Pharmacokinetics and Pharmacogenetics of Carbamazepine in Children

Abstract

Although carbamazepine is one of the oldest anticonvulsant drugs, it is still heavily utilized for treatment of epilepsy in children. The aim of this article was to review the current knowledge about pharmacokinetics and pharmacogenetics of carbamazepine in children. The literature for this review was systematically searched for in the MEDLINE and SCINDEKS databases. Oral bioavailability of carbamazepine in children is about 75-85%, and it is approximately 75-85% bound to plasma proteins. Apparent volume of distribution is 1.2-1.9 l/kg and total clearance between 0.05 and 0.1 l/h/kg. Pharmacokinetics of carbamazepine in children is age and body weight dependent and highly variable due to influence of dosing regimen and co-medication. The current evidence on the importance of pharmacogenetics for carbamazepine efficacy and safety in children supports the association of PXR*1B, HNF4a rs2071197, CYP1A2*1F, ABCC2 1249G>A, and PRRT2 c.649dupC with either pharmacokinetics or pharmacodynamics of carbamazepine. The importance of human leukocyte antigen (HLA) typing for prediction of adverse drug reactions to carbamazepine in children is also confirmed. Both genetic and environmental factors are responsible for shaping pharmacokinetics and pharmacodynamics of carbamazepine in children. To ensure safe and effective use of carbamazepine in this population, physicians should adjust dosing regimen according to existing pattern of genetic and environmental influences.

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

“…PXR*1B, HNF4a rs2071197, CYP1A2*1F, ABCC2 1249G>A, and PRRT2 c.649dupC influence the pharmacokinetics and pharmacodynamics of carbamazepine [297]. ABCB1 c.3435C>T, CYP3A4*1G, CYP3A5*3, POR*28, and EPHX1 c.416A>G and c.128G>C variants influence carbamazepine metabolism in Chinese patients [298]. rs776746 and rs15524 in CYP3A5 affect carbamazepine metabolism, and rs2032582 and rs10234411 in ABCB1 contribute to interindividual variation in carbamazepine and in carbamazepine-10,11-epoxide transport in epileptic patients treated with carbamazepine in combination with phenytoin or phenobarbital [298].…”

“…ABCB1 c.3435C>T, CYP3A4*1G, CYP3A5*3, POR*28, and EPHX1 c.416A>G and c.128G>C variants influence carbamazepine metabolism in Chinese patients [298]. rs776746 and rs15524 in CYP3A5 affect carbamazepine metabolism, and rs2032582 and rs10234411 in ABCB1 contribute to interindividual variation in carbamazepine and in carbamazepine-10,11-epoxide transport in epileptic patients treated with carbamazepine in combination with phenytoin or phenobarbital [298]. SCN1A IVS5-91G>A, UGT2B7 c.802T>C, ABCC2 c.1249G>A, and EPHX1 c.337T>C carriers require higher maintenance doses of oxcarbamazepine [299,300].…”

Current role of carbamazepine and oxcarbazepine in the management of epilepsy

“…The NICE guidelines recommend CBZ or lamotrigine as first-line treatment in children and young people with newly diagnosed focal onset seizures, with a recommendation to use the controlled-release formulation if CBZ is used [86], In fact, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to CBZ, including focal and generalized tonic-clonic seizures [87], resulting in CBZ being still heavily utilized for the treatment of epilepsy in children (Djordjevic, Jankovic et al 2017). When treating children, we should however keep in mind that CBZ can aggravate some seizure types, especially absences (more common in children than in adults), myoclonic seizures, and tonic seizures, and it is contraindicated in Dravet syndrome.…”

“…Pharmacokinetics and pharmacodynamics of CBZ in children also depend on genetic and environmental factors; dosing regimens should take these into account to ensure safe and effective use of CBZ in this population [88]. Evidence also emphasizes the importance of HLA typing for prediction of adverse drug reactions to CBZ in children.…”

Precision Medicine in Non-Communicable Diseases

“…The response to a drug is multifactorial and therefore variability is due to the described set of genetic and environmental factors interacting with each other. In this context, genetic factors can play an important role at various physiological levels: absorption, transport, metabolism, and excretion of molecules (pharmacokinetics), as well as in the interaction with the target and the rapport between the concentration and effect (pharmacodynamics) [13,14]. Genetic differences in these processes in genes coding enzymes, receptors, and proteins involved in these steps may have an effect on efficacy and toxicity [12].…”