Children Versus Adults: Pharmacokinetic and Adverse‐Effect Differences

Abstract

Summary: Pharmacokinetic differences may play a part in the age-related differences in the incidence of adverse effects. The most common idiosyncratic reaction to lamotrigine (LTG) is rash, affecting 10-20% of patients. Risk factors are young age, concurrent valproate (VPA), high starting dose, and rapid escalation. In children, cytochrome P450 (CYP)-catalyzed metabolism is increased, and uridine diphosphate (UDP)-glucuronosyltransferase (UGT)-catalyzed metabolism is not significantly different from that in adults. A CYP-catalyzed arene oxide intermediate of LTG has been identified. The increase CYP metabolism of LTG in children could result in increased formation of the reactive metabolite and a higher incident of rash. Children often received higher milligram per kilogram doses compared with adults. The higher dose would cause an increased amount of LTG metabolized to the reactive arene oxide intermediate. VPA therapy is associated with a transient elevation in liver-function tests in 15-30% of patients and a rare, fatal hepatotoxicity. Most cases of VPA hepatotoxicity occurred in children younger than 2 years who had preexisting neurologic or other physical defects. Hypotheses regarding the pathogenesis of the hepatotoxicity include preexisting mitochondrial disease or inborn errors of metabolism, VPA inhibition of ␤-oxidation, and toxicity from VPA metabolites VPA, 4-ene-VPA, and 2,4-diene-VPA. Infants and children have higher concentration ratios of 4-ene-VPA to VPA. Polytherapy with enzyme inducers increases the formation of the hepatotoxic metabolites. The role of underlying metabolic disorders associated with hepatodegeneration and intractable seizures without VPA is a major confounder in identifying risk factors and demonstrates the difficulty in separating underlying disease factors in rare idiosyncratic reactions. Key Words: Antiepileptic drugs-Pharmacokinetics-Children-LamotrigineValproate.Many physiologic differences between neonates, infants, children, and adults can affect the absorption, distribution, metabolism, and excretion of antiepileptic drugs (AEDs) ( Table 1). The purpose of this article is to (a) provide a brief review of the pharmacokinetic differences between children and adults, and (b) to theorize how pharmacokinetic differences may play a part in the age-related differences in the incidence of adverse effects. Two idiosyncratic reactions, lamotrigine (LTG) rash and valproate (VPA) hepatotoxicity are discussed. For further information about the effects of age on the pharmacokinetics of AEDs, Battino et al. (1,2) recently published an extensive review of the pharmacokinetics of the AEDs in children. EFFECT OF AGE ON PHARMACOKINETICS IN CHILDREN AbsorptionNeonates and infants undergo significant maturation changes in gastric and intestinal pH, gastrointestinal (GI) emptying time, circulation, enzyme activity, and difference in GI flora (3,4). However, because of a lack of clinical studies, relatively little is known regarding the effects of GI maturation on the rate and extent of absor...

Effects of Valproic Acid on Proliferation, Apoptosis, Angiogenesis and Metastasis of Ovarian Cancer in Vitro and in Vivo

“…The side effects of VPA include gastrointestinal disturbances, elevation of hepatic enzymes, hyperammonemia, neurological disturbances, alopecia, weight gain, pancreatitis and thrombocytopenia (Dreifuss et al, 1988). VPA therapy may cause adverse effects other than renal injuries with hepatotoxicity being well known and developing in 15-30% of patients receiving VPA therapy (Anderson, 2002). In this study, no body weight loss or over toxic effects in the treated animals, which could be related to the drug treatment, was observed.…”

Population pharmacokinetic of antiepileptic drugs in different populations

“…Treatment of pediatric and adult patients with carbamazepine could be complicated due to various factors influenced on its disposition. Apart from physiological factors, numerous factors may alter CBZ pharmacokinetics [8,32], like specific diseases, nutritional habits or prior exposure to drug therapy. Many of these factors correlate with age and could be masked or passed unnoticed if pharmacokinetic modelling is based only on one population consisted of both children and adults.…”

Pharmacotherapy in pediatric epilepsy: rational drug and dose selection

“…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].…”

“…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].…”

“…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.…”