Dataset Information

Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children.

ABSTRACT:

Aims

Oxcarbazepine is an antiepileptic drug with an activity mostly due to its monohydroxy derivative metabolite (MHD). A parent-metabolite population pharmacokinetic model in children was developed to evaluate the consistency between the recommended paediatric doses and the reference range for trough concentration (C_trough ) of MHD (3-35 mg l^-1 ).

Methods

A total of 279 plasma samples were obtained from 31 epileptic children (age 2-12 years) after a single dose of oxcarbazepine. Concentration-time data were analysed with Monolix 4.3.2. The probability to obtain C_trough between 3-35 mg l^-1 was determined by Monte Carlo simulations for doses ranging from 10 to 90 mg kg^-1 day^-1 .

Results

A parent-metabolite model with two compartments for oxcarbazepine and one compartment for MHD best described the data. Typical values for oxcarbazepine clearance, central and peripheral distribution volume and distribution clearance were 140 l h^-1 70 kg^-1 , 337 l 70 kg^-1 , 60.7 l and 62.5 l h^-1 , respectively. Typical values for MHD clearance and distribution volume were 4.11 l h^-1 70 kg^-1 and 54.8 l 70 kg^-1 respectively. Clearances and distribution volumes of oxcarbazepine and MHD were related to body weight via empirical allometric models. Enzyme-inducing antiepileptic drugs (EIAEDs) increased MHD clearance by 29.3%. Fifty-kg children without EIAEDs may need 20-30 mg kg^-1 day^-1 instead of the recommended target maintenance dose (30-45 mg kg^-1 day^-1 ) to obtain C_trough within the reference range. By contrast, 10-kg children with EIAEDs would need 90 mg kg^-1 day^-1 instead of the maximum recommended dose of 60 mg kg^-1 day^-1 .

Conclusion

This population pharmacokinetic model of oxcarbazepine supports current dose recommendations, except for 10-kg children with concomitant EIAEDs and 50-kg children without EIAEDs.

SUBMITTER: Rodrigues C

PROVIDER: S-EPMC5698580 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children.

Rodrigues Christelle C Chiron Catherine C Rey Elisabeth E Dulac Olivier O Comets Emmanuelle E Pons Gérard G Jullien Vincent V

British journal of clinical pharmacology 20170920 12

<h4>Aims</h4>Oxcarbazepine is an antiepileptic drug with an activity mostly due to its monohydroxy derivative metabolite (MHD). A parent-metabolite population pharmacokinetic model in children was developed to evaluate the consistency between the recommended paediatric doses and the reference range for trough concentration (C<sub>trough</sub> ) of MHD (3-35 mg l<sup>-1</sup> ).<h4>Methods</h4>A total of 279 plasma samples were obtained from 31 epileptic children (age 2-12 years) after a single d ...[more]

PMID: 28771787

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Project description:BackgroundTherapeutic drug monitoring of antiepileptic drugs (AEDs) is often necessary to prevent associated destructive toxicities. Tandem mass spectrometry (MS/MS) with stable-isotope-labeled internal standards is considered the gold standard for the measurement of AEDs. This study presents the development and validation of a clinical ultra-performance liquid chromatography-MS/MS method for the concurrent measurement of gabapentin, lamotrigine, levetiracetam, monohydroxy derivative of oxcarbazepine, and zonisamide in human serum.MethodsTo determine the optimal assay analyte range, one year of AED therapeutic drug monitoring results (n = 1825) were evaluated. Simple protein precipitation with acetonitrile containing isotopically labeled internal standards was used. Reverse-phase ultra-performance liquid chromatography chromatographic separation was used, having a total run time of 3 minutes. Quantification of analytes was accomplished using electrospray ionization in positive ion mode and collision-induced dissociation MS. Assay parameters were evaluated per Food and Drug Administration bioanalytical guidelines.ResultsAfter evaluating internal patient data, the analytical measuring range (AMR) of the assay was established as 0.1-100 mcg/mL. All AEDs were linear across the AMR, with R values ranging from 0.9988 to 0.9999. Imprecision (% coefficient of variation) and inaccuracy (% difference) were calculated to be <20% for the lower limit of quantitation and <15% for the low, mid, and high levels of quality controls across the AMR. All AEDs demonstrated acceptable assay parameters for carryover, stability under relevant storage conditions, matrix effects, recovery, and extraction and processing efficiency. In addition, the assay displayed acceptable concordance to results obtained from a national reference laboratory, with Deming regression R of 0.99 and slope values ranging from 0.89 to 1.17.ConclusionsA simple, cost-effective, and robust ultra-performance liquid chromatography-tandem mass spectrometry method for monitoring multiple AEDs was developed and validated to address the clinical needs of patients at our institution.

Project description:Teicoplanin is frequently administered to treat Gram-positive infections in pediatric patients. However, not enough is known about the pharmacokinetics (PK) of teicoplanin in children to justify the optimal dosing regimen. The aim of this study was to determine the population PK of teicoplanin in children and evaluate the current dosage regimens. A PK hospital-based study was conducted. Current dosage recommendations were used for children up to 16 years of age. Thirty-nine children were recruited. Serum samples were collected at the first dose interval (1, 3, 6, and 24 h) and at steady state. A standard 2-compartment PK model was developed, followed by structural models that incorporated weight. Weight was allowed to affect clearance (CL) using linear and allometric scaling terms. The linear model best accounted for the observed data and was subsequently chosen for Monte Carlo simulations. The PK parameter medians/means (standard deviation [SD]) were as follows: CL, [0.019/0.023 (0.01)] × weight liters/h/kg of body weight; volume, 2.282/4.138 liters (4.14 liters); first-order rate constant from the central to peripheral compartment (Kcp), 0.474/3.876 h(-1) (8.16 h(-1)); and first-order rate constant from peripheral to central compartment (Kpc), 0.292/3.994 h(-1) (8.93 h(-1)). The percentage of patients with a minimum concentration of drug in serum (Cmin) of <10 mg/liter was 53.85%. The median/mean (SD) total population area under the concentration-time curve (AUC) was 619/527.05 mg · h/liter (166.03 mg · h/liter). Based on Monte Carlo simulations, only 30.04% (median AUC, 507.04 mg · h/liter), 44.88% (494.1 mg · h/liter), and 60.54% (452.03 mg · h/liter) of patients weighing 50, 25, and 10 kg, respectively, attained trough concentrations of >10 mg/liter by day 4 of treatment. The teicoplanin population PK is highly variable in children, with a wider AUC distribution spread than for adults. Therapeutic drug monitoring should be a routine requirement to minimize suboptimal concentrations. (This trial has been registered in the European Clinical Trials Database Registry [EudraCT] under registration number 2012-005738-12.).

Dataset Information

Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children.

Aims

Methods

Results

Conclusion

Publications

Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children.

Similar Datasets

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