Pharmacotherapy in pediatric epilepsy: rational drug and dose selection

KEYWORDS:

• Antiepileptic drugs
• pharmacokinetic
• pharmacodynamic
• genetic polymorphisms
• AEDs metabolism
• P- Glycoprotein
• Cytochromes

1. Introduction

The aim of an optimal treatment of epilepsy is to individuate the appropriate antiepileptic drug (AED) with an adequate dose, to achieve a good control of seizures with few adverse events.

Despite an increasing number of available drugs, there is a poor understanding of pediatric pharmacokinetic and pharmacodynamic with an incomplete knowledge of dosing regimens for a tailored therapy. Children are at greater risk of toxic effects and their therapeutic response is more influenced by age-related variability. Safety and tolerability can be improved by a low starting dose with slow titration and the identification of efficient maintenance dose. Pharmacogenomics could clarify inter-individual genetic variations of treatment response in children. Another problem to take into account is that in the majority of cases the dose of treatment in children is extrapolated by data from studies in adults. In the efficacy of pediatric AED therapy, different aspects regarding physiological pharmacokinetics and pharmacodynamics play an important role, especially polymorphisms of proteins involved in transport of the substrates and enzymes involved in drug metabolism. In that regard must be considered the aspects of normal physiology in children, the consequences of polymorphisms of P-glycoprotein (PgP) and metabolic systems as Cytochrome P450 (CYP450) and UDP Glucuronyl Transferase (UGT).

2. Pharmacokinetic and pharmacodynamics of AEDs in children

Children have a different physiological response to AEDs drugs, due to different drug metabolism of the adults. Pharmacokinetic and pharmacodynamic knowledge suggests the maturing process in a continuing changeable organism at every age, from preterm neonates to adolescence. Children usually have faster drug elimination rates and reduced serum half-lives relative to adults; therefore, some children require almost twice the adult dosage, particularly if combination therapy with enzyme inducers is used. Because of a different gastric and intestinal pH in infant, AEDs absorption may be impaired with the result of a noneffective treatment. For example, gabapentin (GBP) is absorbed through a L-amino acid transporter in the gastrointestinal mucosa and is excreted by the kidney as unchanged drug. Its absorption process is saturable and its bioavailability is dose-dependent. Because renal clearance reaches adult levels at 1–2 years of age, and because GBP is not protein-bound, the higher oral clearance found is due to decreased bioavailability resulting from immature activity of the L-amino acid transporter, which limits absorption [1]. Regarding distribution, AED concentration is directly proportional to plasma-binding proteins and inversely to volume distribution. In healthy children, renal function is full mature at the age of 3 years and drugs elimination is similar to adults.

2.1. Cytochromes P450 and UDP-Glucuronosyltransferase polymorphisms: implication in metabolism of AEDs

Concerning drug metabolism, CYP P450 and UGT catalyze transformation of the most commonly used AEDs, although the latest AEDs GBP, levetiracetam, oxcarbazepine (OXC), and zonisamide (ZNS) are eliminated by renal metabolism and non-CYP or UGT pathways.

CYPs are a family of multiple enzymes, with the individual isozymes and eight primary isozymes are involved in the hepatic metabolism of most drugs (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). In children, isozyme, CYP3A4 accounts for 30% of the total hepatic CYP and is involved in the metabolism of >50% of all drugs.

UGTs are a family of enzymes that catalyze the transfer of a glucuronic acid moiety from a donor co-substrate uridine 5ʹ-diphospho- glucuronic acid (UDPGA) to an aglycone and are separated into two distinct families (UGT1 and UGT2). The influence of age on hepatic metabolism depends on the family of enzymes involved. Young children have an increased ability (greater than that of adults) to metabolize drugs eliminated by CYP-dependent metabolism, while after puberty CYP enzymatic activity has decreased to adult level. Children have an enzymatic performance significantly different from adults and for that reasons needed ‘therapeutic pediatric index’ for a desirable therapeutic window.

Moreover, genetic factors play an important role in AED response. In the following are reported some examples:

• Lamotrigine (LTG) is mainly metabolized by glucuronidation conjugation by UGT enzymes in hepatic microsomal fractions. In children receiving LTG monotherapy, a tendency to reduced serum concentration-to-dose ratio in children compared with adults has been demonstrated, because the oral LTG clearance decreases with increasing age [2]. Polymorphism of UGT1A4 enzyme may be related to low plasmatic concentration of LTG, while patients with single polymorphism for UGT2B7 enzyme showed great plasma concentrations related to lower clearance values [3].

• Also for Phenytoin (PHT) a great inter-individual variability exists. PHT is eliminated for the most part by CYP2C9- and CYP2C19-dependent hepatic metabolism. Young children (0–3 years) have a significantly higher mean maximal rate of metabolism (V_max) than adults, which gradually decreases during childhood to achieve adult levels during puberty [2]. Many studies have focused on genetic polymorphisms of CYP2C9, which makes up about 18% of the CYP450 protein in liver microsomes, more than 50 have been described in the regulatory and coding regions of the CYP2C9 gene. In particular, polymorphism 3 is highly associated with impaired drugs metabolism in epileptic patients. The genetic polymorphisms of CYP2C9*5, *6, *8 and CYP2c*1B, CYP2C9PM, and CYP2C9*3*3 were related to the metabolism of PHT increasing its plasma levels. In a recent study, the presence of CYP450 CYP2C9 polymorphisms in Indian epileptic children (5–12 years) was associated with low PHT levels [4].

• Glucuronidation is the primary passage of valproic acid (VPA) metabolism in adults, and in children expression of many UGTs is low. VPA plasma clearance is greater in young children than adults; however, glucuronidation does not appear to be responsible for the increased clearance. In a study conducted by Reith et al., the proportion of glucuronidation was lower in children less 10 years [2]. Yingjie Guo et al. have studied in Chinese children (mean age 7.8 ± 7.5 SD years) single-nucleotide polymorphisms involving UGT 1A6, UGT2B7, and CYP2C9 genes: patients with double heterozygosities at nucleotide positions T19G, A541G, and A552C in the UGT1A6 gene were associated with higher VPA doses compared to those with wild-type or single heterozygosity, and, on the contrary, there were no differences in VPA dose or concentrations among the UGT2B7*2 or CYP2C9*3 genotypic groups, suggesting that UGT1A6 mutations affect VPA metabolism in epileptic children [5].

• Influence of CYP polymorphisms have been studied on phenobarbital (PB). In an Asian study, the total clearance of PB decreased by 48% in patients with CYP2C9*1/*3 genotype in comparison with those with CYP2C9*1/*1 genotype. Author concluded that CYP2C9 genotype may affects the PB metabolism in routine care, however further evidence should be verified in other ethnic populations [6].

• Influence of CYP2C19 and CYP3A5 on clearance of zonisamide was assessed in patients with epilepsy with evidence of gene–dose effect for defective CYP2C19 but not for CYP3A5*3 genotype [7]. Further studies are needed to assess the extent of polymorphism in other ethnic populations.

2.2. The role of P-glycoprotein

P-glycoprotein is part of the family of ABC (ATP-binding cassette) proteins; in this group are included different kinds of receptors, membrane transporters, and ion channels. ABC family is composed by specialized membrane proteins using ATP hydrolysis to exploit energy; ABC transporters move various substrates across membranes, including ions, sugars, amino acids, polypeptides, an important role of the ATP family of protein is shifting through membranes toxic metabolites, xenobiotics, and even drugs and toxins. P-glycoprotein is the most represented drug efflux pump expressed at the blood brain barrier (BBB). PgP, also known as ABCB1 and CD43, is a transmembrane protein that allows ATP-dependent efflux of substrates from the cytoplasm and lipid bilayer into the blood. There are two genes encoding PgP: multidrug resistance 1 and 2 (MDR 1–2) located on chromosome 7q21.1. The MDR1 encode for the PgP that is considered the most important transporter in the brain. The expression of PgP is low for fetus and newborn and gradually rises to adult levels. PgP is overexpressed in endothelial cells of the BBB, it is located in the luminal membrane, but it is also present in the abluminal side of endothelial cells, pericytes, and astrocytes [8]. It is considered to have an important role on refractory epilepsy because it may reduce brain accumulation of AEDs acting like an efflux transporter. Studies on PgP demonstrated that its expression was higher in epileptic tissues than nonepileptic ones. In astrocytes and neurons of patients with tuberous sclerosis, mesial temporal lobe epilepsy, focal cortical dysplasia, and malformations of cortical development, the PgP is overexpressed. The positioning and the role on pharmacoresistance of PgP in vivo came from studies based on positron emission tomography using (11c) verapamil as substrate and tariquidar as inhibitor [9]. A study on 22 epilaptic patients (14 affected by refractory epilepsy patients and 8 seizure free on AEDs). A higher baseline PgP activity was observed in pharmacoresistant patients compared to seizure free patients in the bilateral hippocampus, ipsilateral amygdala, fusiform gyrus, inferior temporal gyrus and middle temporal gyrus; seizure frequency was directly proportional to its hippocampal activity. The increased activity of PgP on these regions could explain its role as efflux transporter of AEDs, leading to reduced susceptibility to therapy [10].

Studies on polymorphisms of ABCB1 gene revealed a great influence of genetic variability in AED pharmacokinetics, the presence of C 34C35 > T polymorphism was revealed in various ethnicities and was considered important not only for Asian population but also for Caucasian [11]. Some results are controversial; in particular, in a study on 82 children and adolescent (33 months to 18 years) with partial epilepsy, a relationship between this polymorphism of the MDR1 gene and drug resistance is not found, the most common genotype in the study group was the CT genotype (59.7%), followed by TT (28.1%) and CC (12.2%) [12].

In a study on Chinese patients, c.3435C>T was inversely proportional to carbamazepine (CBZ) plasma levels and its major metabolites. These data were confirmed also when CBZ is used in combination with PHT and PB [13].

ABCB1 polymorphisms (C1236T, G2677T/A, C3435T) were associated with reduced plasma levels of LTG, in particular the rs1128503 type [14].

Finally, eslicarbazepine acetate (ESL), oxcarbazepine (OXC), and the metabolite (S)-licarbazepine (S-LC) are described as PgP substrates; in particular, the transport of these drugs in concentration equilibrium conditions was evaluated in this order: ESL> OXC>S-LC>CBZ-E [15].

3. Conclusion

In conclusion, for various reasons, anticonvulsant therapy in pediatric age needs particular attention from clinicians. The knowledge of the different mechanisms of action, pharmacokinetics, pharmacodynamics, and adverse effects of AEDs is essential for a safe treatment in pediatric epilepsy.

4. Expert opinion

The knowledge of pharmacokinetics and pharmacodynamics of AEDs in pediatric patients is very limited. Pediatric dosing regimens are quite often results of empirical extrapolations from studies on adult patients.

Only observational data could help to compare a single medication with different doses, but, at the same time, the inefficacy of monotherapy leads to an add-on approach and a switch to polytherapy, which makes more difficult the dose selection.

In the clinical practice, dose regimens are different from others used on clinical trials because each considered patient overlaps with another. The rationale for starting dose and following adjustment is based on empirical procedures as titration considering the maximum dose tolerated or adjusting dose with body weight as a linear correlation.

Pharmacoresistance in pediatric age is another clinical problem of AED therapy and it is driven by multiple factors (e.g. mutations of transporter systems and voltage-gated ion channels) and not only by variations in pharmacokinetics variables.

For all these reasons, these genetic variables should be taken into account in the prediction of therapeutic response, in patients without an optimal pharmacological range and in these with refractory epilepsy. However, it is important to underline that it is still missing a clear application in the clinical practice of the genetic polymorphisms analysis. In light of the above, it would be advisable that genetic studies of these polymorphisms will be increased in pediatric patients. Recently, new pharmacogenomics approaches have shown promising results toward a tailored therapy to individual patients, with the goal of optimizing efficacy and safety thought better understanding of human genome variability and its influence on drug response. To give a practical example, mutant genotypes of CYP2C9*3 are responsible for reduced metabolism of PHT with increased serum concentrations, with a risk of toxicity, so in these patients might be desirable to reduce PHT dose at minimum effective dose. Similarly, the CYP2C9 status could guide a correct AED choice: in fact in children with two loss of function mutations CYP2C9 alleles (CYP2C9*2/*2, CYP2C9*3/*3, CYP2C9*2/*3), no VPA treatment is advisable to prevent adverse reactions, while a VPA dose adjustment could be enough in children carrying one or two wild-type CYP2C9 alleles.

At present, there are no sufficient and large studies that can contribute to detailed analysis regarding real clinical efficacy, to highlight potential confounding factors and to identify combinations of genetic polymorphisms which would allow generating personalized AED therapy in a select group of patients. The recent use of population pharmacokinetic modeling, incorporating the genotypes of drug-metabolizing enzyme in various studies has the purpose of help clinicians in the determination of individualized dosing regimens in AED therapy. In the recent years, there is an extremely sharp focus on PgP expression, the inhibition of p38 mitogen-activated protein kinase could down-regulate the expression of multidrug PgP in blood–brain barrier. In addition to this, the recent increasing interest to PgP inhibition by using nanoparticles system carrying AEDs should be mentioned.

Future research is directed toward the identification of new therapeutic strategies regarding molecules involved in modulation of drug receptors and molecules capable of modifying the expression of genes coding for MDR transporters and their application in large study population.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded