scholarly journals 1300. ACOG Committee Opinion #797 and the Dose of Intrapartum Vancomycin: a Potential Danger to Mother and Newborn Alike

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S664-S665
Author(s):  
Andras Farkas ◽  
Kristina M Feldman ◽  
Krystina L Woods ◽  
Arsheena Yassin
Keyword(s):  
Cord Blood ◽  
Significant Risk ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Published Data ◽  
Time Data ◽  
Blood Concentrations ◽  
Dosing Regimens ◽  
Neonatal Group ◽  
Group B

Abstract Background Intra-partum (IP) IV vancomycin (VAN) 20 mg/kg every 8 hours is proposed by #797 for the prevention of early onset neonatal group B streptococcal disease (GBS), a recommendation for which the basis of scientific merit is poor. The goal of our study was to analyze the sparsely sampled published data and raise awareness about the underlying risk of VAN toxicity with this dosing approach. Methods Plasma and cord-blood concentration-time data of IV VAN given to mothers in the IP period was analyzed. 5000 Monte Carlo runs were conducted to simulate maternal/fetal exposure (AUC0-24; 24-48) for doses of 1500, 1750 and 2000 mgs q8h and for possible birth times at two-hour intervals. Neonatal VAN clearance was not possible to determine; hence, we used a validated PK model to calculate exposure for the first 24h of life for gestational ages (GA) of 33 to 40 weeks. The AUC range of 400 – 600, and > 600 mg*h/L were considered for indices of efficacy and toxicity, respectively. Results Estimates from 30 pairs of serum and cord-blood concentrations analyzed with a 2-compartment model are shown in Table 1. Maternal VAN exposures seem acceptable up to 2 IP doses given with mean (SD) AUC0-24 of 394 (140), 474 (167), and 540 (193) mg*h/L for the 1500, 1750 and 2000 mg regimens. Most mothers (up to 83%) who receive three or more doses will be subjected to nephrotoxic exposures (Figure 1.). Neonatal evaluations indicate similarly low PTAs for the three dosing regimens when the efficacy target is considered (Figure 2. A). On the other hand, the PTAs for potentially nephrotoxic exposure is expected to reach undesirable levels when three or more doses were to be administered. The risk is profoundly high in GA of 33 to 35 weeks and birth times beyond 20 hours after the initiation of intra-partum prophylaxis (Figure 2. B). Figure 1. Figure 2.A Figure 2.B Conclusion Current recommendations by #797 for dosing of vancomycin pose significant risk to mother and newborn alike, especially in cases with lengthy duration of labor. Based on our results, maternal therapeutic drug monitoring for all cases requiring more than two doses should be considered. With the proposed dosing regimen going un-adjusted, 1 out of 4 newborns and 4 out of 5 mothers may be subjected to nephrotoxic exposures in prolonged labor. Table 1. Disclosures All Authors: No reported disclosures

scholarly journals Amikacin Pharmacokinetics To Optimize Dosing in Neonates with Perinatal Asphyxia Treated with Hypothermia

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Sinziana Cristea ◽  
Anne Smits ◽  
Aida Kulo ◽  
Catherijne A. J. Knibbe ◽  
Mirjam van Weissenbruch ◽  
...  
Keyword(s):  
Perinatal Asphyxia ◽  
Volume Of Distribution ◽  
Stochastic Simulations ◽  
Therapeutic Drug ◽  
Published Data ◽  
Data Set ◽  
Dosing Interval ◽  
Proposed Model ◽  
Dosing Regimens ◽  
The Impact

ABSTRACT Aminoglycoside pharmacokinetics (PK) is expected to change in neonates with perinatal asphyxia treated with therapeutic hypothermia (PATH). Several amikacin dosing guidelines have been proposed for treating neonates with (suspected) septicemia; however, none provide adjustments for cases of PATH. Therefore, we aimed to quantify the differences in amikacin PK between neonates with and without PATH to propose suitable dosing recommendations. Based on amikacin therapeutic drug monitoring data collected retrospectively from neonates with PATH, combined with a published data set, we assessed the impact of PATH on amikacin PK by using population modeling. Monte Carlo and stochastic simulations were performed to establish amikacin exposures in neonates with PATH after dosing according to the current guidelines and according to proposed model-derived dosing guidelines. Amikacin clearance was decreased 40.6% in neonates with PATH, with no changes in volume of distribution. Simulations showed that increasing the dosing interval by 12 h results in a decrease in the percentage of neonates reaching toxic trough levels (>5 mg/liter), from 40 to 76% to 14 to 25%, while still reaching efficacy targets compared to the results of current dosing regimens. Based on this study, a 12-h increase in the amikacin dosing interval in neonates with PATH is proposed to correct for the reduced clearance, yielding safe and effective exposures. As amikacin is renally excreted, further studies into other renally excreted drugs may be required, as their clearance may also be impaired.

scholarly journals Population Pharmacokinetics of intravenous Ganciclovir and oral Valganciclovir in pediatric population to optimize dosing regimens

2020 ◽  
pp. AAC.02254-20
Author(s):  
T. Nguyen ◽  
M. Oualha ◽  
C. Briand ◽  
M. Bendavid ◽  
A. Béranger ◽  
...  
Keyword(s):  
Pediatric Population ◽  
Preventive Treatment ◽  
Compartment Model ◽  
Critically Ill Children ◽  
Therapeutic Drug ◽  
Intravenous Ganciclovir ◽  
Mixed Effect ◽  
First Order ◽  
Dosing Regimens ◽  
Oral Valganciclovir

Context: Ganciclovir is indicated for curative or preventive treatment of cytomegalovirus (CMV) infections. This study aimed to characterize ganciclovir pharmacokinetics, following intravenous ganciclovir and oral valganciclovir administration, in order to optimize dosing scheme.Method: All children aged <18 years receiving ganciclovir or valganciclovir were included in this study. Pharmacokinetics were described using non-linear mixed-effect modelling. Monte Carlo simulations were used to optimize dosing regimen in order to maintain area under the concentration curve (AUC) in the preventive or therapeutic target.Results: Among the 105 children (374 concentration-time observations) included, 78 received intravenous (IV) ganciclovir, 19 oral valganciclovir and 6 both drugs. A two-compartment model with first-order absorption for valganciclovir and first-order elimination best described the data. An allometric model was used to describe bodyweight (BW) effect. Estimated glomerular filtration rate (eGFR) and critically-ill children medical status were significantly associated with ganciclovir elimination.Conclusion: Recommended doses were adapted for prophylactic treatment. To obtain a therapeutic exposure, doses should be increased to 40 mg/kg/day oral or 15-20 mg/kg/day IV in children with normal eGFR and to 56 mg/kg/day oral or 20-25 mg/kg/day IV in children with augmented eGFR. These doses should be prospectively confirmed and a therapeutic drug monitoring could be used to refine them individually.

scholarly journals Optimised Dosing of Vancomycin in Critically Ill Indigenous Australian Patients with Severe Sepsis

2018 ◽  
Vol 46 (4) ◽  
pp. 374-380 ◽  
Author(s):  
D. Tsai ◽  
P. C. Stewart ◽  
S. Hewagama ◽  
S. Krishnaswamy ◽  
S. C. Wallis ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Severe Renal Impairment ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Published Data ◽  
Time Data ◽  
Indigenous Australian ◽  
Final Population ◽  
Population Pk

Vancomycin is a commonly used antibiotic due to the high burden of methicillin-resistant Staphylococcus aureus infections. This study aimed to describe the pharmacokinetics (PK) of vancomycin in Australian Indigenous patients with severe sepsis, and advise an optimal dosing strategy. A population PK study was conducted in a remote Australian intensive care unit (ICU). Serial plasma samples were collected over one to two dosing intervals and assayed by validated chromatography. Concentration–time data collected were analysed using Pmetrics® software. The final population PK model was then used for Monte Carlo dosing simulations to determine optimal loading and intermittent maintenance doses. Fifteen Indigenous subjects were included for analysis with a median (interquartile range, IQR) age, weight and creatinine clearance (CrCL) of 43 (34–46) years, 73 (66–104) kg and 99 (56–139) ml/minute respectively. A two-compartment model described the data adequately. Vancomycin clearance (CL) and volume of distribution of the central compartment (Vc) were described by CrCL and patient weight respectively. Median (IQR) CL, Vc, distribution rate constants from central to peripheral, and from peripheral to central compartments were 4.6 (3.8–5.6) litres per hour, 25.4 (16.1–31.3) litres, 0.46 (0.28–0.52)/hour and 0.25 (0.12–0.37)/hour respectively. No significant interethnic PK differences were observed in comparison to published data. Therapeutic loading doses were significantly dependent on both weight and CrCL, whereas maintenance doses were dependent on CrCL. In the absence of severe renal impairment, initiation of maintenance dose eight hours post–loading dose achieved higher probability of target attainment at 24 hours. This is the first report of vancomycin PK in this patient group.

scholarly journals POS0070 POPULATION PHARMACOKINETICS OF INFLIXIMAB IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 241.2-242
Author(s):  
A. Nassar-Sheikh Rashid ◽  
D. Schonenberg-Meinema ◽  
S. Berends ◽  
J. M. Van den Berg ◽  
R. Mathot
Keyword(s):  
Rheumatoid Arthritis ◽  
Juvenile Idiopathic Arthritis ◽  
Serum Concentration ◽  
Compartment Model ◽  
Patient Characteristics ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Trough Concentrations ◽  
Over Time

Background:Higher dosage regimes for Infliximab (IFX) have been described to be effective in partial- or non-responding adults and children with rheumatic disease and appear to be safe (1,2). To optimize IFX treatment in juvenile idiopathic arthritis (JIA) patients, therapeutic drug monitoring (TDM) might be beneficial. To support routine TDM of IFX and dose regimen optimization in JIA patients, more in-depth knowledge of the pharmacokinetic (PK) variability of IFX is needed. Ultimately, as soon as the optimal therapeutic drug ranges will be known, PK model-based simulation can be used to individualize drug dosing recommendations. Individual dosages may be adjusted by taking specific patient characteristics into account that explain inter-patient variability in pharmacokinetics (PK). Inter-patient variability can be quantified and investigated by the population approach.Objectives:Our hypothesis is that optimizing dosage and frequency of IFX administration for individual patients will improve treatment outcome. In this current study, the population PK for IFX are described for JIA patients.Methods:Data including IFX trough concentrations and anti-IFX antibodies of 27 JIA patients on IFX maintenance treatment were retrieved from electronic charts. Three population pharmacokinetic models from literature were validated for our dataset using nonlinear-mixed effects modeling program NONMEM (3,4,5). A novel population pharmacokinetic model was developed based on our study data.Results:A total of 65 obtained blood samples after a median of 32 days after the last IFX infusion (IQR 28-42) were analyzed. The three published models underpredicted the observed trough concentrations. A newly developed one compartment model best described the IFX serum concentration over time data in JIA patients (see Figure 1).Conclusion:Our study shows a novel and the first PK model for IFX in JIA patients. Our main finding was that a one- compartment model best described the IFX serum concentration over time data. Predictive performance of the known models from literature was insufficient for our patient data. Our data also show that different PK models are needed for different age categories (children or adults) and in different diseases.References:[1]Nozaki Y et al. Infliximab dose adjustment can improve the clinical and radiographic outcomes of rheumatoid arthritis patients: REVIVE study results. Biologics. 2018.[2]Tambralli A et al. High doses of infliximab in the management of juvenile idiopathic arthritis. J Rheumatol. 2013.[3]Fasanmade AA et al. Pharmacokinetic properties of infliximab in children and adults with Crohn’s disease: a retrospective analysis of data from 2 phase III clinical trials. Clin Ther. 2011.[4]Xu Z et al. Population pharmacokinetics of infliximab in patients with ankylosing spondylitis. J Clin Pharmacol. 2008.[5]Ternant D et al. Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis. Br J Clin Pharmacol. 2014.Table 1.Patient characteristicsN=27 patientsWeight (kg)52 [40 – 62]BSA1.6 [1.3 – 1.8]Age (years)14 [11 – 17]Male, N (%)6 (22%)CRP (mg/L)0.5 [0.2 – 0.7]WBC count6.5 [5.6 –7.5]Antibodies-to-IFX1 (4%)Dose (mg)300 [200-400]Dose (mg/kg)5.4 [4.9 -7.0]Hemoglobine (mmol/L)7.9 [7.5 -8.2]ESR (mm/h)5 [5-8]Uveitis3 (11%)Disclosure of Interests:None declared.

scholarly journals Are Standard Dosing Regimens of Ceftriaxone Adapted for Critically Ill Patients with Augmented Creatinine Clearance?

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Julien Ollivier ◽  
Cédric Carrié ◽  
Nicolas d’Houdain ◽  
Sarah Djabarouti ◽  
Laurent Petit ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Creatinine Clearance ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Free Fraction ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Target Attainment ◽  
Dosing Regimens

ABSTRACT The objective of the present study was to determine whether augmented renal clearance (ARC) impacts negatively on ceftriaxone pharmacokinetic (PK)/pharmacodynamic (PD) target attainment in critically ill patients. Over a 9-month period, all critically ill patients treated with ceftriaxone were eligible. During the first 3 days of antimicrobial therapy, every patient underwent 24-h creatinine clearance (CLCR) measurements and therapeutic drug monitoring of unbound ceftriaxone. ARC was defined by a CLCR of ≥150 ml/min. Empirical underdosing was defined by a trough unbound ceftriaxone concentration under 2 mg/liter (percentage of the time that the concentration of the free fraction of drug remained greater than the MIC [fT>MIC], 100%). Monte Carlo simulation (MCS) was performed to determine the probability of target attainment (PTA) of different dosing regimens for various MICs and three groups of CLCR (<150, 150 to 200, and >200 ml/min). Twenty-one patients were included. The rate of empirical ceftriaxone underdosing was 62% (39/63). A CLCR of ≥150 ml/min was associated with empirical target underdosing with an odds ratio (OR) of 8.8 (95% confidence interval [CI] = 2.5 to 30.7; P < 0.01). Ceftriaxone PK concentrations were best described by a two-compartment model. CLCR was associated with unbound ceftriaxone clearance (P = 0.02). In the MCS, the proportion of patients who would have failed to achieve a 100% fT>MIC was significantly higher in ARC patients for each dosage regimen (OR = 2.96; 95% CI = 2.74 to 3.19; P < 0.01). A dose of 2 g twice a day was best suited to achieve a 100% fT>MIC. When targeting a 100% fT>MIC for the less susceptible pathogens, patients with a CLCR of ≥150 ml/min remained at risk of empirical ceftriaxone underdosing. These data emphasize the need for therapeutic drug monitoring in ARC patients.

scholarly journals Population Pharmacokinetics of Intravenous and Oral Acyclovir and Oral Valacyclovir in Pediatric Population To Optimize Dosing Regimens

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
S. Abdalla ◽  
C. Briand ◽  
M. Oualha ◽  
M. Bendavid ◽  
A. Béranger ◽  
...  
Keyword(s):  
Body Weight ◽  
Pediatric Population ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Oral Acyclovir ◽  
Mixed Effect ◽  
Varicella Zoster ◽  
Dosing Regimens ◽  
Trough Concentrations ◽  
Simplex Virus

ABSTRACT Acyclovir is an antiviral currently used for the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. This study aimed to characterize the pharmacokinetics (PK) of acyclovir and its oral prodrug valacyclovir to optimize dosing in children. Children receiving acyclovir or valacyclovir were included in this study. PK were described using nonlinear mixed-effect modeling. Dosing simulations were used to obtain trough concentrations above a 50% inhibitory concentration for HSV or VZV (0.56 mg/liter and 1.125 mg/liter, respectively) and maximal peak concentrations below 25 mg/liter. A total of 79 children (212 concentration-time observations) were included: 50 were taking intravenous (i.v.) acyclovir, 22 were taking oral acyclovir, and 7 were taking both i.v. and oral acyclovir, 57 for preventive and 22 for curative purposes. A one-compartment model with first-order elimination best described the data. An allometric model was used to describe body weight effect, and the estimated glomerular filtration rate (eGFR) was significantly associated with acyclovir elimination. To obtain target maximal and trough concentrations, the more suitable initial acyclovir i.v. dose was 10 mg/kg of body weight/6 h for children with normal renal function (eGFR ≤ 250 ml/min/1.73 m2) and 15 to 20 mg/kg/6 h for children with augmented renal clearance (ARC) (eGFR > 250 ml/min/1.73 m2). The 20-mg/kg/8 h dose for oral acyclovir and valacyclovir produced effective concentrations in more than 75% of children; however, a 15-mg/kg/6 h dose, if possible, is preferred. These doses should be prospectively confirmed, and therapeutic drug monitoring could be used to refine them individually. (This study has been registered at ClinicalTrials.gov under identifier NCT02539407.)

scholarly journals Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

2020 ◽  
Vol 75 (9) ◽  
pp. 2641-2649
Author(s):  
Nynke G L Jager ◽  
Reinier M van Hest ◽  
Jiao Xie ◽  
Gloria Wong ◽  
Marta Ulldemolins ◽  
...  
Keyword(s):  
Protein Binding ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Binding Capacity ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Population Pk ◽  
Non Linear ◽  
Dosing Regimens

Abstract Background Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. Objectives To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients. Methods First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. Results A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT&gt;MIC) was 91% for patients with eGFR of 33 mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h. Conclusions For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations.

Parameters of vancomycin pharmacokinetics in postoperative patients with renal dysfunction: comparing the results of a pharmacokinetic study and mathematical modeling

2018 ◽  
pp. 58-64
Author(s):  
G. V. Ramenskaya ◽  
I. E. Shokhin ◽  
M. V. Lukina ◽  
T. B. Andrushishina ◽  
M. A. Chukina ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Renal Dysfunction ◽  
High Performance ◽  
Kidney Injury ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Drug Concentrations ◽  
Dosing Regimens

Mathematical modeling of pharmacokinetic (PK) and pharmacodynamic (PD) parameters essential for establishing correct dosing regimens is an alternative to pharmacokinetic studies (PKS) adopted in the clinical setting. The aim of this work was to compare the values of PK parameters for vancomycin obtained in an actual PKS and through MM in postoperative patients with kidney injury. Our prospective study included 61 patients (47 males and 14 females aged 60.59 ± 12.23 years). During PKS, drug concentrations at steady state Сtrough and Cpeak were measured by high-performance liquid chromatography followed by the calculation of the area under the plasma concentration-time curve AUC24. For mathematical modeling, a single-compartment model was employed; PK parameters were estimated using R 3.4.0. The values of Ctrough measured 48 h after the onset of antibiotic therapy during PKS were significantly lower than those predicted by MM (р = 0.004). In a group of patients with acute kidney injury (AKI), AUC24 measured at the end of treatment was significantly higher than its value predicted by MM (р = 0.011). The probability of achieving the target AUC24 to MIC ratio of over 400 μg•h /ml is higher in the group of patients with Ctrough = 10–15 μg /ml. Our findings confirm that the use of MM in postoperative patients with renal dysfunction is limited and therapeutic drug monitoring should be used instead.

scholarly journals Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1821
Author(s):  
David Ternant ◽  
Olivier Le Tilly ◽  
Laurence Picon ◽  
Driffa Moussata ◽  
Christophe Passot ◽  
...  
Keyword(s):  
Drug Disposition ◽  
Elimination Rate ◽  
Compartment Model ◽  
Central Compartment ◽  
Therapeutic Drug ◽  
Peripheral Compartment ◽  
Time Data ◽  
Elimination Kinetics ◽  
Tnf Α ◽  
Target Mediated Drug Disposition

Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (RC0 = 3.3 nM and RP0 = 0.46 nM), steady-stated dissociation rates (KCSS = 15.4 nM and KPSS = 0.49 nM), and first-order elimination rates of complexes (kCint = 0.17 day−1 and kPint = 0.0079 day−1). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.

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