Dataset Information

Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children.

ABSTRACT: AIMS:Population pharmacokinetic modelling has been widely used across many therapeutic areas to identify sources of variability, which are incorporated into models as covariate factors. Despite numerous publications on pharmacokinetic drug-drug interactions (DDIs) between antiepileptic drugs (AEDs), such data are not used to support the dose rationale for polytherapy in the treatment of epileptic seizures. Here we assess the impact of DDIs on plasma concentrations and evaluate the need for AED dose adjustment. METHODS:Models describing the pharmacokinetics of carbamazepine, clobazam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproic acid and zonisamide in adult and paediatric patients were collected from the published literature and implemented in NONMEM v7.2. Taking current clinical practice into account, we explore simulation scenarios to characterize AED exposure in virtual patients receiving mono- and polytherapy. Steady-state, maximum and minimum concentrations were selected as parameters of interest for this analysis. RESULTS:Our simulations show that DDIs can cause major changes in AED concentrations both in adults and children. When more than one AED is used, even larger changes are observed in the concentrations of the primary drug, leading to significant differences in steady-state concentration between mono- and polytherapy for most AEDs. These results suggest that currently recommended dosing algorithms and titration procedures do not ensure attainment of appropriate therapeutic concentrations. CONCLUSIONS:The effect of DDIs on AED exposure cannot be overlooked. Clinical guidelines must consider such covariate effects and ensure appropriate dosing recommendations for adult and paediatric patients who require combination therapy.

SUBMITTER: van Dijkman SC

PROVIDER: S-EPMC5736836 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children.

van Dijkman Sven C SC Rauwé Willem M WM Danhof Meindert M Della Pasqua Oscar O

British journal of clinical pharmacology 20171107 1

<h4>Aims</h4>Population pharmacokinetic modelling has been widely used across many therapeutic areas to identify sources of variability, which are incorporated into models as covariate factors. Despite numerous publications on pharmacokinetic drug-drug interactions (DDIs) between antiepileptic drugs (AEDs), such data are not used to support the dose rationale for polytherapy in the treatment of epileptic seizures. Here we assess the impact of DDIs on plasma concentrations and evaluate the need f ...[more]

PMID: 28815754

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Project description:BackgroundPhysicians, nurses and hospital pharmacists were surveyed to assess attitudes of hospital-based pediatric caregivers regarding the dosing of medicine to children. Our objectives were to gauge how current resources are utilized to guide the management of pediatric pharmacotherapy, assess drugs and drug classes where guidance is most critical and examine the prevalence and practice of dose adjustment in pediatric patients.MethodsQuestionnaire categories included demographics, pharmacotherapy resources, dosing adjustment and modification, and valuation of additional tools to provide improved pharmacotherapy guidance. The questionnaire was developed in collaboration with representative nurse, pharmacist and physician team members using the SurveyMonkey.com site and survey tool. The survey link was distributed to caregivers via email. The questionnaire results of 303 respondents were collected into MS Excel and imported into SAS for data summarization.ResultsA total of 313 responses were obtained. Physician and nurse practitioner groups comprised the majority of the responses. Approximately 80% of the responders considered dosing adjustment important in pediatric pharmacotherapy. While there was general satisfaction with available resources, nearly 75% responded in support of access to predictive tools that facilitate individualized patient pharmacotherapy. The majority of respondents (> 65%) indicated that dosing outside standard practice occurs in 1-20% of their patients, while still a substantial number of respondents (a range of 8 to 20% reflecting the resident and fellow categories) estimated between 20 and 50% of their patients required adjustments outside the standard practice.ConclusionsDifferences in prescribing habits based on caregiver role, specialty and location were small and likely require further exploration. Existing resources are generally viewed as helpful but inadequate to guide recommendations for individual patients. Decision support systems connected to hospital-based electronic medical records offer the promise of informative and individualized pharmacotherapy guidance.

Project description:ImportanceBreastfeeding is known to have beneficial effects, but concern exists that breastfeeding during maternal antiepileptic drug (AED) therapy may be harmful. We previously noted no adverse effects of breastfeeding associated with AED use on IQ at age 3 years, but IQ at age 6 years is more predictive of school performance and adult abilities.ObjectivesTo examine the effects of AED exposure via breastfeeding on cognitive functions at age 6 years.Design, setting, and participantsProspective observational multicenter study of long-term neurodevelopmental effects of AED use. Pregnant women with epilepsy receiving monotherapy (ie, carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled from October 14, 1999, through April 14, 2004, in the United States and the United Kingdom. At age 6 years, 181 children were assessed for whom we had both breastfeeding and IQ data. All mothers in this analysis continued taking the drug after delivery.Main outcomes and measuresDifferential Ability Scales IQ was the primary outcome. Secondary measures included measures of verbal, nonverbal, memory, and executive functions. For our primary analysis, we used a linear regression model with IQ at age 6 years as the dependent variable, comparing children who breastfed with those who did not. Similar secondary analyses were performed for the other cognitive measures.ResultsIn total, 42.9% of children were breastfed a mean of 7.2 months. Breastfeeding rates and duration did not differ across drug groups. The IQ at age 6 years was related to drug group (P < .001 [adjusted IQ worse by 7-13 IQ points for valproate compared to other drugs]), drug dosage (regression coefficient, -0.1; 95% CI, -0.2 to 0.0; P = .01 [higher dosage worse]), maternal IQ (regression coefficient, 0.2; 95% CI, 0.0 to 0.4; P = .01 [higher child IQ with higher maternal IQ]), periconception folate use (adjusted IQ 6 [95% CI, 2-10] points higher for folate, P = .005), and breastfeeding (adjusted IQ 4 [95% CI, 0-8] points higher for breastfeeding, P = .045). For the other cognitive domains, only verbal abilities differed between the breastfed and nonbreastfed groups (adjusted verbal index 4 [95% CI, 0-7] points higher for breastfed children, P = .03).Conclusions and relevanceNo adverse effects of AED exposure via breast milk were observed at age 6 years, consistent with another recent study at age 3 years. In our study, breastfed children exhibited higher IQ and enhanced verbal abilities. Additional studies are needed to fully delineate the effects of all AEDs.Trial registrationclinicaltrials.gov Identifier: NCT00021866.

Dataset Information

Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children.

Publications

Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children.

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