and Dr. L. Tritsmans, of the Janssen Research Foundation, for technical help and assistance in preparing this publication.
166 EPIRES 00369
Efficacy and safety evaluation of loreclezole as add-on treatment in therapy-resistant epilepsy patients
T. Rentme~ster and J, Hulsman Epilepsy Centre Kempenhaeghe,
Heeze (The Netherlands)
(Received 7 June 1990; revision received 20 July 1990; accepted 27 July 1990) Key words: ~erapy-resistant
epilepsy; Add-on; Loreclezole
Thirteen drug-resistant epilepsy patients received loreclezole as add-on therapy. The trial lasted 6 months. Loreclezole was dosed to reach a target plasma concentration between 1 and 3 mg/i. The seizure frequency in the total group decreased by 23%. A reduction of 50% or more was observed in four patients. These effects are most likely related to Ioreclezole, as doses and plasma levels of the associated anti-epileptic drugs remained unch~ged during the study. Loreclezole was tolerated well and no changes in haematologicai or biochemical parameters were observed.
INTRODUCTION Loreclezole (R 72063) is a triazole derivative (Fig. 1) with potent anticonvulsive properties, as demonstrated in several animal models of epilepsy. It antagonizes both chemically and electrically induced convulsions and is active in models of genetic epilepsy. In dogs, loreclezole concentrations from 1 mg/l are efficacious and side-effects (ataxia and drowsiness) appear at doses of 10 times the effective dose. Loreclezole’s activity profile is comparable to that of well-known broad-spectrum antiepileptics such as diazepam, phenobarbital and sodium valproate’,‘-‘. In principle, it would therefore be expected to be clinically useful in both generalized and partial epilepsy. Correspondence
Kempenhaeghe, lands.
roe: T. Rentmeester M.D., Epilepsy Centre P.O. Box 61, 5590 AB Heeze, The Nether-
0920-1211/91/$03.SO~ 1991 Elsevier Science Publishers B.V.
Administration of single and multiple doses of loreclezole to volunteers is well tolerated. The test drug is rapidly absorbed, with peak plasma concentrations appearing l-2 h after oral administration Initial volunteer trials established that the terminal half-life is 3-4 weeks2-4. It was decided to assess the clinical usefulness of this novel compound by observing its effect as an add-on therapy in patients with refractory epilepsy. PATIENTS AND METHODS Thirteen drug-resistant patients (7 male and 6 female) with a minimum of 4 seizures per month were included in the trial. Twelve patients had partial epilepsy with complex symptomatology. Three of them also had secondary generalization. The rem~ning patient had generalized epilepsy with mixed seizure types (Table I). The age of the patients ranged from 20 to 52 (mean 37) years and
167 TABLE I Individualpatientdata Patient number
Sex @f/Q
Age tYr1
Age at orlset(yr)
Anti-epilepticdrugsb fmgiday~
W
I 1 2 3 4 5 6 7 8 9 10 11 12 13
Duration of Typeof therapyresistance seizurefl
M F M F M M F M F M M F F
37 38 26 20 52 36 30 37 44 41 42 31 31
8 10 20 11 45 16 14 11 8 25 8 25 12
29 27 6 9 7 20 16 17 36 10 34 18 19
CP, PSG CP, PSG CP CP, PSG CP CP CP CP CP A, TC, T, At CP CP CP
CBZ CBZ PHT CBZ CBZ CBZ oxc PHT PHT VPA CBZ CBZ CBZ
(WO), VPA (2700), CL2 (20) (500), VPA (1500), AZA (750) (400), VPA (2000) (400), AZA (750) (1000) (1600), PRI (1000) (1200), PRI (250) (350), AZA (500) (400) (2000) (lloa), CLB (40) (800), PHT (350) (700), CLN (5), AZA (500)
a CP, complex partial; PSG, partial secondary generalizing; A, absence; TC, tonic-clonic; T, tonic; At, atonic. b CBZ, carbamazepine; VPA, valproate; PHT, phenytoin; AZA, acetazolamide; PRI, primidone; OXC, oxcarbazepine; CLZ, clora- ezepate; CLB, clobazam; CLN, clonazepam.
the duration of therapy resistance from 6 to 36 (mean 19) years. Patients were excluded if they presented hepatic or renal disorders or progressive neurological anomalies. In addition, noncompliance, mental retardation, pregnancy, pregnancy potential and the use of co-medication (other than anti-epileptics or ~ntraceptives) were grounds for exclusion. The trial was run on an open basis. At the start of the study, all patients were using anti-epileptics, the dose of which was maintained throughout the trial. Two were on monotherapy, 7 were taking 2 anti-epileptics and 4 were using 3 anti-epileptic drugs. The most frequently prescribed anti-epileptics were carbamazepine (9 patients) and phenytoin and valproate (4 patients each) (Table I). The seizure frequency over the 12 weeks preceding the add-on administration of loreclezole was adopted as a baseline for the efficacy evaluation. The total treatment period lasted 6 months, and at the end of the trial the patient was given the option of continuing on the experimental drug. Initially, the investigator dosed loreclezole so as to reach a target plasma level of 1 mg/l. The loreclezole dose could be increased up to a m~imum of 3 mg/l as a function of the currently attained plasma levels
(measured regularly) and clinical need. The protocol allowed the dose to be lowered to that previously tolerated in the event of adverse experiences occurring. For safety analysis, the following haematological and biochemical variables were monitored monthly: haemoglobin, RBC, haematocrit, WBC, leucocyte differential count, platelet count, calcium, chloride, phosphorus, potassium, sodium, total protein, glucose, total cholesterol, total bilirubin, alkaline phosphatase, SGGT, LDH, ASAT, ALAT, creatinine, BUN and uric acid. Plasma concentrations of the anti-epileptic drugs and loreclezole were determined, by HPLC method, at the laboratory of the Kempenhaeghe epilepsy centre in Heeze (The Netherlands).
Fig. 1. Two-d~ension~
representation of the molecular structure of loreclezole.
168 TABLE II Mean (range) serum concentrations (mgll) of anti-epileptic drugs before and during treatment with loreclezole -Anti-epileptic drug
N
Basefine
At 2 months
At 4 months
Carbamazepine Valproate Phenytoin
9 4 4
6.9 (4.5-10.2) 59 (55-67) 16.7 (10.3-27.3)
7.4 (4.1-12.0) 56 (41-77) 16.7 (10.8-27.1)
6.3 (3.6-9.6)” 55 (42-67) 16.8 (12.2-25.3)
At 6 months __~_______.
6.9(4.0-11.3)a 57 (41-76) 18.4 (13.1-28.6)
a N = 8; one patient withdrawn because of change in carbamazepine dosage.
RESULTS Loreclezole add-on therapy was initiated at 40 mgiday in 4 patients and at 50 mglday in 9 patients. The doses were increased throughout the trial, and varied between 50 and 120 mglday at the end of treatment. The total daily dose was always administered as a single intake in the morning, During the trial, the mean plasma concentrations increased from 0.9 mg/l after 2 months to 1.7 and 2.1 mg/l after 4 and 6 months of treatment with loreclezole . The median seizure frequency before add-on therapy with loreclezole was 0.61 per day (range 0.20-2.23). At 2,4 and 6 months of treatment, the median frequencies were 0.34 (range 0.06-2.32) 0.27 (range 0.02-2.97) and 0.33 (range 0.07-2.69). All 3 decreases from baseline are sig% change +4n
~_
____~.
..--
r
nificant (Ztailed Wilcoxon test for intragroup comparisons: P = 0.001, P = 0.003 and P = 0.05). In addition to a substantial response at the initial dose, three patients presented further gains in the course of the dose increase. An overall reduction in seizure frequency of 23% was observed. A clinically relevant reduction (of 50% or more) in seizure frequency was observed in four patients (Fig. 2). One patient who had experienced only slight reduction in seizure frequency reported an appreciable diminution of seizure duration; whereas he had had sequences of seizures lasting on average 2 h before treatment, these lasted 10 min at the end of the study. Loreclezole was tolerated very well by most of the patients. One patient reported nausea and vomiting immediately after intake of the trial medication. This patient turned out to be intolerant of capsules (the dosage formulation of loreclezole in the study). Drowsiness and fatigue were reported by one patient. These adverse effects are, however, unlikely to be related to loreclezole, as they disappeared after reducing the dose of carbamazepine. No clinically significant changes were observed in haematological or biochemical variables. There were no systematic trends in changes in the serum levels of the concomitant antiepileptic drugs (Table II). The observed changes were minor and considered normal fluctuations, unrelated to the add-on therapy with loreclezole. DISCUSSION AND CONCLUSIONS
10
5. 12
7
3
8.- 8 --9 -.b lj
2
1
13
patient number Fig. 2. Individual % change in seizure frequency during the add-on treatment with loreclezole with respect to baseline.
Although results from an open trial should be interpreted with caution, it is tempting to conclude that the findings of this trial bear out the predic-
169
tion, based on animal models of epilepsy, that loreclezole has anticonvulsant properties. This trial clearly demonstrated that add-on therapy with loreclezole is useful for more than one-third of the patients. Given that these patients had been refractory to all commercially available antiepileptic drugs for several years, this result can be seen as being of particular clinical significance. The effects observed in this trial relate to loreclezole plasma concentrations in the range of l-3 mg/l. The plasma concentrations in the patients who did not respond were of the same order. For these patients, the question remains whether higher concentrations would be efficacious.
Loreclezole add-on treatment did not significantly interfere with the plasma levels of the concurrent anti-epileptic drugs. The reported effects cannot, therefore, be attributed to metabolic interaction with these substances. Finally, loreclezole was very well tolerated.
REFERENCES
4 Van de Velde, V. , Van Peer, A., De Beukelaar, F., Van Rooy, P., Woestenborghs, R., Heykants, J. and Vanden Bussche, G., Pharmacokinetics of R 72063 after single oral administration of a 100 mg dose to a healthy volunteer, Junssen Research Foundation, Clinical Research Report, January (1988) R 7206314(N 59724). 5 Wauquier, A., Fransen, J., Melis, W., Ashton, D., Gillardin, J.M. and Van Clemen, G., R 72063: a broad spectrum anticonvulsant, Janssen Research Foundation, Preclinical Research Report, February (1988) R 7206312(N 56239). 6 Wauquier, A., Melis, W. and Van den Broeck, W., R 72063 increases the threshold to generalized EEG seizures in dogs induced by metrazol infusion, Janssen Research Foundation, Preclinical Research Report, March (1988) R 7206316 (N 59941). 7 Wauquier, A., Smeyers, F., Melis, W. and Woestenborghs, R., R 72063 protects against metrazol-induced convulsions in dogs. Relationship to plasma levels, Junssen Research Foundation, Preclinical Research Report, March (1988) R 72063l7 (N 59942).
1 Jenkins, S.A., Edmonds, Jr., Paloheimo, M. and Zhang, Y.P., Anticonvulsant testing of R 72063 in a rat model of postischemic sound-induced convulsions, Janssen Research Foundation, Preclinical Reseach Report, December (1987) R 72063/g (N 62089). 2 Van de Velde, V., De Beukelaar, F., Van Rooy, P., Van Peer, A., Woestenborghs, R., Heykants, J. and Vanden Bussche, G., Multiple dose pharmacokinetics of R 72063 in healthy volunteers after oral administration of 50 mg o.d. for 7 days, followed by 10 mg/day for 14 days, Janssen Research Foundation, Clinical Research Report, April (1988) R 7206315(N 62347). 3 Van de Velde, V., De Beukelaar, F., Van Rooy, P., Van Peer, A., Woestenborghs, R., Vanden Bussche, G. and Heykants, J., Oral pharmacokinetics and bioavailability of R 72063 in healthy volunteers, Janssen Research Foundation, Clinical Research Report, September (1987) R 7206312 (N 56899).
ACKNOWLEDGEMENTS The authors thank F. de Beukelaar and Dr. L. Tritsmans, of the Janssen Research Foundation, for technical help and assistance in preparing this publication.