scholarly journals Remedial dosing recommendation for delayed or missed rivaroxaban doses for patients with non-valvular atrial fibrillation based on Monte Carlo simulation

2020 ◽  
Author(s):  
Xiao-qin Liu ◽  
Yin-wei Yin ◽  
Chen-yu Wang ◽  
Zi-ran Li ◽  
Xiao Zhu ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Factor Xa ◽  
Heart Rhythm ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Drug Concentrations ◽  
Simulation Based ◽  
Dosing Regimens

Background Rivaroxaban is a non-vitamin K oral anticoagulant used widely for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). During long-term anticoagulant therapy, delayed or missed doses are common. However, a lack of practical instructions on remedial methods has created a barrier for patients to maximise the benefit of their medications. This study aimed to explore appropriate remedial dosing regimens for rivaroxaban-treated patients with NVAF. Methods Monte Carlo simulation based on a previously established rivaroxaban population pharmacokinetic/pharmacodynamic model for patients with NVAF was employed to design remedial dosing regimens. Both the European Heart Rhythm Association (EHRA) recommendations and the model were used to establish remedial dosing regimens, which were assessed considering the on-therapy range of drug concentration, factor Xa activity, and prothrombin time under various scenarios of non-adherence. Results Recommendations of EHRA guide may not be optimal. Our findings suggested that a missed dose is taken immediately when the delay is less than or equal to 6 h; a half dose is advisable when the delay exceeds 6 h but is less than 4 h before the next dose. It is recommended to skip a dose when there are less than 4 h before the next dose. Age or renal function do not significantly influence the remedial dosing regimen. Conclusion A remedial dosing regimen based on model-based Monte Carlo simulation was systematically developed for rivaroxaban-treated patients with NVAF with poor adherence to quickly restore drug concentrations to the on-therapy range and to reduce the risk of bleeding and thromboembolism.

scholarly journals How to handle the delayed or the missed dose of edoxaban in patients with non-valvular atrial fibrillation: model-informed remedial strategy

2021 ◽  
Author(s):  
Yi-wei Yin ◽  
Xiaoqin Liu ◽  
Jiaqin Gu ◽  
Ziran Li ◽  
Zheng Jiao
Keyword(s):  
Atrial Fibrillation ◽  
Monte Carlo ◽  
Delay Time ◽  
Factor Xa ◽  
Heart Rhythm ◽  
Total Deviation ◽  
Delay Duration ◽  
Half Dose ◽  
Dosing Regimens ◽  
Remedial Strategies

Aim: Edoxaban is a non-vitamin K antagonist oral anticoagulant (NOAC) widely used for long-term stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Adherence to NOACs is unsatisfactory and decreases over time. The aim of this study was to explore appropriated remedial dosing regimens for non-adherent edoxaban-treated NVAF patients through the Monte Carlo simulation. Methods: Six proposed regimens were compared with the recommendations in the European Heart Rhythm Association (EHRA) guide regarding the trough total deviation time considering both edoxaban plasma concentration and inactive factor Xa activity. Monte Carlo simulations were performed using RxODE based on the published population pharmacokinetics/pharmacodynamics model. Results: The proposed remedial strategies were different from EHRA recommendations and were related to delay duration. The missed dose can be taken immediately if the delay time is within 11 h. When the delay period is between 12 and 19 h, a half dose followed by a regular dosing schedule is recommended. When the delay time exceeds 19 h, a full dose followed by a half dose is preferred compared to that recommended in the EHRA guide. Our proposed strategies resulted in a shorter total deviation time than EHRA guide. Conclusion: PK/PD modelling and simulation are effective in developing and evaluating the remedial strategies of edoxaban, which could help maximize its therapeutic effect.

scholarly journals Population Pharmacokinetics and Use of Monte Carlo Simulation To Evaluate Currently Recommended Dosing Regimens of Ciprofloxacin in Adult Patients with Cystic Fibrosis

2001 ◽  
Vol 45 (12) ◽  
pp. 3468-3473 ◽  
Author(s):  
Megan J. Montgomery ◽  
Paul M. Beringer ◽  
Amir Aminimanizani ◽  
Stan G. Louie ◽  
Bertrand J. Shapiro ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Half Life ◽  
Volume Of Distribution ◽  
Therapeutic Drug ◽  
Serum Drug Concentration ◽  
Concentration Data ◽  
Drug Concentrations ◽  
Dosing Regimens

ABSTRACT Pharmacodynamic data on ciprofloxacin indicate that a target area under the concentration-time curve from 0 to 24 h (AUC0–24)/MIC ratio of ≥125 is necessary to achieve optimal bactericidal activity for the treatment of gram-negative pneumonia. The purpose of this prospective study was to (i) develop a pharmacokinetic (PK) model to be utilized for therapeutic drug monitoring (TDM) of ciprofloxacin and (ii) evaluate current ciprofloxacin dosing regimens for pneumonias in cystic fibrosis (CF) patients. Twelve adult CF patients received a single 400-mg dose of IV ciprofloxacin. Six blood samples were obtained over a 12-h interval. Serum drug concentrations were determined by high-pressure liquid chromotography and were fitted to one- and two-compartment models by using NPEM2. Ciprofloxacin MIC data for Pseudomonas aeruginosa were obtained from 1,213 CF patients enrolled in a large clinical trial. A Monte Carlo simulation was performed to estimate the fractional attainment of an AUC0–24/MIC ratio of ≥125. A two-compartment model best describes the serum drug concentration data. The mean fitted PK parameter values are volume of distribution in the central compartment, 0.29 liter/kg; volume of distribution at steady state, 1.1 liters/kg; total clearance, 0.34 liter/h/kg; distributional clearance, 0.89 liter/h/kg; half-life at α phase, 0.16 h; and half-life at β phase, 2.9 h. The overall fractional attainment of achieving an AUC0–24/MIC ratio of ≥125 against P. aeruginosa isolates with ciprofloxacin (400 mg every 12 h [q12h] and 8 qh) were 10 and 30%, respectively. A clinical breakpoint MIC of <0.5 μg/ml for susceptibility is suggested, based on an examination of the fractional attainment of the AUC0–24/MIC target at each MIC. The recommended doses of 400 mg q8h or q12h may be inadequate to treat an acute pulmonary exacerbation when given alone. The poor and variable AUC0–24/MIC ratios support the use of TDM to monitor and adjust the dosage to optimize the efficacy of ciprofloxacin therapy in these patients.

scholarly journals Pharmacokinetic Modeling of Voriconazole To Develop an Alternative Dosing Regimen in Children

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Silke Gastine ◽  
Thomas Lehrnbecher ◽  
Carsten Müller ◽  
Fedja Farowski ◽  
Peter Bader ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Modeling ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Concentration Data ◽  
Days Of Therapy ◽  
Dosing Regimens

ABSTRACT The pharmacokinetic variability of voriconazole (VCZ) in immunocompromised children is high, and adequate exposure, particularly in the first days of therapy, is uncertain. A population pharmacokinetic model was developed to explore VCZ exposure in plasma after alternative dosing regimens. Concentration data were obtained from a pediatric phase II study. Nonlinear mixed effects modeling was used to develop the model. Monte Carlo simulations were performed to test an array of three-times-daily (TID) intravenous dosing regimens in children 2 to 12 years of age. A two-compartment model with first-order absorption, nonlinear Michaelis-Menten elimination, and allometric scaling best described the data (maximal kinetic velocity for nonlinear Michaelis-Menten clearance [V max] = 51.5 mg/h/70 kg, central volume of distribution [V 1] = 228 liters/70 kg, intercompartmental clearance [Q] = 21.9 liters/h/70 kg, peripheral volume of distribution [V 2] = 1,430 liters/70 kg, bioavailability [F] = 59.4%, Km = fixed value of 1.15 mg/liter, absorption rate constant = fixed value of 1.19 h−1). Interindividual variabilities for V max, V 1, Q, and F were 63.6%, 45.4%, 67%, and 1.34% on a logit scale, respectively, and residual variability was 37.8% (proportional error) and 0.0049 mg/liter (additive error). Monte Carlo simulations of a regimen of 9 mg/kg of body weight TID simulated for 24, 48, and 72 h followed by 8 mg/kg two times daily (BID) resulted in improved early target attainment relative to that with the currently recommended BID dosing regimen but no increased rate of accumulation thereafter. Pharmacokinetic modeling suggests that intravenous TID dosing at 9 mg/kg per dose for up to 3 days may result in a substantially higher percentage of children 2 to 12 years of age with adequate exposure to VCZ early during treatment. Before implementation of this regimen in patients, however, validation of exposure, safety, and tolerability in a carefully designed clinical trial would be needed.

scholarly journals Identification of Optimal Renal Dosage Adjustments for Traditional and Extended-Infusion Piperacillin-Tazobactam Dosing Regimens in Hospitalized Patients

2009 ◽  
Vol 54 (1) ◽  
pp. 460-465 ◽  
Author(s):  
N. Patel ◽  
M. H. Scheetz ◽  
G. L. Drusano ◽  
T. P. Lodise
Keyword(s):  
Monte Carlo Simulation ◽  
Free Drug ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Population Pharmacokinetic Modeling ◽  
Dosing Interval ◽  
Drug Concentrations ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Extended Infusion

ABSTRACT This study examined the effect of various levels of renal impairment on the probability of achieving free drug concentrations that exceed the MIC for 50% of the dosing interval (50% fT > MIC) for traditional and extended-infusion piperacillin-tazobactam (TZP) dosing strategies. It also identified optimal renal dosage adjustments for traditional and extended-infusion dosing schemes that yielded probability of target attainment (PTA) and exposure profiles that were isometric to those of the parent regimens. Data from 105 patients were analyzed using the population pharmacokinetic modeling program BigNPAG. To assess the effect of creatinine clearance (CLCR) on overall clearance, TZP clearance was made proportional to the estimated CLCR. A Monte Carlo simulation (9,999 subjects) was performed for the traditional dosing scheme (4.5 g infused during 30 min every 6 h) and the extended-infusion TZP dosing scheme (3.375 g infused during 4 h every 8 h). The fraction of simulated subjects who achieved 50% fT > MIC was calculated for the range of piperacillin MICs from 0.25 to 32 mg/liter and stratified by CLCR. The traditional TZP regimen displayed the greatest variability in PTA across MIC values, especially for MIC values exceeding 4 mg/liter, when stratified by CLCR. In contrast, the PTA for the extended-infusion TZP regimen exceeded ≥80% for MIC values of ≤8 mg/liter across all CLCR strata. All regimens were associated with suboptimal PTA for MIC values of ≥32 mg/liter irrespective of the CLCR. The CLCR adjustments for traditional and extended-infusion TZP dosing regimens should be considered at a CLCR of ≤20 ml/min.

scholarly journals Voronoi diagram and Monte-Carlo simulation based finite element optimization for cost-effective 3D printing

2021 ◽  
Vol 50 ◽  
pp. 101301
Author(s):  
A.Z. Zheng ◽  
S.J. Bian ◽  
E. Chaudhry ◽  
J. Chang ◽  
H. Haron ◽  
...  
Keyword(s):  
Monte Carlo Simulation ◽  
Finite Element ◽  
Monte Carlo ◽  
3D Printing ◽  
Voronoi Diagram ◽  
Cost Effective ◽  
Simulation Based
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