scholarly journals Micafungin population PK analysis in plasma and peritoneal fluid in septic patients with intra-abdominal infections: a prospective cohort study

2021 ◽  
Author(s):  
Nicolas Garbez ◽  
Litaty Mbatchi ◽  
Steven C. Wallis ◽  
Laurent Muller ◽  
Jeffrey Lipman ◽  
...  
Keyword(s):  
Peritoneal Fluid ◽  
Central Compartment ◽  
Population Pharmacokinetic Analysis ◽  
Peritoneal Exudate ◽  
Fat Free Mass ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
The Mean ◽  
Abdominal Infections

Objectives: To describe the pharmacokinetics (PK) of micafungin in plasma and peritoneal fluid in septic patients with intra-abdominal infections. Methods: Twelve patients with secondary peritonitis in septic shock receiving 100 mg micafungin once daily were included. Total micafungin plasma and peritoneal fluid were subject to a population pharmacokinetic analysis using Pmetrics®. Monte Carlo simulations were performed considering total AUC0-24h/MIC ratios in plasma. Results: Micafungin concentrations in both plasma and peritoneal exudate were best described by a three-compartmental PK model with the fat free mass (FFM) as a covariate of clearance (CL) and volume of the central compartment (Vc). The mean parameter estimates (standard deviation, SD) were 1.18 (0.40) L/h for CL and 12.85 (4.78) L for Vc. The mean peritoneal exudate/plasma ratio (SD) of micafungin was 25% (5%) on day 1 and 40% (8%) between day 3-5. Dosing simulations supported the use of standard 100 mg daily dosing for C. albicans (FFM < 60 kg), C. glabrata (FFM < 50 kg) and C. tropicalis (FFM < 30 kg) on the second day of therapy. Conclusions: There is a moderate penetration of micafungin into peritoneal cavity (25 to 40%). For empirical treatment, a dose escalation of at least a loading dose of 150 mg depending on the FFM of patients and Candida species is suggested to be effective from the first day of therapy.

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 A Population Pharmacokinetic Analysis Shows that Arylacetamide Deacetylase (AADAC) Gene Polymorphism and HIV Infection Affect the Exposure of Rifapentine

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Jose Francis ◽  
Simbarashe P. Zvada ◽  
Paolo Denti ◽  
Mark Hatherill ◽  
Salome Charalambous ◽  
...  
Keyword(s):  
Food Intake ◽  
Hiv Infection ◽  
Pregnane X Receptor ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
Fat Free Mass ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Antituberculosis Treatment

ABSTRACT Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 drug concentration measurements from 326 patients were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have a 10.4% lower clearance. HIV-infected patients had a 21.9% lower bioavailability. Once-weekly doses of 1,200 mg were associated with a reduced clearance (13.2%) compared to that achieved with more frequently administered doses. Bioavailability was 23.3% lower among patients participating in the Daily RPE study than in those participating in the RIFAQUIN study. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the differences in food intake concomitant with the dose. HIV-coinfected patients had lower rifapentine exposures.

scholarly journals Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

2011 ◽  
Vol 55 (7) ◽  
pp. 3423-3431 ◽  
Author(s):  
C. Bazzoli ◽  
H. Bénech ◽  
E. Rey ◽  
S. Retout ◽  
D. Salmon ◽  
...  
Keyword(s):  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Intracellular Metabolites ◽  
Drug Concentrations ◽  
The Mean ◽  
Intracellular Concentrations ◽  
Apparent Bioavailability

ABSTRACTThe population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once- versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.

scholarly journals Population Pharmacokinetic Assessment of Vancomycin Dosing in the Large Pediatric Patient

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Brady S. Moffett ◽  
Vijay Ivaturi ◽  
Jennifer Morris ◽  
Ayse Akcan Arikan ◽  
Ankhi Dutta
Keyword(s):  
Pediatric Patients ◽  
Population Pharmacokinetic Analysis ◽  
Fat Free Mass ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Kidney Dysfunction ◽  
Time Curve ◽  
Concentration Time ◽  
Pharmacokinetic Assessment ◽  
Dosing Strategy

ABSTRACT The most appropriate vancomycin dosing strategy in pediatric patients weighing ≥70 kg (weight based versus non-weight based) to achieve an area under the concentration-time curve (AUC) of ≥400 mg·liter/h and a trough concentration of <20 mg/liter is not known. Population pharmacokinetic analysis determined that dosing of vancomycin should be weight based using fat-free mass, with appropriate adjustment for kidney dysfunction.

scholarly journals Pharmacokinetics of Ciprofloxacin in the Human Eye: a Clinical Study and Population Pharmacokinetic Analysis

2000 ◽  
Vol 44 (6) ◽  
pp. 1674-1679 ◽  
Author(s):  
Nigel Morlet ◽  
Garry G. Graham ◽  
Barrie Gatus ◽  
Andrew J. McLachlan ◽  
Chris Salonikas ◽  
...  
Keyword(s):  
High Performance ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Ocular Surgery ◽  
Human Eye ◽  
Number Of Patients ◽  
The Mean ◽  
Oral Ciprofloxacin ◽  
Oral Doses

ABSTRACT Ciprofloxacin, a fluoroquinolone antibiotic active against a wide variety of bacteria, is one of a few antibiotics which enters the human eye after oral administration. However, little is known about its pharmacokinetics in the human eye. One or two oral doses of 750 mg of ciprofloxacin (at a 12-h interval) were administered to 48 patients at various times prior to ocular surgery. Clotted blood, aqueous, and vitreous were collected at surgery, and the concentrations of ciprofloxacin were assayed by high-performance liquid chromatography. Our data were combined with those of others, and a population pharmacokinetic analysis was conducted. The concentrations of ciprofloxacin in both aqueous and vitreous were lower than those in serum and peaked at a later time. The pharmacokinetics of ciprofloxacin in aqueous and vitreous were fitted to a compartmental model in which the antibiotic was transferred into and out of the two compartments (aqueous and vitreous) by first-order processes. Population pharmacokinetic software, P-Pharm, was used to calculate the mean half-lives of the loss of ciprofloxacin from aqueous and vitreous, which were 3.5 and 5.3 h, respectively. At steady state, the mean ratios of then concentrations in aqueous and vitreous to the concentrations in serum were 23 and 17%, respectively. After the administration of one or two doses of 750 mg of ciprofloxacin, the concentrations in both aqueous and vitreous in a number of patients were lower than the MICs at which 90% of isolates are inhibited (0.5 mg/liter) for common intraocular bacterial pathogens. Simulations of concentrations in the eye after the administration of higher doses (1,500 mg of ciprofloxacin as a single dose, two doses of 750 mg 2 h apart, and 750 mg every 6 h) indicated that in approximately 20% of patients the concentrations would still be below 0.5 mg/liter. Although oral ciprofloxacin may be a beneficial adjunctive therapy, the use of oral ciprofloxacin alone may not be adequate for perioperative prophylaxis or for treatment of bacterial endophthalmitis.

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 Using Population Pharmacokinetic Modeling and Monte Carlo Simulations To Determine whether Standard Doses of Piperacillin in Piperacillin-Tazobactam Regimens Are Adequate for the Management of Febrile Neutropenia

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Fekade Bruck Sime ◽  
Uwe Hahn ◽  
Morgyn S. Warner ◽  
Ing Soo Tiong ◽  
Michael S. Roberts ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Febrile Neutropenia ◽  
Rate Constant ◽  
Central Compartment ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Target Attainment ◽  
Neutropenic Patients

ABSTRACT Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A two-compartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 ± 12 years [means ± standard deviations] and weight of 77 ± 16 kg). Parameter estimates were CL of 18.0 ± 4.8 liters/h, volume of distribution of the central compartment of 14.3 ± 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 ± 1.35 h−1, and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 ± 7.81 h−1. High creatinine clearance (CLCR) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of >90% for an unbound concentration of piperacillin remaining above the MIC (fT >MIC) of 50%. Only continuous regimens achieved >90% PTA for 100% fT >MIC when CLCR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal (<85%) for conventional regimens for both empirical and directed therapy considering 50% and 100% fT >MIC. FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CLCR or with known/presumed infections from high-MIC bacteria.

scholarly journals A Population Pharmacokinetic Analysis of the Penetration of the Prostate by Levofloxacin

2000 ◽  
Vol 44 (8) ◽  
pp. 2046-2051 ◽  
Author(s):  
G. L. Drusano ◽  
S. L. Preston ◽  
M. Van Guilder ◽  
D. North ◽  
M. Gombert ◽  
...  
Keyword(s):  
Design Theory ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Drug Concentrations ◽  
Constant Rate ◽  
Penetration Ratio ◽  
The Mean ◽  
The University

ABSTRACT Prostatitis has remained a pathological entity that is difficult to treat. Part of the difficulty revolves about the putative offending pathogens. For acute prostatitis, members of theEnterobacteriaceae, particularly Escherichia coli, play a central role, while intracellular pathogens such asChlamydia are more frequently seen in chronic prostatitis. Consequently, a drug needs to be able to penetrate to this specialized site in both the acute and chronic infection forms of the disease and also have potent activity against the most common causative pathogens, both intracellular and extracellular. Levofloxacin has such an activity profile. We wished to document its ability to penetrate to the site of infection. Patients undergoing prostatectomies were administered 500 mg of levofloxacin orally every 24 h for 2 days prior to surgery, and then on the day of surgery, 500 mg was administered as an hour-long, constant-rate intravenous (i.v.) infusion. A set of blood samples was obtained as guided by stochastic optimal design theory. Prostate biopsy times were determined by randomizing subjects into one of four groups, based on the interval after the i.v. dose. All plasma and prostate drug concentrations were comodeled by a population modeling program, BigNPEM, implemented on the Cray T3E Supercomputer housed at the Supercomputer Center at the University of California at San Diego. Penetration was determined as the ratio of the area under the concentration-time curve (AUC) of levofloxacin in the prostate to the plasma levofloxacin AUC. When calculated from the mean population parameters, this penetration ratio was 2.96. We also performed a 1,000-subject Monte Carlo simulation from the mean parameter vector and covariance matrix. The mean penetration ratio here was 4.14 with a 95% confidence interval of 0.20 to 19.6. Over 70% of the population had a penetration ratio in excess of 1.0. Levofloxacin adequately penetrates a noninflamed prostate and should be evaluated for the therapy of prostatitis.

scholarly journals Population Pharmacokinetics of Fosfomycin in Critically Ill Patients

2015 ◽  
Vol 59 (10) ◽  
pp. 6471-6476 ◽  
Author(s):  
Suzanne L. Parker ◽  
Frantzeska Frantzeskaki ◽  
Steven C. Wallis ◽  
Chryssa Diakaki ◽  
Helen Giamarellou ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Pharmacokinetic Analysis ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Blood Samples ◽  
The Mean ◽  
Dosing Intervals

ABSTRACTThis study describes the population pharmacokinetics of fosfomycin in critically ill patients. In this observational study, serial blood samples were taken over several dosing intervals of intravenous fosfomycin treatment. Blood samples were analyzed using a validated liquid chromatography-tandem mass spectrometry technique. A population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Five hundred fifteen blood samples were collected over one to six dosing intervals from 12 patients. The mean (standard deviation) age was 62 (17) years, 67% of patients were male, and creatinine clearance (CLCR) ranged from 30 to 300 ml/min. A two-compartment model with between-subject variability on clearance and volume of distribution of the central compartment (Vc) described the data adequately. Calculated CLCRwas supported as a covariate on fosfomycin clearance. The mean parameter estimates for clearance on the first day were 2.06 liters/h,Vcof 27.2 liters, intercompartmental clearance of 19.8 liters/h, and volume of the peripheral compartment of 22.3 liters. We found significant pharmacokinetic variability for fosfomycin in this heterogeneous patient sample, which may be explained somewhat by the observed variations in renal function.

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