scholarly journals Ανάλυση πληθυσμιακής φαρμακοκινητικής της τεϊκοπλανίνης σε νεογνά με ενδονοσοκομειακές λοιμώξεις

2020 ◽  
Author(s):  
Αγγελική Κοντού
Keyword(s):  
Monte Carlo ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Intercompartmental Clearance

Σκοπός της παρούσας μελέτης ήταν η διερεύνηση της φαρμακοκινητικής συμπεριφοράς της τεϊκοπλανίνης και η ανάπτυξη ενός μοντέλου πληθυσμιακής φαρμακοκινητικής για την εκτίμηση του υπάρχοντος δοσολογικού σχήματος του φαρμάκου και των παραγόντων που μπορεί να επηρεάζουν τη σχέση δόσης-συγκέντρωσης, σε τελειόμηνα και πρόωρα νεογνά, προκειμένου να εξαχθούν συμπεράσματα για την ασφαλή και αποτελεσματική χορήγησή της. Με τη χρήση βέλτιστου σχεδιασμού σχεδιάστηκε μια προοπτική πληθυσμιακή φαρμακοκινητική μελέτη που συμπεριέλαβε 60 νεογνά με ηλικία μετά την τελευταία έμμηνο ρύση από 26 έως 43 εβδομάδων. Η τεϊκοπλανίνη χορηγήθηκε ενδοφλέβια με το εξής δοσολογικό σχήμα: δόση εφόδου 16 mg/kg και δόση συντήρησης 8 mg/kg, μία φορά την ημέρα, 24 ώρες μετά τη δόση εφόδου. Οι συγκεντρώσεις της τεϊκοπλανίνης στο πλάσμα των νεογνών μετρήθηκαν με Υγρή χρωματογραφία υψηλής απόδοσης - φασματομετρία μάζας. Η πληθυσμιακή φαρμακοκινητική ανάλυση έγινε με την ανάπτυξη ενός μη γραμμικού μοντέλου μικτών επιδράσεων μέσω του προγράμματος NONMEM. Ο δείκτης AUC24/MIC ≥ 400 επιλέχθηκε ως ο βέλτιστος ΦΚ/ΦΔ στόχος, που σχετίζεται με την αποτελεσματικότητα της τεϊκοπλανίνης, για τη διενέργεια των Monte Carlo προσομοιώσεων. Ένα δι-διαμερισματικό μοντέλο με πρωτοταξικό ρυθμό απομάκρυνσης περιέγραψε καλύτερα τις συγκεντρώσεις της τεϊκοπλανίνης στον πληθυσμό. Οι φαρμακοκινητικές παράμετροι περιγράφονται από τις εξισώσεις: CL(clearance)=0.0227*(WT/1765)^0.75*(eCRCL/22)^0.672, V1(central compartment volume)=0.283*(WT/1765), Q (intercompartmental clearance)=0.151*(WT/1765)^0.75, V2(peripheral compartment volume)=0.541*(WT/1765). Η διατομική μεταβλητότητα για την κάθαρση, τον όγκο κατανομής του κεντρικού διαμερίσματος και τον όγκο κατανομής του περιφερικού διαμερίσματος ήταν 36.5 %, 45.7% και 51,4% αντίστοιχα. Το βάρος σώματος και η κάθαρση κρεατινίνης ερμήνευσαν σημαντικά την παρατηρούμενη μεταβλητότητα. Με το υπάρχον δοσολογικό σχήμα ο ΦΚ/ΦΔ δείκτης AUC24/MIC ≥ 400 επιτεύχθηκε στο 68.5% των νεογνών με Β.Σ. < 1Kg, για παθογόνα με MIC = 1 mg/L, έναντι 82.2%, 89.7% και 92.7% των νεογνών με Β.Σ. 1 έως <2 kg, 2 έως <3 kg ή ≥3 kg αντίστοιχα. Αύξηση της δόσης συντήρησης σε 10 και 11 mg/kg στα πρόωρα νεογνά με Β.Σ. από 1 έως < 2 kg ή < 1 Kg, αντίστοιχα, αυξάνει την πιθανότητα επίτευξης του ΦΚ/ΦΔ στόχου. Το υπάρχον δοσολογικό σχήμα φαίνεται να είναι κατάλληλο για τα νεογνά με Β.Σ. ≥ 2 kg. Η φαρμακοκινητική της τεϊκοπλανίνης παρουσιάζει σημαντική μεταβλητότητα στον νεογνικό πληθυσμό. Τα νεογνά με Β.Σ. < 2 kg χρειάζονται υψηλότερες δόσεις ιδιαίτερα στην περίπτωση παθογόνων με MIC ≥ 1 mg/l.

scholarly journals Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Abdulaziz S. Alobaid ◽  
Steven C. Wallis ◽  
Paul Jarrett ◽  
Therese Starr ◽  
Janine Stuart ◽  
...  
Keyword(s):  
Critical Illness ◽  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Central Compartment ◽  
Pharmacokinetic Analysis ◽  
Peripheral Compartment ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Intercompartmental Clearance

ABSTRACT The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma samples were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean ± standard deviation age, weight, and BMI were 50 ± 15 years, 104 ± 35 kg, and 38.0 ± 15.0 kg/m2, respectively. The concentration-time data were best described by a two-compartment linear model. The mean ± SD parameter estimates for the final covariate model were a clearance of 14.0 ± 7.1 liters/h, a volume of distribution of the central compartment of 49.0 ± 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 ± 0.6 liters · h−1, and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 ± 2.8 liters · h−1. A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations.

scholarly journals Effect of Obesity on the Population Pharmacokinetics of Meropenem in Critically Ill Patients

2016 ◽  
Vol 60 (8) ◽  
pp. 4577-4584 ◽  
Author(s):  
Abdulaziz S. Alobaid ◽  
Steven C. Wallis ◽  
Paul Jarrett ◽  
Therese Starr ◽  
Janine Stuart ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Compartment Model ◽  
Central Compartment ◽  
Lower Probability ◽  
Peripheral Compartment ◽  
Morbidly Obese ◽  
Parameter Estimates ◽  
Population Pk ◽  
Intercompartmental Clearance

ABSTRACTSevere pathophysiological changes in critical illness can lead to dramatically altered antimicrobial pharmacokinetics (PK). The additional effect of obesity on PK potentially increases the challenge for effective dosing. The aim of this prospective study was to describe the population PK of meropenem for a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients prescribed meropenem were recruited into the following three body mass index (BMI) groups: nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial plasma samples were taken, and meropenem concentrations were determined using a validated chromatographic method. Population PK analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Nineteen critically ill patients with different BMI categories were enrolled. The patients' mean ± standard deviation (SD) age, weight, and BMI were 49 ± 15.9 years, 95 ± 22.0 kg, and 33 ± 7.0 kg/m2, respectively. A two-compartment model described the data adequately. The mean ± SD parameter estimates for the final covariate model were as follows: clearance (CL), 15.5 ± 6.0 liters/h; volume of distribution in the central compartment (V1), 11.7 ± 5.8 liters; intercompartmental clearance from the central compartment to the peripheral compartment, 25.6 ± 35.1 liters h−1; and intercompartmental clearance from the peripheral compartment to the central compartment, 8.32 ± 12.24 liters h−1. Higher creatinine clearance (CLCR) was associated with a lower probability of target attainment, with BMI having little effect. Although obesity was found to be associated with an increasedV1, dose adjustment based on CLCRappears to be more important than patient BMI.

scholarly journals Population Pharmacokinetic Model and Meta-analysis of Outcomes of Amphotericin B Deoxycholate Use in Adults with Cryptococcal Meningitis

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Katharine E. Stott ◽  
Justin Beardsley ◽  
Sarah Whalley ◽  
Freddie Mukasa Kibengo ◽  
Nguyen Thi Hoang Mai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Rate Constant ◽  
Cryptococcal Meningitis ◽  
Drug Exposure ◽  
Meta Analysis ◽  
Central Compartment ◽  
Order Rate Constant ◽  
Peripheral Compartment ◽  
First Order ◽  
Amphotericin B Deoxycholate

ABSTRACT There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis. A PK study was conducted in n = 42 patients receiving DAmB (1 mg/kg of body weight every 24 h [q24h]). A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of treatment of cryptococcal meningitis patients with DAmB monotherapy, and a meta-analysis was performed. The PK parameter means (standard deviations) were as follows: clearance, 0.03 (0.01) × weight + 0.67 (0.01) liters/h; volume, 0.82 (0.80) × weight + 1.76 (1.29) liters; first-order rate constant from central compartment to peripheral compartment, 5.36 (6.67) h−1; first-order rate constant from peripheral compartment to central compartment, 9.92 (12.27) h−1. The meta-analysis suggested that the DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility outcomes but not in mortality outcomes. Simulations of values corresponding to the area under concentration-time curve from h 144 to h 168 (AUC144–168) resulted in median (interquartile range) values of 5.83 mg · h/liter (4.66 to 8.55), 10.16 mg · h/liter (8.07 to 14.55), and 14.51 mg · h/liter (11.48 to 20.42) with dosages of 0.4, 0.7, and 1.0 mg/kg q24h, respectively. DAmB PK is described adequately by a linear model that incorporates weight with clearance and volume. Interpatient PK variability is modest and unlikely to be responsible for variability in clinical outcomes. There is discordance between the impact that drug exposure has on CSF sterility and its impact on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.

scholarly journals Population Pharmacokinetics of Vincristine Related to Infusion Duration and Peripheral Neuropathy in Pediatric Oncology Patients

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1789 ◽  
Author(s):  
Mirjam Esther van de Velde ◽  
John Carl. Panetta ◽  
Abraham J. Wilhelm ◽  
Marleen H. van den Berg ◽  
Inge M. van der Sluis ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Population Pharmacokinetics ◽  
Pediatric Oncology ◽  
High Performance ◽  
Peripheral Compartment ◽  
Time Curve ◽  
Mixed Effect ◽  
Liquid Chromatography Tandem Mass ◽  
Post Hoc ◽  
Intercompartmental Clearance

Vincristine (VCR) is frequently used in pediatric oncology and can be administered intravenously through push injections or 1 h infusions. The effects of administration duration on population pharmacokinetics (PK) are unknown. We described PK differences related to administration duration and the relation between PK and VCR-induced peripheral neuropathy (VIPN). PK was assessed in 1–5 occasions (1–8 samples in 24 h per occasion). Samples were analyzed using high-performance liquid chromatography/tandem mass spectrometry. Population PK of VCR and its relationship with administration duration was determined using a non-linear mixed effect. We estimated individual post-hoc parameters: area under the concentration time curve (AUC) and maximum concentration (Cmax) in the plasma and peripheral compartment. VIPN was assessed using Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score (ped-mTNS). Overall, 70 PK assessments in 35 children were evaluated. The population estimated that the intercompartmental clearance (IC-Cl), volume of the peripheral compartment (V2), and Cmax were significantly higher in the push group. Furthermore, higher IC-Cl was significantly correlated with VIPN development. Administration of VCR by push led to increased IC-Cl, V2, and Cmax, but were similar to AUC, compared to 1 h infusions. Administration of VCR by 1 h infusions led to similar or higher exposure of VCR without increasing VIPN.

scholarly journals Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 380 ◽  
Author(s):  
Quentin Allard ◽  
Zoubir Djerada ◽  
Claire Pouplard ◽  
Yohann Repessé ◽  
Dominique Desprez ◽  
...  
Keyword(s):  
Half Life ◽  
Random Effect ◽  
Real Life ◽  
Compartment Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Severe Haemophilia ◽  
Fviii Activity ◽  
Data Files

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

scholarly journals A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

2014 ◽  
Vol 58 (11) ◽  
pp. 6735-6741 ◽  
Author(s):  
Michael Neely ◽  
Edward L. Kaplan ◽  
Jeffrey L. Blumer ◽  
Dennis J. Faix ◽  
Michael P. Broderick
Keyword(s):  
Young Adults ◽  
Central Compartment ◽  
Penicillin G ◽  
Simulated Patients ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Benzathine Penicillin ◽  
Final Population ◽  
Benzathine Penicillin G

ABSTRACTSerum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group AStreptococcus pyogenes(GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.

The Reactivating and Therapeutic Efficacy of Oximes to Counteract Russian VX Poisonings

2006 ◽  
Vol 25 (5) ◽  
pp. 397-401 ◽  
Author(s):  
Jiri Kassa ◽  
Daniel Jun ◽  
Kamil Kuca
Keyword(s):  
Therapeutic Efficacy ◽  
Central Compartment ◽  
Toxic Effects ◽  
Peripheral Compartment ◽  
Structural Analogue ◽  
Hi 6 ◽  
Alkyl Groups ◽  
Brain Acetylcholinesterase ◽  
Acute Toxic

Russian VX ( O-isobutyl- S-(2-diethylaminoethyl)methylphosphonothioate) is the structural analogue of VX agent. It differs from VX agent ( O-ethyl- S-(2-diisopropylaminoethyl) methylphosphonothioate) by two alkyl groups. The potency of currently available oximes (pralidoxime, obidoxime, HI-6) to reactivate Russian VX–inhibited acetylcholinesterase and to eliminate Russian VX–induced acute toxic effects was evaluated using in vivo methods. In vivo determined percentage of reactivation of Russian VX–inhibited blood and brain acetylcholinesterase in poisoned rats shows that HI-6 seems to be the most efficacious reactivator of Russian VX–inhibited acetylcholinesterase among currently used oximes in the peripheral compartment, whereas no difference between reactivating efficacy of all tested oximes was observed in the central compartment. The oxime HI-6 was also found to be the most efficacious oxime in the elimination of acute lethal toxic effects in Russian VX–poisoned mice among all studied oximes. Thus, the oxime HI-6 seems to be the most suitable oxime for the antidotal treatment of acute poisonings with Russian VX as in the case of VX, sarin, cyclosarin, and soman poisonings.

Population Pharmacokinetics of the Novel Anticancer Agent E7070 During Four Phase I Studies: Model Building and Validation

2002 ◽  
Vol 20 (19) ◽  
pp. 4065-4073 ◽  
Author(s):  
Ch. van Kesteren ◽  
R. A.A. Mathôt ◽  
E. Raymond ◽  
J. P. Armand ◽  
Ch. Dittrich ◽  
...  
Keyword(s):  
Phase I ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Anticancer Agent ◽  
Central Compartment ◽  
Pharmacokinetic Parameters ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Data Set ◽  
Phase I Studies

PURPOSE: N-(3-Chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) is a novel sulfonamide anticancer agent currently in phase II clinical development for the treatment of solid tumors. Four phase I studies have been finalized, with E7070 administered at four different treatment schedules to identify the maximum-tolerated dose and the dose-limiting toxicities. Pharmacokinetic analyses of all studies revealed E7070 to have nonlinear pharmacokinetics. A population pharmacokinetic model was designed and validated to describe the pharmacokinetics of E7070 at all four treatment schedules and to identify the possible influences of patient characteristics on the pharmacokinetic parameters. PATIENTS AND METHODS: Plasma concentration-time data of all patients (n = 143) were fitted to several pharmacokinetic models using NONMEM. Seventeen covariables were investigated for their relation with individual pharmacokinetic parameters. A bootstrap procedure was performed to check the validity of the model. RESULTS: The data were best described using a three-compartment model with nonlinear distribution to a peripheral compartment and two parallel pathways of elimination from the central compartment: a linear and a saturable pathway. Body-surface area (BSA) was significantly correlated to both the volume of distribution of the central compartment and to the maximal elimination capacity. The fits of 500 bootstrap replicates of the data set demonstrated the robustness of the developed population pharmacokinetic model. CONCLUSION: A population pharmacokinetic model has been designed and validated that accurately describes the data of four phase I studies with E7070. Furthermore, it has been demonstrated that BSA-guided dosing for E7070 is important.

scholarly journals Nemonoxacin Dosage Adjustment in Patients with Severe Renal Impairment Based on Population Pharmacokinetic and Pharmacodynamic Analysis

2021 ◽  
Author(s):  
Yi Li ◽  
Jianda Lu ◽  
Yue Kang ◽  
Xiaoyong Xu ◽  
Xin Li ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Compartment Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Healthy Controls ◽  
Dosing Regimen ◽  
Open Label ◽  
Optimal Dosing

Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic/pharmacodynamic (PPK/PD) analysis. Methods: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 48 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) against S. Pneumoniae and S. aureus was calculated by Monte Carlo simulation. Results: The data best fitted to a two-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L), and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4±6.5% in severe renal impairment patients and 66.1±16.8% in healthy controls. PPK/PD modeling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in severe renal impairment patients, evidenced by higher PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if MIC ≤ 0.5 mg/L. Conclusion: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

scholarly journals Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Saeed A. Alqahtani ◽  
Abdullah S. Alsultan ◽  
Hussain M. Alqattan ◽  
Ahmed Eldemerdash ◽  
Turki B. Albacker
Keyword(s):  
Heart Surgery ◽  
Open Heart Surgery ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Albumin Concentration ◽  
Open Heart ◽  
Blood Samples ◽  
Dosing Regimens

ABSTRACTThe purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analyzed using an Architect i4000SR immunoassay analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 168 blood samples were analyzed from 28 patients. The pharmacokinetics of vancomycin are best described by a two-compartment model with between-subject variability in clearance (CL), the volume of distribution of the central compartment (V1), and volume of distribution of the peripheral compartment (V2). The CL and theV1of vancomycin were related to creatinine CL (CLCR), body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC0–24/MIC > 400 for an MIC of 1 mg/liter, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, the administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15- and 20-mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 and 30 mg/kg) of vancomycin.

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