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

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.

Ανάλυση πληθυσμιακής φαρμακοκινητικής της τεϊκοπλανίνης σε νεογνά με ενδονοσοκομειακές λοιμώξεις

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.

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

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.

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

ABSTRACTOur objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese (n= 6) and morbidly obese (n= 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m2, respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment (Vc) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of >30 kg/m2. A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.

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

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.

Population Pharmacokinetic Analysis of Piperacillin in Burn Patients

ABSTRACTPiperacillin in combination with tazobactam, a β-lactamase inhibitor, is a commonly used intravenous antibiotic for the empirical treatment of infection in intensive care patients, including burn patients. The purpose of this study was to develop a population pharmacokinetic (PK) model for piperacillin in burn patients and to predict the probability of target attainment (PTA) using MICs and concentrations simulated from the PK model. Fifty burn patients treated with piperacillin-tazobactam were enrolled. Piperacillin-tazobactam was administered via infusion for approximately 30 min at a dose of 4.5 g (4 g piperacillin and 0.5 g tazobactam) every 8 h. Blood samples were collected just prior to and at 1, 2, 3, 4, and 6 h after the end of the infusion at steady state. The population PK model of piperacillin was developed using NONMEM. A two-compartment first-order elimination PK model was finally chosen. The covariates included were creatinine clearance (CLCR), day after burn injury (DAI), and sepsis. The final PK parameters were clearance (liters/h) (equal to 16.6 × [CLCR/132] + DAI × [−0.0874]), central volume (liters) (equal to 25.3 + 14.8 × sepsis [0 for the absence or 1 for the presence of sepsis]), peripheral volume (liters) (equal to 16.1), and intercompartmental clearance (liters/h) (equal to 0.636). The clearance and volume of piperacillin were higher than those reported in patients without burns, and the terminal half-life and PTA decreased with the increased CLCR. Our PK model suggests that higher daily doses or longer durations of infusion of piperacillin should be considered, especially for burn patients with a CLCRof ≥160 ml/min.

Pharmacokinetics of Penicillin G in Infants with a Gestational Age of Less than 32 Weeks

ABSTRACT The pharmacokinetics of penicillin G were studied in 20 preterm neonates with a gestational age of less than 32 weeks on day 3 of life by using a population approach performed with the nonlinear mixed effects modeling program NONMEM. The derived population estimates and the correlation matrix of these estimates were used to perform Monte Carlo simulations and obtain the probability of target attainment (PTA). The pharmacokinetics of penicillin G were best described by a two-compartment pharmacokinetic model. The population estimates of the central volume of distribution, the peripheral volume of distribution, the intercompartmental clearance, and the total body clearance were 0.359 ± 0.06 liter, 0.152 ± 0.03 liter, 0.774 ± 0.28 liter/h, and 0.103 ± 0.01 liter/h (mean ± standard error), respectively. The terminal half-life was 3.9 h. Clearance increased significantly with increasing birth weight. Assuming the percentage of time that the concentration of unbound drug remained above the MIC of 50% for preterm neonates, the susceptibility breakpoint based on a 100% PTA was ≤4 mg/liter, simulating the current dosing regimen of 50,000 U/kg every 12 h. This regimen is therefore adequate for the treatment of common infections in neonates on the third day of life.