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Development of an innovative paediatric formulation of an antiepileptic agent for the treatment of absence epilepsy in children

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Childhood epilepsy treatment

Epilepsy is a common chronic neurologic disorder that affects 1-3 % of the population. When it comes to childhood absence epilepsy (CAE), a paediatric formulation of an antiepileptic drug is long overdue.

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A significant proportion of epilepsy syndromes have their onset in childhood and adolescence, and there is a great heterogeneity with respect to syndrome type, causes and prognoses. CAE manifests with frequent, unpredictable, unprovoked absence seizures that usually involve impairment of consciousness. Patients often have family history, and in some cases, the condition is transmitted by autosomal recessive inheritance. The symptoms and potential comorbidities of CAE could affect patient social behaviour, self-esteem and learning ability. The current treatment strategy is to initiate a monotherapy with one of the anti-epileptic drugs. However, the currently available formulation of one of the first-line treatment options is not adapted to paediatric needs. According to the European Medicines Agency, this gap in pharmacokinetic and safety data in children restricts the widespread use of the drug and emphasises the need for an age-appropriate formulation. With this in mind, the EU-funded KIEKIDS project performed the pharmaceutical development of a paediatric formulation for the treatment of CAE with documented safety and efficacy. The consortium conducted a complete clinical programme, previously endorsed by scientific advice and approval of a paediatric investigation plan (PIP) on an adapted paediatric free-sugar formulation (ADV6770) of a first-line CAE antiepileptic drug. Researchers assessed the pharmacokinetic profile of ADV6770 alongside its palatability before proceeding to safety and tolerability studies. A tasteless formulation avoided compliance problems linked to the bitter taste of the active compound while the emission of sugar was compatible with a ketogenic diet that is sometimes the next step in the treatment process. The drug was stable in human plasma and required no further clinical validation, given that the active compound had been previously documented for efficacy. A clinical trial was conducted to obtain the pharmacokinetic, pharmacodynamic, and safety data of different formulations against the commercially available reference formulation. Results conform towards the clinical use of ADV6770, which is expected to help researchers obtain a paediatric use marketing authorisation (PUMA). The availability of this novel age-adapted formulation across the EU is expected to improve the conditions of care for CAE patients.

Keywords

Childhood absence epilepsy, paediatric formulation, pharmacokinetic, safety, KIEKIDS

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