Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy.
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC4186992 | biostudies-other | 2014 Oct
REPOSITORIES: biostudies-other
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Project description:AIM: To establish a population pharmacokinetics (PPK) model of levetiracetam in Chinese children with epilepsy. METHODS: A total of 418 samples from 361 epileptic children in Peking University First Hospital were analyzed. These patients were divided into two groups: the PPK model group (n=311) and the PPK validation group (n=50). Levetiracetam concentrations were determined by HPLC. The PPK model of levetiracetam was established using NONMEM, according to a one-compartment model with first-order absorption and elimination. To validate the model, the mean prediction error (MPE), mean squared prediction error (MSPE), root mean-squared prediction error (RMSPE), weight residues (WRES), and the 95% confidence intervals (95% CI) were calculated. RESULTS: A regression equation of the basic model of levetiracetam was obtained, with clearance (CL/F)=0.988 L/h, volume of distribution (V/F)=12.3 L, and K(a)=1.95 h(-1). The final model was as follows: K(a)=1.56 h(-1), V/F=12.1 (L), CL/F=1.04×(WEIG/25)(0.583) (L/h). For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95%CI were 9.834 (-0.587-197.720), 50.919 (0.012-1286.429), 1.680 (0.021-34.184), and 0.0621 (-1.100-1.980). For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were 0.199 (-0.369-0.563), 0.002082 (0.00001-0.01054), 0.0293 (0.001-0.110), and 0.153 (-0.030-1.950). CONCLUSION: A one-compartment model with first-order absorption adequately described the levetiracetam concentrations. Body weight was identified as a significant covariate for levetiracetam clearance in this study. This model will be valuable to facilitate individualized dosage regimens.
| S-EPMC4010372 | biostudies-other
Project description:PurposeThe aims of the study were to develop a population pharmacokinetic model of orally administered brivaracetam in paediatric patients and to provide dosing suggestions.MethodsAnalysis included 600 brivaracetam plasma concentrations from a phase 2a study (NCT00422422; N01263) in 96 paediatric patients with epilepsy aged 1 month to 16 years, taking one to three concomitant antiepileptic drugs (AEDs). Pharmacokinetic analysis was performed using non-linear mixed effects modelling, and a stepwise covariate search was used to determine factors influencing brivaracetam clearance. Simulations were performed to investigate dosing regimens.ResultsThe final model consisted of first-order absorption, single compartment distribution and first-order elimination components with allometric scaling of clearance and volume using lean body weight and fixed allometric exponents. Co-administration with phenobarbital or carbamazepine was associated with a 29% (95%CI 17%/39%) and 32% (22%/42%) decrease in exposure, respectively. Co-administration with valproate was associated with an 11% (1%/23%) increase in exposure. Simulations demonstrated that the majority of children were predicted to have an exposure similar to that in adults, using an age-independent dosing regimen of 2.0 mg/kg bid with a maximum of 100 mg bid for body weight >50 kg.ConclusionsA paediatric dose adaptation of 2.0 mg/kg twice daily with a maximum of 100 mg twice daily for body weight >50 kg is predicted to ensure steady-state plasma concentrations in the same range as in adult patients receiving 100 mg twice daily (highest recommended dose). Data suggest no need to change brivaracetam dosing when used concomitantly with carbamazepine, phenobarbital or valproate.
| S-EPMC5423986 | biostudies-literature
Project description:Cyclosporine (CsA) is characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability, particularly in juvenile patients. The aims of this study were to build a population pharmacokinetic model of CsA in Chinese children with hematopathy who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to identify covariates affecting CsA pharmacokinetics. A total of 86 Chinese children aged 8.4 ± 3.8 years (range 1.1-16.8 years) who received allo-HSCT were enrolled. Whole blood samples were collected before allo-HSCT. Genotyping was performed using an Agena MassARRAY system. A total of 1010 trough plasma concentration values of CsA and clinical data were collected. The population pharmacokinetic model of CsA was constructed using nonlinear mixed-effects modeling (NONMEM) software. The stability and performance of the final model were validated using bootstrapping and normalized prediction distribution errors. We showed that a one-compartment model with first-order elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL) and volume of distribution (V) were 42.3 L/h and 3100 L, respectively. Body weight, postoperative days, CYP3A4*1 G genotype, estimated glomerular filtration rate and coadministration of triazole antifungal drugs were identified as significant covariates for CL. Weight and postoperative days were significant covariates for the V of CsA. Our model can be adopted to optimize the CsA dosing regimen for Chinese children with hematopathy receiving allo-HSCT.
| S-EPMC7471407 | biostudies-literature
Project description:Children with epilepsy (EPI) have a higher rate of attention-deficit/hyperactivity disorder (ADHD; 28-70%) than typically developing (TD) children (5-10%); however, attention is multidimensional. Thus, we aimed to characterize the profile of attention difficulties in children with epilepsy.Seventy-five children with localization-related epilepsy ages 6-16 years and 75 age-matched controls were evaluated using multimodal, multidimensional measures of attention including direct performance and parent ratings of attention as well as intelligence testing. We assessed group differences across attention measures, determined if parent rating predicted performance on attention measures, and examined if epilepsy characteristics were associated with attention skills.The EPI group performed worse than the TD group on timed and complex attention aspects of attention (p < 0.05), whereas performance on simple visual and simple auditory attention tasks was comparable. Children with EPI were 12 times as likely as TD children to have clinically elevated symptoms of inattention as rated by parents, but ratings were a weak predictor of attention performance. Earlier age of onset was associated with slower motor speed (p < 0.01), but no other epilepsy-related clinical characteristics were associated with attention skills.This study clarifies the nature of the attention problems in pediatric epilepsy, which may be under-recognized. Children with EPI had difficulty with complex attention and rapid response, not simple attention. As such, they may not exhibit difficulty until later in primary school when demands increase. Parent report with standard ADHD screening tools may under-detect these higher-order attention difficulties. Thus, monitoring through direct neuropsychological performance is recommended.
| S-EPMC4457628 | biostudies-other
Project description:Vortioxetine is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder. Vortioxetine is orally administered once daily at 5- to 20-mg doses. The pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing. The mean absolute oral bioavailability of vortioxetine is 75%. No food effect on pharmacokinetics was observed. Vortioxetine is metabolized by cytochrome P450 enzymes and subsequently by uridine diphosphate glucuronosyltransferase. The major metabolite is pharmacologically inactive, and the minor pharmacologically active metabolite is not expected to cross the blood-brain barrier, making the parent compound primarily responsible for in-vivo activity. No clinically relevant differences were observed in vortioxetine exposure by sex, age, race, body size, and renal or hepatic function. Dose adjustment is only recommended for cytochrome P450 2D6 poor metabolizers based on polymorphism of the cytochrome P450 enzymes involved. Similarly, except for bupropion, a strong cytochrome P450 2D6 inhibitor, and rifampin, a broad cytochrome P450 inducer, co-administration of other drugs evaluated did not affect the vortioxetine exposure or safety profile in any clinically meaningful way. Pharmacodynamic studies demonstrated that vortioxetine achieved high levels of serotonin transporter occupancy in relevant brain areas, affected neurotransmitter levels in the cerebrospinal fluid, and modified abnormal resting state networks in the brain over the therapeutic dose range. Overall, vortioxetine can be administered in most populations studied to date without major dose adjustments; however, dose adjustments should be considered on a patient-by-patient basis.
| S-EPMC5973995 | biostudies-literature
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.).
| S-EPMC4249354 | biostudies-literature
Project description:Doxycycline is a tetracycline-class antimicrobial labeled by the United States (U.S.) Food and Drug Administration for children >8 years of age for many common childhood infections. Doxycycline is not labeled for children ≤8 years of age, due to the association between tetracycline class antibiotics and tooth staining, although doxycycline may be used off-label in severe conditions. Accordingly, there is a paucity of pharmacokinetic (PK) data to guide dosing in children 8 years and younger. We leveraged opportunistically-collected plasma samples after intravenous (IV) and oral doxycycline doses received per standard of care to characterize the PK of doxycycline in children of different ages, and evaluated the effect of obesity and fasting status on PK parameters.We developed a population PK model of doxycycline using data collected from 47 patients 0-18 years of age, including 14 participants ≤8 years. We developed a 1 compartment PK model and found doxycycline clearance to be 3.32 L/h/70 kg and volume to be 96.8 L/70kg for all patients; comparable to values reported in adults. We estimated a bioavailability of 89.6%, also consistent with adult data. Allometrically scaled clearance and volume of distribution did not differ between children 2 to ≤8 years of age and children >8 to ≤18 years of age, suggesting that younger children may be given the same per kg dosing. Obese and fasting status were not selected for inclusion in the final model. Additional doxycycline PK samples collected in future studies may be used to improve model performance and maximize its clinical value.
| S-EPMC6879254 | biostudies-literature
Project description:Background: Intranasal application is a comfortable, effective, nearly non-invasive, and easy route of administration in children. To date, there is, however, only one pharmacokinetic study on intranasal dexmedetomidine in pediatric populations and none in Chinese children available. Therefore, this study aimed to characterize the pharmacokinetics of intranasally administered dexmedetomidine in Chinese children. Methods: Thirteen children aged 4 to 10 years undergoing surgery received 1 µg/kg dexmedetomidine intranasally. Arterial blood samples were drawn at various time points until 180 min after dose. Dexmedetomidine plasma concentrations were measured with high performance liquid chromatography (HPLC) and mass spectrometry. Pharmacokinetic modeling was performed by population analysis using linear compartment models with first-order absorption. Results: An average peak plasma concentration of 748 ± 30 pg/ml was achieved after 49.6 ± 7.2 min. The pharmacokinetics of dexmedetomidine was best described by a two-compartment model with first-order absorption and an allometric scaling with estimates standardized to 70-kg body weight. The population estimates (SE) per 70 kg bodyweight of the apparent pharmacokinetic parameters were clearance CL/F = 0.32 (0.02) L/min, central volume of distribution V1/F = 34.2 (4.9) L, intercompartmental clearance Q2/F = 10.0 (2.2) L/min, and peripheral volume of distribution V2/F = 34.9 (2.3) L. The estimated absorption rate constant was Ka = 0.038 (0.004) min-1. Conclusions: When compared with studies in Caucasians, Chinese children showed a similar time to peak plasma concentration after intranasal administration, but the achieved plasma concentrations were about three times higher. Possible reasons are differences in age, ethnicity, and mode of administration.
| S-EPMC6624439 | biostudies-literature
Project description:Background:In order to improve the precision of treatment with tacrolimus in Chinese patients undergoing pediatric liver transplantation, the optimum initial dose of tacrolimus was determined based on population pharmacokinetics and pharmacogenomics. Methods:Demographic data, clinical parameters, drug combinations and pharmacogenomics were integrated to build a population pharmacokinetic model using NONMEM. Additionally, Monte Carlo simulations were used to optimize the recommended initial dose. Results:Weight, patient cytochrome 450 3A (CYP3A)5 genotype, and co-administration with wuzhi-capsule (WZ) were incorporated into the final model. For children with a CYP3A5*3/*3 genotype not co-administered WZ, 0.10 mg/kg/day split into two doses was recommended for patients weighing 5-17 kg, and 0.05 mg/kg/day split into two doses was recommended for patients weighing 17-60 kg. For children with a CYP3A5*1 allele not co-administered WZ, 0.25 mg/kg/day for patients weighing 5-10 kg, 0.20 mg/kg/day for patients weighing 10-17 kg, 0.15 mg/kg/day for patients weighing 17-36 kg, and 0.10 mg/kg/day for patients weighing 36-60 kg; all split into two doses was recommended. For children with a CYP3A5*3/*3 genotype co-administered WZ, 0.10 mg/kg/day for patients weighing 5-11 kg, and 0.05 mg/kg/day for patients weighing 11-60 kg; both split into two doses was recommended. For children with a CYP3A5*1 allele who were co-administered WZ, 0.20 mg/kg/day for patients weighing 5-10 kg, 0.15 mg/kg/day for patients weighing 10-22 kg, and 0.10 mg/kg/day for patients weighing 22-60 kg all split into two doses was recommended. Conclusions:The optimal initial dose of tacrolimus was determined based on population pharmacokinetics and pharmacogenomics in Chinese patients undergoing pediatric liver transplantation.
| S-EPMC7658763 | biostudies-literature
Project description:Lamotrigine (LTG) is a second-generation anti-epileptic drug widely used for focal and generalized seizures in adults and children, and as a first-line medication in pregnant women and women of childbearing age. However, LTG pharmacokinetics shows high inter-individual variability, thus potentially leading to therapeutic failure or side effects in patients. This prospective study aimed to establish a population pharmacokinetics model for LTG in Chinese patients with epilepsy and to investigate the effects of genetic variants in uridine diphosphate glucuronosyltransferase (UGT) 1A4, UGT2B7, MDR1, ABCG2, ABCC2, and SLC22A1, as well as non-genetic factors, on LTG pharmacokinetics. The study population consisted of 89 patients with epilepsy, with 419 concentrations of LTG. A nonlinear mixed effects model was implemented in NONMEM software. A one-compartment model with first-order input and first-order elimination was found to adequately characterize LTG concentration. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. The use of valproic acid decreased CL/F by 38.5%, whereas the co-administration of rifampicin caused an increase in CL/F of 64.7%. The CL/F decreased by 52.5% in SLC22A1-1222AA carriers. Patients with the ABCG2-34AA genotype had a 42.0% decrease in V/F, whereas patients with the MDR1-2677TT and C3435TT genotypes had a 136% increase in V/F. No obvious genetic effect of UGT enzymes was found relative to the concentrations of LTG in Chinese patients. Recommended dose regimens for patients with different gene polymorphisms and comedications were estimated on the basis of Monte Carlo simulations and the established model. These findings should be valuable for developing individualized dosage regimens in adult and adolescent Chinese patients 13-65 years of age.
| S-EPMC6669232 | biostudies-literature