scholarly journals Adjunctive Perampanel Oral Suspension in Pediatric Patients From ≥2 to <12 Years of Age With Epilepsy: Pharmacokinetics, Safety, Tolerability, and Efficacy

2019 ◽  
Vol 34 (5) ◽  
pp. 284-294 ◽  
Author(s):  
J. Ben Renfroe ◽  
Mark Mintz ◽  
Ronald Davis ◽  
Jose Ferreira ◽  
Sharon Dispoto ◽  
...  
Keyword(s):  
Population Pharmacokinetic Analysis ◽  
Oral Suspension ◽  
Extension Phase ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Open Label ◽  
Core Study ◽  
Adults And Children

Study 232, an open-label pilot study with an extension phase, evaluated the pharmacokinetics and preliminary safety/tolerability and efficacy of adjunctive perampanel oral suspension (≤0.18 mg/kg/d) in epilepsy patients aged ≥2 to <12 years. Patients were grouped into cohorts 1 (aged ≥7 to <12 years) and 2 (aged ≥2 to <7 years). The Core Study included pretreatment (≤2 weeks) and treatment phases (7-week titration; 4-week maintenance; 4-week follow-up [for those not entering the extension]). The extension phase consisted of 41-week maintenance and 4-week follow-up periods. Pharmacokinetic data were pooled with adolescent pharmacokinetic data from phase II/III studies. Population pharmacokinetic analysis showed that perampanel pharmacokinetics was independent of age, weight, or liver function, suggesting age- or weight-based dosing is not required and that the same dose can be given to adults and children to achieve exposures shown to be efficacious. Perampanel was well tolerated and efficacious for ≤52 weeks.

scholarly journals A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children

2016 ◽  
Vol 81 (4) ◽  
pp. 679-687 ◽  
Author(s):  
Alessandro Schipani ◽  
Henry Pertinez ◽  
Rachel Mlota ◽  
Elizabeth Molyneux ◽  
Nuria Lopez ◽  
...  
Keyword(s):  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Adults And Children

Prospective evaluation of a developed S-1 dosage formula based on renal function.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 86-86
Author(s):  
Takuro Mizukami ◽  
Masashi Takeuchi ◽  
Chiyo K. Imamura ◽  
Eisuke Booka ◽  
HIROYA TAKEUCHI ◽  
...  
Keyword(s):  
Renal Function ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Target Area ◽  
Time Curve ◽  
And Gender ◽  
A Prospective Study ◽  
Clinical Trial Information

86 Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP, inhibitor of dihydoropyrimidine dehydrogenase) and potassium oxonate. Because CDHP is excreted in urine, renal dysfunction increases incidence of severe adverse drug reactions due to higher exposure of 5-FU. As approved dose of S-1 is determined by body surface area (BSA) for patients with normal renal function, dose of S-1 is practically reduced according to renal function of creatinine clearance (CLcr) estimated by the Cockcroft-Gault equation. In a previous pharmacokinetic study (n = 16), we had developed an S-1 dosage formula based on renal function achieving the target area under the concentration-time curve (AUC) of 5-FU: Dose = target AUC x (21.9 + 0.375 x CLcr) x BSA. We conducted a prospective study to evaluate and refine this formula if necessary. Methods: Thirty patients with various renal function received S-1 at dose determined by our developed formula. A series of blood samples were obtained at predefined times after the first dose to calculate the AUC of 5-FU. Predictability of the formula was evaluated by comparison between the observed and the target AUCs. Results: The observed daily AUC was ranged from 712.6 to 2868.7 ng‧h/mL in 30 patients with BSA in the range of 1.14-1.84 m2 and CLcr in the range of 23.8-96.4 mL/min. Eighteen patients of them achieved the target AUC (1447.8 ± 545.4 ng‧h/mL). Since population pharmacokinetic analysis using combined pharmacokinetic data of 30 patients in this study and 16 patients in the previous study demonstrated that clearance of 5-FU is significantly lower in female than in male, the S-1 dosage formula was refined including gender as an additional factor: Dose = target AUC × (14.5 + 8.23 x GENDER [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms showing recommended daily dose of S-1 were proposed for males and females taking into account tablet strengths. Conclusions: The refined formula for determining S-1 dosage on the basis of renal function, BSA and gender can be applied to clinical practice to ensure efficacy and safety for cancer patients treated with S-1. Clinical trial information: UMIN 000023880.

scholarly journals Population pharmacokinetic analysis of oxaliplatin in adults and children identifies important covariates for dosing

2015 ◽  
Vol 75 (3) ◽  
pp. 495-503 ◽  
Author(s):  
Mina Nikanjam ◽  
Clinton F. Stewart ◽  
Chris H. Takimoto ◽  
Timothy W. Synold ◽  
Orren Beaty ◽  
...  
Keyword(s):  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Adults And Children

scholarly journals Population Pharmacokinetics of Vancomycin in the Pediatric Cardiac Surgical Population

2019 ◽  
Vol 24 (2) ◽  
pp. 107-116 ◽  
Author(s):  
Brady S. Moffett ◽  
Karla Resendiz ◽  
Jennifer Morris ◽  
Ayse Akcan-Arikan ◽  
Paul A. Checchia
Keyword(s):  
Serum Concentration ◽  
Creatinine Clearance ◽  
Cardiac Surgical Procedures ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Population Pharmacokinetic Study ◽  
Postmenstrual Age ◽  
Dosing Strategy

OBJECTIVE Vancomycin is often used in the pediatric cardiac surgical population, but few pharmacokinetic data are available to guide dosing. METHODS A retrospective, population pharmacokinetic study was performed for patients &lt;19 years of age initiated on vancomycin after cardiac surgery in the cardiac intensive care unit from 2011–2016 in our institution. Patient data were summarized by using descriptive statistical methods, and population pharmacokinetic analysis was performed by using NONMEM. Simulation was performed to determine a dosing strategy that most frequently obtained an AUC0–24:MIC (minimum inhibitory concentration) ratio of &gt;400. RESULTS A total of 261 patients (281 cardiac surgical procedures, cardiopulmonary bypass 82.3%) met inclusion criteria (60.1% male, median age 0.31 [IQR, 0.07–0.77] years). Vancomycin (14.5 ± 1.7 mg/kg/dose) was administered at median postoperative day 9 (IQR, 4–14), with a mean serum concentration of 11.5 ± 5.5 mg/L at 8.9 ± 3.8 hours after a dose. Population pharmacokinetic analysis demonstrated that a 1-compartment proportional error model with allometrically scaled weight best fit the data, with creatinine clearance and postmenstrual age as significant covariates. Simulation identified that a dosing regimen of 20 mg/kg/dose every 8 hours was most likely to achieve an AUC0–24:MIC ratio &gt; 400 at a mean trough serum concentration of 12.9 ± 3.2 mg/L. CONCLUSIONS Vancomycin dosing in the postoperative pediatric cardiac surgical population should incorporate postmenstrual age and creatinine clearance. A vancomycin dose of 20 mg/kg every 8 hours is a reasonable empiric strategy.

scholarly journals Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Infants

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Zhong-Ren Shi ◽  
Xing-Kai Chen ◽  
Li-Yuan Tian ◽  
Ya-Kun Wang ◽  
Gu-Ying Zhang ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
High Performance ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Generation Cephalosporin ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Dosing Regimen ◽  
Age Range

ABSTRACT Ceftazidime, a third-generation cephalosporin, can be used for the treatment of adults and children with infections due to susceptible bacteria. To date, the pediatric pharmacokinetic data are limited in infants, and therefore we aimed to evaluate the population pharmacokinetics of ceftazidime in infants and to define the appropriate dose to optimize ceftazidime treatment. Blood samples were collected from children treated with ceftazidime, and concentrations of the drug were quantified by high-performance liquid chromatography with UV detection (HPLC-UV). A population pharmacokinetic analysis was performed using NONMEM software ( version 7.2.0). Fifty-one infants ( age range, 0.1 to 2.0 years ) were included. Sparse pharmacokinetic samples ( n = 90 ) were available for analysis. A one-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that body weight and creatinine clearance (CL CR ) were significant covariates influencing ceftazidime clearance. Monte Carlo simulation demonstrated that the currently used dosing regimen of 50 mg / kg twice daily was associated with a high risk of underdosing in infants. In order to reach the target of 70% of the time that the free antimicrobial drug concentration exceeds the MIC ( fT >MIC ), 25 mg/kg every 8 h (q8h) and 50 mg/kg q8h were required for MICs of 4 and 8 mg/liter, respectively. The population pharmacokinetic characteristics of ceftazidime were evaluated in infants. An evidence-based dosing regimen was established based on simulation.

scholarly journals Pooled Population Pharmacokinetic Analysis of Tribendimidine for the Treatment of Opisthorchis viverrini Infections

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Isabel Meister ◽  
Piyanan Assawasuwannakit ◽  
Fiona Vanobberghen ◽  
Melissa A. Penny ◽  
Peter Odermatt ◽  
...  
Keyword(s):  
Population Pharmacokinetic Analysis ◽  
Opisthorchis Viverrini ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Therapeutic Success ◽  
Time Curve ◽  
Content Type ◽  
Mixed Effects Modeling ◽  
Younger Age

ABSTRACT Opisthorchiasis, caused by the foodborne trematode Opisthorchis viverrini, affects more than 8 million people in Southeast Asia. In the framework of a phase 2b clinical trial conducted in Lao People’s Democratic Republic, pharmacokinetic samples were obtained from 125 adult and adolescent O. viverrini-infected patients treated with 400 mg tribendimidine following the design of a sparse sampling scheme at 20 min and 2, 7.75, 8, and 30 h after treatment using dried blood spot sampling. Pharmacokinetic data for the metabolites deacetylated amidantel (dADT) and acetylated dADT (adADT) were pooled with data from two previous ascending-dose trials and evaluated using nonlinear mixed-effects modeling. The observed pharmacokinetic data were described using a flexible transit absorption model for the active metabolite dADT, followed by one-compartment disposition models for both metabolites. Significant covariates were age, body weight, formulation, and breaking of the enteric coating on the tablets. There were significant associations between O. viverrini cure and both the dADT maximum concentration and the area under the concentration-time curve (P < 0.001), with younger age being associated with a higher probability of cure. Modeling and simulation of exposures in patients with different weight and age combinations showed that an oral single dose of 400 mg tribendimidine attained therapeutic success in over 90% of adult patients. Our data confirmed that tribendimidine could be a valuable novel alternative to the standard treatment, praziquantel, for the treatment of O. viverrini infections.

scholarly journals Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Ashley M. Hopkins ◽  
Jessica Wojciechowski ◽  
Ahmad Y. Abuhelwa ◽  
Stuart Mudge ◽  
Richard N. Upton ◽  
...  
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Delayed Release

ABSTRACT The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion (P < 0.01) and then backward deletion (P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (F), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens.

scholarly journals A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants

2016 ◽  
Vol 60 (11) ◽  
pp. 6626-6634 ◽  
Author(s):  
Stéphanie Leroux ◽  
Jean-Michel Roué ◽  
Jean-Bernard Gouyon ◽  
Valérie Biran ◽  
Hao Zheng ◽  
...  
Keyword(s):  
High Performance ◽  
Sampling Strategy ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Dosing Regimen ◽  
Model Based ◽  
Young Infants

ABSTRACTCefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates (gestational age [GA] range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants.

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