scholarly journals Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization

2022 ◽  
Vol 12 ◽  
Author(s):  
SiChan Li ◽  
SanLan Wu ◽  
WeiJing Gong ◽  
Peng Cao ◽  
Xin Chen ◽  
...  
Keyword(s):  
Maintenance Dose ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Immunocompromised Patients ◽  
First Order ◽  
Dosing Regimens

Purpose: The aims of this study were to establish a joint population pharmacokinetic model for voriconazole and its N-oxide metabolite in immunocompromised patients, to determine the extent to which the CYP2C19 genetic polymorphisms influenced the pharmacokinetic parameters, and to evaluate and optimize the dosing regimens using a simulating approach.Methods: A population pharmacokinetic analysis was conducted using the Phoenix NLME software based on 427 plasma concentrations from 78 patients receiving multiple oral doses of voriconazole (200 mg twice daily). The final model was assessed by goodness of fit plots, non-parametric bootstrap method, and visual predictive check. Monte Carlo simulations were carried out to evaluate and optimize the dosing regimens.Results: A one-compartment model with first-order absorption and mixed linear and concentration-dependent-nonlinear elimination fitted well to concentration-time profile of voriconazole, while one-compartment model with first-order elimination well described the disposition of voriconazole N-oxide. Covariate analysis indicated that voriconazole pharmacokinetics was substantially influenced by the CYP2C19 genetic variations. Simulations showed that the recommended maintenance dose regimen would lead to subtherapeutic levels in patients with different CYP2C19 genotypes, and elevated daily doses of voriconazole might be required to attain the therapeutic range.Conclusions: The joint population pharmacokinetic model successfully characterized the pharmacokinetics of voriconazole and its N-oxide metabolite in immunocompromised patients. The proposed maintenance dose regimens could provide a rationale for dosage individualization to improve clinical outcomes and minimize drug-related toxicities.

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 Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

2014 ◽  
Vol 58 (8) ◽  
pp. 4718-4726 ◽  
Author(s):  
Ping Liu ◽  
Diane R. Mould
Keyword(s):  
Invasive Aspergillosis ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Institutional Review Boards ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
First Order ◽  
Two Compartment Model

ABSTRACTTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).

scholarly journals Population Pharmacokinetic Analysis of Cefaclor in Healthy Korean Subjects

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 754
Author(s):  
Seung-Hyun Jeong ◽  
Ji-Hun Jang ◽  
Hea-Young Cho ◽  
Yong-Bok Lee
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Factors Affecting ◽  
Population Pharmacokinetic Study ◽  
Final Population ◽  
Subject Variability

The aims of this study were: (1) to perform population pharmacokinetic analysis of cefaclor in healthy Korean subjects, and (2) to investigate possible effects of various covariates on pharmacokinetic parameters of cefaclor. Although cefaclor belongs to the cephalosporin family antibiotic that has been used in various indications, there have been very few population studies on factors affecting its pharmacokinetics. Therefore, this study is very important in that effective therapy could be possible through a population pharmacokinetic study that explores effective covariates related to cefaclor pharmacokinetic diversity between individuals. Pharmacokinetic results of 48 subjects with physical and biochemical parameters were used for the population pharmacokinetic analysis of cefaclor. A one-compartment with lag-time and first-order absorption/elimination was constructed as a base model and extended to include covariates that could influence between-subject variability. Creatinine clearance and body weight significantly influenced systemic clearance and distribution volume of cefaclor. Cefaclor’s final population pharmacokinetic model was validated and some of the population’s pharmacokinetic diversity could be explained. Herein, we first describe the establishment of a population pharmacokinetic model of cefaclor for healthy Koreans that might be useful for customizing cefaclor or exploring additional covariates in patients.

scholarly journals A Personalized CYP2C19 Phenotype-Guided Dosing Regimen of Voriconazole Using a Population Pharmacokinetic Analysis

2019 ◽  
Vol 8 (2) ◽  
pp. 227 ◽  
Author(s):  
Yun Kim ◽  
Su-jin Rhee ◽  
Wan Beom Park ◽  
Kyung-Sang Yu ◽  
In-Jin Jang ◽  
...  
Keyword(s):  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Dependent Inhibition ◽  
Dosing Regimens ◽  
Three Compartment Model ◽  
Time Dependent Inhibition ◽  
Intermediate Metabolizers

Highly variable and non-linear pharmacokinetics of voriconazole are mainly caused by CYP2C19 polymorphisms. This study aimed to develop a mechanistic population pharmacokinetic model including the CYP2C19 phenotype, and to assess the appropriateness of various dosing regimens based on the therapeutic target. A total of 1,828 concentrations from 193 subjects were included in the population pharmacokinetic analysis. A three-compartment model with an inhibition compartment appropriately described the voriconazole pharmacokinetics reflecting auto-inhibition. Voriconazole clearance in the CYP2C19 intermediate metabolizers (IMs) and poor metabolizers (PMs) decreased by 17% and 53% compared to that in the extensive metabolizers (EMs). There was a time-dependent inhibition of clearance to 16.2% of its original value in the CYP2C19 EMs, and the extent of inhibition differed according to the CYP2C19 phenotypes. The proposed CYP2C19 phenotype-guided initial dosing regimens are 400 mg twice daily (bid) for EMs, 200 mg bid for IMs, and 100 mg bid for PMs. This CYP2C19 phenotype-guided initial dosing regimen will provide a rationale for individualizing the optimal voriconazole therapy.

scholarly journals Integrated Population Pharmacokinetic Analysis of Voriconazole in Children, Adolescents, and Adults

2012 ◽  
Vol 56 (6) ◽  
pp. 3032-3042 ◽  
Author(s):  
Lena E. Friberg ◽  
Patanjali Ravva ◽  
Mats O. Karlsson ◽  
Ping Liu
Keyword(s):  
Pediatric Population ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Loading Dose ◽  
Time Curve ◽  
Individual Parameter ◽  
Dosing Regimens

ABSTRACTTo further optimize the voriconazole dosing in the pediatric population, a population pharmacokinetic analysis was conducted on pooled data from 112 immunocompromised children (2 to <12 years), 26 immunocompromised adolescents (12 to <17 years), and 35 healthy adults. Different maintenance doses (i.e., 3, 4, 6, 7, and 8 mg/kg of body weight intravenously [i.v.] every 12 h [q12h]; 4 mg/kg, 6 mg/kg, and 200 mg orally q12h) were evaluated in these children. The adult dosing regimens (6 mg/kg i.v. q12h on day 1, followed by 4 mg/kg i.v. q12h, and 300 mg orally q12h) were evaluated in the adolescents. A two-compartment model with first-order absorption and mixed linear and nonlinear (Michaelis-Menten) elimination adequately described the voriconazole data. Larger interindividual variability was observed in pediatric subjects than in adults. Deterministic simulations based on individual parameter estimates from the final model revealed the following. The predicted total exposure (area under the concentration-time curve from 0 to 12 h [AUC0-12]) in children following a 9-mg/kg i.v. loading dose was comparable to that in adults following a 6-mg/kg i.v. loading dose. The predicted AUC0-12s in children following 4 and 8 mg/kg i.v. q12h were comparable to those in adults following 3 and 4 mg/kg i.v. q12h, respectively. The predicted AUC0-12in children following 9 mg/kg (maximum, 350 mg) orally q12h was comparable to that in adults following 200 mg orally q12h. To achieve voriconazole exposures comparable to those of adults, dosing in 12- to 14-year-old adolescents depends on their weight: they should be dosed like children if their weight is <50 kg and dosed like adults if their weight is ≥50 kg. Other adolescents should be dosed like adults.

scholarly journals Effect of Pregnancy on Unbound Raltegravir Concentrations in the ANRS 160 RalFe Trial

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Yi Zheng ◽  
Déborah Hirt ◽  
Sandrine Delmas ◽  
Gabrielle Lui ◽  
Sihem Benaboud ◽  
...  
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Third Trimester ◽  
Open Label ◽  
First Order ◽  
The Third ◽  
Pregnancy And Postpartum

ABSTRACT A population pharmacokinetic model was developed to explore the pharmacokinetics modification of unbound raltegravir during pregnancy. The RalFe ANRS160 study was a nonrandomized, open-label, multicenter trial enrolling HIV-infected pregnant women receiving a combined antiretroviral regimen containing 400 mg raltegravir twice daily. Biological samples were collected during the third trimester of pregnancy (between 30 and 37 weeks of gestational age) and at postpartum (4 to 6 weeks after delivery). A population pharmacokinetic model was developed with Monolix software. A total of 360 plasma samples were collected from 43 women during pregnancy and postpartum. The unbound raltegravir was described by a one-compartment model with a transit compartment with first-order absorption, evolving to bound raltegravir (by a linear binding to albumin) or metabolism to RAL-glucuronide or to a first-order elimination, with a circadian rhythm. During pregnancy, the absorption was decreased and delayed and the raltegravir elimination clearance and glucuronidation increased by 37%. Median total and unbound area under the curve from 0 to 12 h significantly decreased by 36% and 27% during pregnancy. Median total trough concentration (Ctrough) decreased significantly in the evening (28%); however, the median total Ctrough in the morning, unbound Ctrough in the morning, and unbound Ctrough in the evening showed a nonsignificant decrease of 16%, 1%, and 15%, respectively, during pregnancy compared to the postpartum period. This is the first study reporting the pharmacokinetics of unbound raltegravir during pregnancy. As unbound Ctrough did not significantly decrease during the third trimester, the pregnancy effect on raltegravir unbound concentrations was not considered clinically relevant. (This study has been registered at ClinicalTrials.gov under identifier NCT02099474.)

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.

scholarly journals Population pharmacokinetics of dalbavancin and dosing consideration for optimal treatment of adult patients with staphylococcal osteoarticular infections

2021 ◽  
Author(s):  
Pier Giorgio Cojutti ◽  
Matteo Rinaldi ◽  
Eleonora Zamparini ◽  
Nicolò Rossi ◽  
Sara Tedeschi ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Term Treatment ◽  
Adult Patients ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Long Term Treatment ◽  
Prosthetic Joint Infections ◽  
Dosing Regimens

Background: Dalbavancin is gaining interest in the treatment of complex osteoarticular (OA) infections. Objective: To conduct a population pharmacokinetic analysis of dalbavancin in a prospective cohort of adult patients with Gram-positive OA infections and to identify optimal dosing regimens for long term-treatment. Methods: Non-linear mixed-effects modelling was performed with Monolix. Monte Carlo simulations were performed with six dalbavancin regimens (1500mg at day 1; 1000mg at day 1 plus 500mg at day 8; 1500mg at day1 and 8; 1500mg at day1 and 8 plus 500, 1000 or 1500mg at day 36) to assess the PTA of three pharmacodynamic target of fAUC24h/MIC against S. aureus (>27.1, 53.3 and 111.1). Cumulative fraction of response (CFR) was calculated against MIC distribution of both MRSA and MSSA as well. Desirable PTAs and CFRs were ≥90%. Results: Fifteen patients provided 120 plasma concentrations. Most (73.3%) had prosthetic joint infections. Clinical cure rate was 87%. A two-compartment model with linear elimination well described the data. No covariate was retained in the final model. Pharmacokinetic dalbavancin estimates were 0.106L/h for CL and 36.4L for Vss. The tested dosing regimens granted desirable CFRs against S. aureus at the most effective PK/PD target for a period ranging 3-to-9 weeks. Conclusion: Giving a two 1500mg dosing regimen of dalbavancin one week apart may ensure efficacy against both MSSA and MRSA up to 5 weeks in patients with OA infections. Clinical assessment at that time may allow for considering whether or not an additional dose should be administered for prolonging effective treatment.

scholarly journals Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 54 ◽  
Author(s):  
Amaia Soraluce ◽  
Helena Barrasa ◽  
Eduardo Asín-Prieto ◽  
Jose Ángel Sánchez-Izquierdo ◽  
Javier Maynar ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Standard Dose ◽  
Compartment Model ◽  
Antimicrobial Treatment ◽  
Population Pharmacokinetic ◽  
Renal Replacement Therapies ◽  
Continuous Renal Replacement Therapies

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

scholarly journals Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by Gram-Negative Bacteria

2009 ◽  
Vol 53 (8) ◽  
pp. 3430-3436 ◽  
Author(s):  
D. Plachouras ◽  
M. Karvanen ◽  
L. E. Friberg ◽  
E. Papadomichelakis ◽  
A. Antoniadou ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Colistin Methanesulfonate

ABSTRACT Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

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