Medicines optimisation of phenytoin in Saudi children: a pharmacokinetics approach

Abstract

Epilepsy is a chronic neurological disorder which causes unprovoked recurrent seizures. A seizure occurs because of an unexpected rush, due to abnormal and sudden electrical activity in the brain. In Saudi Arabia, epilepsy is a common neurological disorder, occurring in 6.54 per 1,000 of the general population and with a prevalence rate recorded of between 0.5–1% among a paediatric population (Khan, 2015). The pediatric population consists of very distinct subtypes. These subpopulations vary in terms of body weight and size, physiology, as well as biochemistry. Thus, disease pathophysiology and receptors’ response to medication significantly alters during this process from infancy to childhood, and distinctly differs from that of adulthood. These differences will exert a huge impact on the drug’s concentration levels over time, which includes the absorption, distribution, metabolism and excretion (ADME) profile. Also, these age-dependent changes play an important role in the way in which the body’s organs work, the pathophysiology of disease, biotransformation inside the body and the pharmacological receptors’ response in the first two years of life. Taking these changes into account is crucial in determining the PK parameters, in order to identify the initial doses and to ensure that the optimal therapeutic outcomes result in a paediatric population (Hong Lu, 2014). Selecting appropriate AED is critical in light of the clinical challenges associated with the narrow therapeutics index. This presents as an even greater challenge in a paediatric population. Phenytoin (PHT) is one of the most widely used drugs to treat epilepsy in a paediatric population. As one of the oldest AED, it is commonly administered as a broad spectrum of seizures can exist . Therefore, the aim of this study is to evaluate the paediatric population pharmacokinetics (PKs) of phenytoin (PHT) in Saudi patients, as well as to identify factors affecting therapeutic outcomes. Methodology : SimCyp v.17.0 is a virtual clinical trials simulation system designed by SimCyp Ltd (Sheffield, UK), was used to perform population-based physiologically-based pharmacokinetic (PBPK) modelling. This study was applied a pre-validated phenytoin model which was developed by Simcyp to the Saudi population. Then to validate our data and model, and to examine the consistence of phenytoin (PHT) in Saudi paediatric patients, other clinical studies were used. simulations were performed for adults healthy volunteers , geriatric population, obese , morbidly obese population , liver cirrhosis A,B, and , C population , Caucasian , and Saudi paediatric population as well as for phenytoin-Rifampicin drug-drug interaction. The Data were extract from clinical studies using WebPlotDigitizer v.3.10 (San Francisco, CA, USA). Statistical analysis was performed using t-test. Results : The findings indicate significant differences between the Saudi peadiatric population and the Caucasian peadiatric population for 0-11 age group in our study. For the age group of 11-17 years, however, the differences were limited.