Eur J Clin Pharmacol (1991) 40:197-198 European J . . . . . ' o f ( ~ l i ~ : ~ i ( ~ e l
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0031697091000568
© Springer-Verlag 1991
Letters to the editors
Interaction between isoniazid and valproate: a case of valproate overdosage A. P. Jonville 1, A. S. Gauchez 2, E. Autret 1, C. Billard 3, R B arbier 1, F. Ns abiyumva 2, and M. Breteau 2 Departments of 1 Pharmaco-Toxicovigilance, 2 Pharmacology and Toxicology and :~ PaediatricNeurology, C.H.U. Bretnonneau, Tours, France Received: June 13/July 4, 1990/Accepted in revised form: July 27,1990
Key words: Isoniazid - valproate; interaction, valproate overdosage, Case report A number of studies has shown that isoniazid can inhibit the metabolism of several drugs, including phenytoin [1] and carbamazepine [2]. Only one previous case of a possible interaction between isoniazid and valproate has been described, in which the sequence of events suggested a pharmacodynamic interaction, manifested as an adverse reaction [3]. A case of possible enzymatic inhibition of valproate metabolism by isoniazid is now presented. A 51/2-year-old girl with left partial seizures as a sequel of meningeal haemorrhage had been unsuccessfully treated with phenobarbitone, carbamazepine, diazepam and clonazepam. In February 1988, valproate 600 mg/d and clonazepam 1.25 mg/d were prescribed, since when she has been seizure free. In September 1988, because of a positive tuberculin reaction, she received isoniazid 200 mg/d (10 mg-kg-1). Shortly afterwards, she became drowsy and asthenic. On 17th October 88 the plasma valproate was 121 mg-1 -~ (therapeutic range 50-100 rag. l- t). On 30th November 88 she had tremor and hypersomnia associated with a plasma valproate of 139 mg-1-1. Clonazepam therapy was stopped and the dose of valproate was decreased to 450 mg daily. On 28th December 88 the plasma concentration of valproate was 108 mg. 1-1, and the dose was further decreased to 325 mg/d. The activity of the polymorphic hepatic N-acetyltransferase indicated that she was a slow acetylator of isoniazid, so the dose was decreased to 50 mg daily. In February 1989, convulsions recurred and ethosuccimide was added (250 rag/d). The plasma concentrations then w e r e : valproate 61 mg. 1-1, ethosuccimide 102 rag- 1-1 and isoniazid 0.6 gg. ml- ~. Because of its low plasma concentration, the dose of isoniazid was increased to 100 mg/d. The plasma valproate level was then 81 mg- 1 1. Isoniazid was stopped in March 1989, after 6 months of monotherapy. On 4th April 89, the plasmatic level of valproate was 75 rag. 1-I at the dose of 225 mg/d. She was admitted to hospital on 7th September 1989, after 3 episodes of
seizures, with a plasma valproate of 51 mg-1 l and of ethosuccimide 40 mg-1-1 within the lower therapeutic limit. The daily dose of valproate had to be increased to 400 mg and then to 600 mg to obtain a therapeutic plasma valproate concentration of 75 mg- 1-1. The sequence of events in this case suggest a valproate-isoniazid interaction, in which isoniazid led to the toxic plasma concentrations of valproate. The child had previously received valproate 600 mg daily for 7 months without any problem. A 62% decrease in the valproate dose was needed to maintain a therapeutic plasma level of valproate when isoniazid was co-administered. On the 700
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@%e ecele@
0031697091000568
© Springer-Verlag 1991
Letters to the editors
Interaction between isoniazid and valproate: a case of valproate overdosage A. P. Jonville 1, A. S. Gauchez 2, E. Autret 1, C. Billard 3, R B arbier 1, F. Ns abiyumva 2, and M. Breteau 2 Departments of 1 Pharmaco-Toxicovigilance, 2 Pharmacology and Toxicology and :~ PaediatricNeurology, C.H.U. Bretnonneau, Tours, France Received: June 13/July 4, 1990/Accepted in revised form: July 27,1990
Key words: Isoniazid - valproate; interaction, valproate overdosage, Case report A number of studies has shown that isoniazid can inhibit the metabolism of several drugs, including phenytoin [1] and carbamazepine [2]. Only one previous case of a possible interaction between isoniazid and valproate has been described, in which the sequence of events suggested a pharmacodynamic interaction, manifested as an adverse reaction [3]. A case of possible enzymatic inhibition of valproate metabolism by isoniazid is now presented. A 51/2-year-old girl with left partial seizures as a sequel of meningeal haemorrhage had been unsuccessfully treated with phenobarbitone, carbamazepine, diazepam and clonazepam. In February 1988, valproate 600 mg/d and clonazepam 1.25 mg/d were prescribed, since when she has been seizure free. In September 1988, because of a positive tuberculin reaction, she received isoniazid 200 mg/d (10 mg-kg-1). Shortly afterwards, she became drowsy and asthenic. On 17th October 88 the plasma valproate was 121 mg-1 -~ (therapeutic range 50-100 rag. l- t). On 30th November 88 she had tremor and hypersomnia associated with a plasma valproate of 139 mg-1-1. Clonazepam therapy was stopped and the dose of valproate was decreased to 450 mg daily. On 28th December 88 the plasma concentration of valproate was 108 mg. 1-1, and the dose was further decreased to 325 mg/d. The activity of the polymorphic hepatic N-acetyltransferase indicated that she was a slow acetylator of isoniazid, so the dose was decreased to 50 mg daily. In February 1989, convulsions recurred and ethosuccimide was added (250 rag/d). The plasma concentrations then w e r e : valproate 61 mg. 1-1, ethosuccimide 102 rag- 1-1 and isoniazid 0.6 gg. ml- ~. Because of its low plasma concentration, the dose of isoniazid was increased to 100 mg/d. The plasma valproate level was then 81 mg- 1 1. Isoniazid was stopped in March 1989, after 6 months of monotherapy. On 4th April 89, the plasmatic level of valproate was 75 rag. 1-I at the dose of 225 mg/d. She was admitted to hospital on 7th September 1989, after 3 episodes of
seizures, with a plasma valproate of 51 mg-1 l and of ethosuccimide 40 mg-1-1 within the lower therapeutic limit. The daily dose of valproate had to be increased to 400 mg and then to 600 mg to obtain a therapeutic plasma valproate concentration of 75 mg- 1-1. The sequence of events in this case suggest a valproate-isoniazid interaction, in which isoniazid led to the toxic plasma concentrations of valproate. The child had previously received valproate 600 mg daily for 7 months without any problem. A 62% decrease in the valproate dose was needed to maintain a therapeutic plasma level of valproate when isoniazid was co-administered. On the 700
250
°-°
/
600
200 i
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.\
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/
Z,O0
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200 50 tsoniazid/./J
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