Tolerability of tariquidar - A third generation P-gp inhibitor as add-on medication to antiseizure medications in drug-resistant epilepsy.
Seizure
; 119: 44-51, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38776617
ABSTRACT
PURPOSE:
P-glycoprotein (P-gp) has been hypothesized to be involved in drug-resistance of epilepsy by actively extruding antiseizure medications (ASMs) from the brain. The P-gp inhibitor tariquidar (TQD) has been shown to effectively inhibit P-gp at the human blood-brain barrier, improving brain entry of several ASMs. A potential strategy to overcome drug-resistance is the co-administration of P-gp inhibitors such as TQD to ASMs. Here we present data on the tolerability of single-dose TQD as a potential add-on medication to ASMs.METHODS:
We performed a multi-centre cohort study including drug-resistant epilepsy patients and healthy controls from the United Kingdom and Austria. TQD was administered intravenously at five different doses (2 mg/kg or 3 mg/kg of TQD were given to drug-resistant epilepsy patients and healthy controls, higher doses of TQD at 4 mg/kg, 6 mg/kg and 8 mg/kg as well as a prolonged infusion aiming at a dose of 6 mg/kg were only given to healthy controls). Adverse events were recorded and graded using the Common Terminology Criteria (CTCAE) scale. Additionally, TQD plasma concentration levels were measured and compared between drug-resistant patients and healthy controls.RESULTS:
In total, 108 participants received TQD once at variable doses and it was overall well tolerated. At doses of 2 or 3 mg/kg TQD, only two of the 19 drug-resistant epilepsy patients and a third of the healthy controls (n = 14/42) reported adverse events probably related to TQD. The majority of those adverse events (96 %) were reported as mild. One drug-resistant epilepsy patient reported adverse events 24-hours after TQD administration possibly related to TQD-induced increased ASMs levels in the brain.CONCLUSIONS:
TQD is an effective and well tolerated P-gp inhibitor as a single dose and could potentially be used intermittently in conjunction with ASMs to improve efficacy. This promising strategy to overcome drug-resistance in epilepsy should be investigated further in clinical randomised controlled trials.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
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Epilepsia Resistente a Medicamentos
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Anticonvulsivantes
Limite:
Adolescent
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Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Seizure
Ano de publicação:
2024
Tipo de documento:
Article