The impact of age on lamotrigine and oxcarbazepine kinetics: A historical cohort study

Wegner, Ilse; Wilhelm, Abraham J.; Sander, Josemir W.; Lindhout, Dick

doi:10.1016/j.yebeh.2013.07.016

Cited by 24 publications

(14 citation statements)

References 28 publications

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“…In the structural model selection step, we observed that a one-compartment model with first-order absorption and elimination best characterized the PK in Chinese epileptic children aged 2 months to 18 years according to a preliminary analysis of the goodness-of-fit. This result is the same as previous modeling performed in other studies [1][2][3]19] . The typical population values of the pharmacokinetic parameters estimated in final model were as follows: θ Ka =0.83 h -1 , θ Vd =0.67 L/kg, θ CL =0.035 L·kg -1 ·h -1 , and the corresponding t 1/2 =13.3 h, t max =3.6 h. These values are similar to the existing parameters that were reported in traditional PK studies [4,5,7,8,18,20] focusing on healthy adult subjects (V d =0.7-0.8 L/kg or 49 L, t 1/2 =7-20 h, t max =3-12 h).…”

Section: Discussionsupporting

confidence: 91%

“…The typical population values of the pharmacokinetic parameters estimated in final model were as follows: θ Ka =0.83 h -1 , θ Vd =0.67 L/kg, θ CL =0.035 L·kg -1 ·h -1 , and the corresponding t 1/2 =13.3 h, t max =3.6 h. These values are similar to the existing parameters that were reported in traditional PK studies [4,5,7,8,18,20] focusing on healthy adult subjects (V d =0.7-0.8 L/kg or 49 L, t 1/2 =7-20 h, t max =3-12 h). The typical absorption rate constant (θ Ka ) of this study was higher than was found in pediatric patients aged 4 to 17 years in an earlier PPK study (θ Ka =0.598 h -1 ) [2] , but lower than in adults (θ Ka =1.0 h -1 ) [19] . In the current study, the typical apparent volume of distribution (θ Vd ) was lower than Northam et al [1] found in infants and young children aged 1 month to 4 years [θ Vd =1.45±0.11 L/kg (monotherapy or concomitant nonenzyme-inducing antiepileptic drugs) or θ Vd =1.39±0.23 L/kg (concomitant enzyme-inducing antiepileptic drugs)], but similar to Park's result [3] (θ Vd =49 L, equals 0.78 L/kg normalized by a typical weight of 62.8 kg).…”

Section: Discussioncontrasting

confidence: 76%

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Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy

et al. 2014

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Aim: To develop a population pharmacokinetics model of oxcarbazepine in Chinese pediatric patients with epilepsy, and to study the interactions between oxcarbazepine and other antiepileptic drugs (AEDs). Methods: A total of 688 patients with epilepsy aged 2 months to 18 years were divided into model (n=573) and valid (n=115) groups. Serum concentrations of the main active metabolite of oxcarbazepine, 10-hydroxycarbazepine (MHD), were determined 0.5-48 h after the last dosage. A population pharmacokinetics (PPK) model was constructed using NLME software. This model was internally evaluated using Bootstrapping and goodness-of-fit plots inspection. The data of the valid group were used to calculate the mean prediction error (MPE), mean absolute prediction error (MAE), mean squared prediction error (MSE) and the 95% confidence intervals (95% CI) to externally evaluate the model.

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Section: Discussionsupporting

confidence: 91%

Section: Discussioncontrasting

confidence: 76%

Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy

et al. 2014

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“…However, the use of steroid hormones was an exclusion criterion . By contrast, a third study from the same group as the second one, found no effect of postmenopausal age on LTG clearance . Finally, the fourth study found a lower LTG clearance in women of postmenopausal age .…”

Section: Discussionmentioning

confidence: 83%

“…A PubMed search identified only four relevant studies, and they produced conflicting results. Increased, unchanged, and reduced LTG clearance was found in postmenopausal women . Moreover, only one of these studies specifically addressed HRT …”

mentioning

confidence: 99%

Hormone replacement therapy with estrogens may reduce lamotrigine serum concentrations: A matched case–control study

Reimers

2016

Epilepsia

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SUMMARYLamotrigine (LTG) is an antiepileptic drug that is metabolized via glucuronidation. Since the glucuronidizing enzyme is inducible by estrogens, LTG serum concentrations may fall by 50-60% when combined with hormonal contraceptives that contain ethinyl estradiol (EE). Little is known about a possible interaction between estrogens used for hormone replacement therapy (HRT) and LTG, and the few available data are conflicting. Data from serum samples analyzed for LTG were therefore retrieved from a routine therapeutic drug monitoring database. Users of HRT and EE were identified and matched with controls for age and dose. No enzyme-inducing or enzyme-inhibiting comedication was allowed. LTG serum concentration-todose ratios (CDRs) were calculated. Case groups and their respective control groups were compared by the Mann-Whitney U test. Seventy-nine HRT users (dose range 1-4 mg/day) and 200 EE users (dose range 20-40 lg/day), as well as 158 and 400 matching controls, respectively, could be included. Both EE users and HRT users had significantly lower mean LTG CDRs than their respective matched controls. These results suggest that HRT with estrogens may reduce serum LTG concentrations.

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“…Much of this can be explained by the induction of the cytochrome P450 enzyme CYP3A4. 22 A limitation of the study is that AED dosage was not reliably recorded in our cohort and we had to make an assumption that the measurement of CBZ metabolic ratio was independent of the individual subject's dosage. 17 Phenytoin and phenobarbital induce CYP3A4 and thus can lower plasma CBZ levels but leave the metabolite levels unaltered, which results in the observed higher metabolic ratio.…”

Section: Modelmentioning

confidence: 99%

A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

et al. 2019

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Summary Objective To ascertain the clinical and genetic factors contributing to carbamazepine‐ and oxcarbazepine‐induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross‐sectional cohort of people with epilepsy. Methods We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ‐diol to unchanged drug precursor substrate as measured in serum. Results Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome‐wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome‐wide significant associations with CBZ metabolic ratio were found. Significance Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.

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The impact of age on lamotrigine and oxcarbazepine kinetics: A historical cohort study

Cited by 24 publications

References 28 publications

Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy

Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy

Hormone replacement therapy with estrogens may reduce lamotrigine serum concentrations: A matched case–control study

A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

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