scholarly journals A Review of Population Pharmacokinetic Studies of Levetiracetam

2020 ◽  
Author(s):  
Ziran Li ◽  
Chenyu Wang ◽  
Xiao Zhu ◽  
Zheng Jiao
Keyword(s):  
Renal Function ◽  
Target Population ◽  
Volume Of Distribution ◽  
Drug Clearance ◽  
The Body ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Apparent Clearance ◽  
Adults And Children ◽  
Study Designs

Background: Levetiracetam has been widely used as a treatment option for different types of epilepsy in both adults and children. Because of its large between-subject variability, several population pharmacokinetic studies have been performed to identify its pharmacokinetic covariates, and thus facilitate individualised therapy. Objective: The aim of this review was to provide a synopsis for population pharmacokinetic studies of levetiracetam and explore identified influencing covariates. Methods: We systematically searched PubMed and Embase databases from inception to June 30, 2020. The information on study designs, target population, model characteristics, and identified covariates were summarised. Moreover, the pharmacokinetic profiles were compared among neonates, children, and adults. Results: A total of 14 studies were included, among which two involved neonates, four involved children, two involved both children and adults, and six involved only adults. The median value of apparent clearance for children (0.074 [range: 0.038 to 0.079] L/h/kg) was higher than that for adults (0.054 [range: 0.039 to 0.061] L/h/kg). Body weight was found to influence the apparent clearance and volume of distribution significantly, whereas renal function influenced the clearance. Likewise, co-administration with enzyme-inducing antiepileptic drugs (such as carbamazepine and phenytoin) increased the drug clearance by 9 to 22%, whereas coadministration with valproate acid decreased it by 18.8%. Conclusion: Levetiracetam dose regimen is dependent on the body size and renal function of patients. Further studies are needed to evaluate levetiracetam pharmacokinetics in neonates and pregnant women.

scholarly journals Population Pharmacokinetic Study of Ceftriaxone in Elderly Patients, Using Cystatin C-Based Estimates of Renal Function To Account for Frailty

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Shu Jin Tan ◽  
Matthew Cockcroft ◽  
Madhu Page-Sharp ◽  
Glenn Arendts ◽  
Timothy M. E. Davis ◽  
...  
Keyword(s):  
Renal Function ◽  
Elderly Patients ◽  
Cystatin C ◽  
Pharmacokinetic Study ◽  
Severe Renal Impairment ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Total Exposure ◽  
Population Pharmacokinetic Study ◽  
Trough Concentrations

ABSTRACT Ceftriaxone is widely used for respiratory and urinary infections in elderly and frail patients, but there are few pharmacokinetic studies. A prospective population pharmacokinetic study of ceftriaxone in adults over 65 years old was undertaken. Dried blood spots collected at baseline (predose) and 0.5, 1, 4, 8, and 24 h after administration of 1 g of ceftriaxone were assayed using a validated liquid chromatography-mass spectroscopy analytical method. Frailty was classified using the Edmonton frailty scale and grip strength via a hand dynamometer. Estimates of glomerular filtration rate were determined using creatinine-based and cystatin C-based equations. Of 26 patients recruited, 23 (88%) were vulnerable or very frail. Estimates of drug clearance improved significantly with a cystatin C-based estimate of renal function that accounted for frailty. Simulations indicate that the combined effects of ranges of size and renal function resulted in a 6-fold range in peak ceftriaxone concentrations and 9-fold range in total exposure (area under the concentration-time curve [AUC]). For elderly patients with moderate or severe renal impairment, 48-h dosing results in greater trough concentrations and total exposure than the trough concentrations and total exposure in patients with normal renal function receiving 24-h dosing. Cystatin C-based measures of renal function improved predictions of ceftriaxone clearance in elderly patients.

scholarly journals Population Pharmacokinetic Study of Cefathiamidine in Infants With Augmented Renal Clearance

2021 ◽  
Vol 12 ◽  
Author(s):  
Bin Du ◽  
Yue Zhou ◽  
Bo-Hao Tang ◽  
Yue-E Wu ◽  
Xin-Mei Yang ◽  
...  
Keyword(s):  
Renal Clearance ◽  
Pharmacokinetic Study ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Augmented Renal Clearance ◽  
Population Pharmacokinetic Study ◽  
Dosing Regimens

Objectives: Augmented renal clearance (ARC) of primarily renally eliminated antibacterial agents may result in subtherapeutic antibiotic concentrations and, as a consequence, worse clinical outcomes. Cefathiamidine is frequently used as empirical antimicrobial therapy in children with ARC, but pharmacokinetic studies in infants are lacking. This population pharmacokinetic study in infants with ARC was conducted to determine optimal dosing regimens of cefathiamidine.Methods: The population pharmacokinetics was conducted in 20 infants treated with cefathiamidine. Plasma samples of cefathiamidine were collected using opportunistic sampling, and the concentrations were detected by UPLC-MS/MS. Data analysis was performed to determine pharmacokinetic parameters and to characterize pharmacokinetic variability of cefathiamidine using nonlinear mixed effects modelling (NONMEM) software program.Results: The data (n = 36) from 20 infants (age range, 0.35–1.86 years) with ARC were fitted best with a 1-compartment model. Allometrically scaled weight and age as significant covariates influenced cefathiamidine pharmacokinetics. The median (range) values of estimated clearance and the volume of distribution were 0.22 (0.09–0.29) L/h/kg and 0.34 (0.24–0.41) L/kg, respectively. Monte Carlo simulations showed that the cefathiamidine doses of 100 mg/kg/day q12 h, 50 mg/kg/day q8 h and 75 mg/kg/day q6 h were chosen for bacteria with MIC 0.25, 0.5 and 2 mg/L, respectively.Conclusion: The population pharmacokinetic model of cefathiamidine for infants with ARC was developed. The PTA - based dosing regimens were recommended based on the final model.

scholarly journals Population Pharmacokinetics of Peramivir in Healthy Volunteers and Influenza Patients

2015 ◽  
Vol 59 (11) ◽  
pp. 6755-6762 ◽  
Author(s):  
Yumiko Matsuo ◽  
Toru Ishibashi ◽  
Alan S. Hollister ◽  
Toshihiro Wajima
Keyword(s):  
Renal Function ◽  
Plasma Concentration ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
The United States ◽  
Volume Of Distribution ◽  
Elderly Subjects ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Concentration Data

ABSTRACTPeramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. subjects. Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.

scholarly journals Population Pharmacokinetic Analyses for BC-3781 Using Phase 2 Data from Patients with Acute Bacterial Skin and Skin Structure Infections

2014 ◽  
Vol 59 (1) ◽  
pp. 282-288 ◽  
Author(s):  
C. M. Rubino ◽  
B. Xue ◽  
S. M. Bhavnani ◽  
W. T. Prince ◽  
Z. Ivezic-Schoenfeld ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Size ◽  
Phase 1 ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Phase 2 ◽  
Data Set ◽  
Skin Structure ◽  
Population Pk

ABSTRACTBC-3781, a pleuromutilin antimicrobial agent, is being developed for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia. Data from a phase 2 study of patients with ABSSSI were used to refine a previous population pharmacokinetic (PK) model and explore potential predictors of PK variability. The previously derived population PK model based on data from three phase 1 studies was applied to sparse sampling data from a phase 2 ABSSSI study and modified as necessary. Covariate analyses were conducted to identify descriptors (e.g., body size, renal function, age) associated with interindividual variability in PK. All population PK analyses were conducted by using Monte Carlo parametric expectation maximization implemented in S-ADAPT 1.5.6. The population PK data set contained 1,167 concentrations from 129 patients; 95% of the patients had 5 or more PK samples (median, 11). The previous population PK model (three-compartment model with first-order elimination and nonlinear protein binding) provided an acceptable and unbiased fit to the data from the 129 patients. Population PK parameters were estimated with acceptable precision; individual clearance values were particularly well estimated (median individual precision of 9.15%). Graphical covariate evaluations showed no relationships between PK and age or renal function but modest relationships between body size and clearance and volume of distribution, which were not statistically significant when included in the population PK model. This population PK model will be useful for subsequent PK-pharmacodynamic analyses and simulations conducted to support phase 3 dose selection. (This study has been registered at ClinicalTrials.gov under registration no. NCT01119105.)

scholarly journals Factors influencing elimination and distribution of fleroxacin: metaanalysis of individual data from 10 pharmacokinetic studies.

1996 ◽  
Vol 40 (3) ◽  
pp. 575-580 ◽  
Author(s):  
B G Reigner ◽  
H A Welker
Keyword(s):  
Body Weight ◽  
Volume Of Distribution ◽  
Linear Increase ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Lean Body Weight ◽  
Systemic Availability ◽  
Pharmacokinetic Studies ◽  
Age And Gender ◽  
And Gender

A metaanalysis was conducted on data from 172 subjects (healthy volunteers and uninfected patients) included in 10 pharmacokinetic studies of fleroxacin after oral administration. The objectives of this analysis were (i) to estimate the typical values of two key pharmacokinetic parameters, clearance over systemic availability (CL/F) and volume of distribution over systemic availability (V/F), after the administration of therapeutic doses and (ii) to study qualitatively and quantitatively the factors which influence the elimination and distribution of fleroxacin. The main pharmacokinetic parameters, CL/F and V/F, were analyzed separately by a standard two-stage approach. The covariates investigated were predicted creatinine clearance (CLCR), age, gender, body surface area, body weight, and lean body weight (LBW). The predicted CL/F and V/F were 83.5 ml/min and 101 liters, respectively, for a typical male subject (CLCR, 70 ml/min; LBW, 54 kg; age, 54 years). Modeling of CL/F indicated that this parameter increases linearly with CLCR, decreases linearly with age, and is 10.8 ml/min lower in females than in males. The best model for V/F showed a linear increase with LBW and a linear decrease with age. V/F was found to be 20.4 liters greater in males than in females. In conclusion, this metaanalysis has shown that CLCR, age, and gender influence the elimination of fleroxacin from the body, whereas V/F is influenced by LBW, age, and gender.

scholarly journals Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia

2017 ◽  
Vol 88 (5) ◽  
pp. 316-323 ◽  
Author(s):  
Rika Kizu ◽  
Kazuko Nishimura ◽  
Reiko Sato ◽  
Kenjiro Kosaki ◽  
Toshiaki Tanaka ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
The Body ◽  
Pharmacokinetic Analysis ◽  
Hyperinsulinemic Hypoglycemia ◽  
Population Pharmacokinetic ◽  
Nonlinear Mixed Effects Model ◽  
First Time

Background: Diazoxide is the first-line treatment for pediatric hyperinsulinemic hypoglycemia (HI). This study aimed to elucidate the pharmacokinetics of diazoxide in children with HI. Methods: We obtained 81 blood samples from 22 children with HI. Measured serum diazoxide concentrations were used for population pharmacokinetic analysis. Patient factors influencing pharmacokinetics were estimated using nonlinear mixed-effects model analysis. Relationships between drug exposure and adverse drug reactions were also investigated. Results: Diazoxide disposition in the body was described by a 1-compartment model. Oral clearance (CL/F) and the volume of distribution were proportional to body weight (WT), as expressed by CL/F in males (liters/h) = 0.0358 + 0.00374 × WT (kg). CL/F in females was 39% greater than that in males. Steady-state concentrations of diazoxide were similar following twice- and 3 times-daily dosing when the total daily doses were comparable. A patient whose serum diazoxide concentration exceeded 100 μg/mL over a 4-month period developed hyperglycemia. No significant correlation was observed between severity of hirsutism and diazoxide concentration. Conclusion: We have proposed for the first time a population pharmacokinetic model for diazoxide in children with HI. The potential risk of diabetes mellitus and/or hyperglycemia increases when serum concentrations of diazoxide exceed 100 μg/mL.

scholarly journals Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1708
Author(s):  
Alexandre Marouille ◽  
Emma Petit ◽  
Courèche Kaderbhaï ◽  
Isabelle Desmoulins ◽  
Audrey Hennequin ◽  
...  
Keyword(s):  
Mean Transit Time ◽  
Real Life ◽  
Metastatic Breast ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Poppk Model ◽  
Apparent Clearance ◽  
Kinetics Of

Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A population pharmacokinetic (popPK) model was first constructed to describe palbociclib pharmacokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/pharmacodynamic (PK/PD) model to depict the relation between palbociclib concentrations and absolute neutrophil counts (ANC). The models were built with a population of 143 patients. Palbociclib samples were routinely collected during therapeutic drug monitoring, whereas ANC were retrospectively retrieved from the patient files. The optimal popPK model was a mono-compartmental model with a first-order absorption constant of 0.187 h−1 and an apparent clearance Cl/F of 57.09 L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (Tlag: 0.658 h) were fixed to values from the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib Cl/F. To describe ANC kinetics during treatment, Friberg’s PK/PD model, with linear drug effect, was used. Parameters estimated were Base (2.92 G/L; 29.6% IIV), Slope (0.0011 L/µg; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and γ (0.102). The only significant covariate was age on the initial ANC (Base), with lower ANC in younger patients. PK/PD model-based simulations show that the higher the estimated CressSS (trough concentration at steady state), the higher the risk of developing neutropenia. In order to present a risk lower than 20% to developing a grade 4 neutropenia, the patient should show an estimated CressSS lower than 100 µg/L.

scholarly journals Population Pharmacokinetic Analysis of Amikacin for Optimal Pharmacotherapy in Korean Patients with Nontuberculous Mycobacterial Pulmonary Disease

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 784
Author(s):  
Xuanyou Jin ◽  
Jaeseong Oh ◽  
Joo-Youn Cho ◽  
SeungHwan Lee ◽  
Su-jin Rhee
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Pulmonary Disease ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Compartment Model ◽  
The Body ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Properties

Amikacin is used as a therapy for patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) who are resistant to macrolide antibiotics or have severe symptoms. This study aimed to characterize the pharmacokinetic properties of amikacin in patients with NTM-PD by developing a population pharmacokinetic model and to explore the optimal pharmacotherapy in patients with NTM-PD. For this study, all data were retrospectively collected. The amikacin pharmacokinetic properties were best described by a two-compartment model with first-order elimination. The estimated glomerular filtration rate and body weight were identified as significant covariates for clearance and the volume of distribution, respectively. A model-based simulation was conducted to explore the probability of reaching the target therapeutic range when various dose regimens were administered according to the body weight and renal function. The simulation results indicated that the amikacin dosage should be determined based on the body weight, and for patients who weigh over 70 kg, it is necessary to adjust the dose according to renal function. In conclusion, the optimal pharmacotherapy of amikacin for patients with NTM-PD was recommended based on the population pharmacokinetic model, which is expected to enable the personalization of drug therapy and improve the clinical outcomes of amikacin therapy.

Pharmacokinetic studies on Sulfamonomethoxine in rabbits

2019 ◽  
Vol 20 (2) ◽  
pp. 92-97
Author(s):  
M Amer ◽  
M Elsayed ◽  
S Kazawaki ◽  
W Fathy ◽  
Eman El-Ashry
Keyword(s):  
Half Life ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
The Body ◽  
Pharmacokinetic Studies ◽  
Plasma Drug ◽  
Time Data ◽  
Drug Concentrations ◽  
Two Compartment Model

The present study was performed to determine the pharmacokinetics of sulfamonomethoxine (20mg/kg) in 5 rabbits after its oral and intravenous administration. Blood samples were collected immediately before (time 0) and at 0.08, 0.25, 0.5, 1, 3, 5 and 8 hours post-dosing to evaluate the pharmacokinetics of sulfamonomethoxine. Plasma sulfamonomethoxine concentrations were quantified with HPLC-UV, and plasma drug concentration versus time data after IV was best fitted to the two-compartment model, characterized with the distribution phase (α) equaled to 2.05 h-1 with a distribution half-life [t0.5(α)] equaled to 0.61 h. The volume of distribution of (V1c) was 0.15 ml/kg., whereas the volume of distribution at a steady – state [Vdss] was 0.20 ml/kg, and the body clearance was 0.03 ml/ kg / h. After oral administration of SMM, plasma drug concentrations were best fitted to a two-compartment model, of which the mean half-life of absorption (t1/2ab) and elimination (t1/2β) were 0.02 and 1.99 h, respectively. The maximal absorption concentration (Cmax) was estimated as 114.06 µg/ml at 0.12 h, and the Area under the curve (AUC) was 340.42 µg/ml/h.

Sign in / Sign up

Export Citation Format

Share Document