scholarly journals Population Pharmacokinetics of Fluconazole in Young Infants

2008 ◽  
Vol 52 (11) ◽  
pp. 4043-4049 ◽  
Author(s):  
K. C. Wade ◽  
D. Wu ◽  
D. A. Kaufman ◽  
R. M. Ward ◽  
D. K. Benjamin ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Relative Standard Error ◽  
Data Set ◽  
Mixed Effect ◽  
Young Infants ◽  
Relative Standard ◽  
Population Pk ◽  
The Impact

ABSTRACT Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75 · (BGA/26)1.739 · (PNA/2)0.237 · serum creatinine (SCRT)−4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

scholarly journals Population Pharmacokinetic Analyses for BC-3781 Using Phase 2 Data from Patients with Acute Bacterial Skin and Skin Structure Infections

2014 ◽  
Vol 59 (1) ◽  
pp. 282-288 ◽  
Author(s):  
C. M. Rubino ◽  
B. Xue ◽  
S. M. Bhavnani ◽  
W. T. Prince ◽  
Z. Ivezic-Schoenfeld ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Size ◽  
Phase 1 ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Phase 2 ◽  
Data Set ◽  
Skin Structure ◽  
Population Pk

ABSTRACTBC-3781, a pleuromutilin antimicrobial agent, is being developed for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia. Data from a phase 2 study of patients with ABSSSI were used to refine a previous population pharmacokinetic (PK) model and explore potential predictors of PK variability. The previously derived population PK model based on data from three phase 1 studies was applied to sparse sampling data from a phase 2 ABSSSI study and modified as necessary. Covariate analyses were conducted to identify descriptors (e.g., body size, renal function, age) associated with interindividual variability in PK. All population PK analyses were conducted by using Monte Carlo parametric expectation maximization implemented in S-ADAPT 1.5.6. The population PK data set contained 1,167 concentrations from 129 patients; 95% of the patients had 5 or more PK samples (median, 11). The previous population PK model (three-compartment model with first-order elimination and nonlinear protein binding) provided an acceptable and unbiased fit to the data from the 129 patients. Population PK parameters were estimated with acceptable precision; individual clearance values were particularly well estimated (median individual precision of 9.15%). Graphical covariate evaluations showed no relationships between PK and age or renal function but modest relationships between body size and clearance and volume of distribution, which were not statistically significant when included in the population PK model. This population PK model will be useful for subsequent PK-pharmacodynamic analyses and simulations conducted to support phase 3 dose selection. (This study has been registered at ClinicalTrials.gov under registration no. NCT01119105.)

scholarly journals 1540. A Population Pharmacokinetic Model for Vancomycin in Korean Patients Receiving Extracorporeal Membrane Oxygenation Therapy: A Prospective Study

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S562-S562
Author(s):  
Younghee Jung ◽  
Dong-Hwan Lee ◽  
Hyoung Soo Kim
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Creatinine Clearance ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Test Model ◽  
Mixed Effect ◽  
Korean Patients ◽  
Membrane Oxygenation ◽  
Population Pk

Abstract Background There is no literature on population pharmacokinetics (PK) of vancomycin in Korean patients receiving extracorporeal membrane oxygenation (ECMO) therapy. The aim of this study was to develop a population PK model for vancomycin in Korean ECMO patients. Methods We prospectively enrolled adult patients who were undergoing ECMO and receiving vancomycin from July 2018 to April 2019. After initial dose of vancomycin was administrated, serial blood samples (seven to nine times per patient) were drawn before the next dose. A population PK model for vancomycin was developed using a nonlinear mixed-effect modeling. Age, sex, creatinine clearance, and body weight were tested as potential covariates in the model. Model selection was based on log-likelihood test, model diagnostic plots, and clinical plausibility. Results Fourteen patients were included over the period. Ten received venovenous, three venoarterial, and one both type ECMO. Eleven were men and the median age was 54 (interquartile range 45–66.3). Mean estimated glomerular filtration rate (eGFR) was 69 ± 46 mL/minute/1.73m2 by the modification of diet in renal disease equation. A total of 123 vancomycin concentrations from the patients were included in the analysis. The population PK of vancomycin was best described by a two-compartment model with a proportional residual error model. The typical value (%between-subject variability) for total clearance was estimated to be 4.33 L/h (21.6%), central volume of distribution was 9.22 L, the intercompartmental clearance was 10.75 L/hr (34.9%) and the peripheral volume of distribution was 19.6 L (26.6%). The proportional residual variability was 8.81%. Creatinine clearance significantly influenced vancomycin clearance (CL). The proposed equation to estimate vancomycin clearance in Korean ECMO patients was CL = 4.33 + 0.199 × (eGFR – 56). Conclusion A two-compartment population PK model successfully describes vancomycin PK profiles in Korean ECMO patients. The model could be used to optimize the dosing regimen if more data become available from currently ongoing clinical study. Disclosures All authors: No reported disclosures.

scholarly journals Population Pharmacokinetics of Ropeginterferon Alfa-2b: A Comparison Between Healthy Caucasian and Chinese Subjects

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Zhu ◽  
Mei-xia Wang ◽  
Zi-ran Li ◽  
Wei Wang ◽  
Xia Su ◽  
...  
Keyword(s):  
Drug Disposition ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Relative Standard Error ◽  
Quasi Equilibrium ◽  
Phase I Clinical Trials ◽  
Two Phase ◽  
Relative Standard ◽  
Population Pk ◽  
Chinese Subjects

Objective: To develop a population pharmacokinetic (PK) model for ropeginterferon alfa-2b and to compare its PK properties between Caucasian and Chinese populations.Methods: A population PK model was developed based on data from two phase I clinical trials conducted in Caucasian and Chinese individuals, to evaluate the influence of ethnicity on the PKs of ropeginterferon alfa-2b.Results: We included 456 observations from 30 healthy Caucasian subjects and 438 observations from 27 healthy Chinese subjects in the population PK analysis. The PKs of ropeginterferon alfa-2b were best described by a one-compartment quasi-equilibrium approximated target-mediated drug disposition model with first-order absorption and absorption lag times. The typical value (relative standard error%) of apparent clearance (CL/F) and volume of distribution of ropeginterferon alfa-2b in 70-kg subjects were 0.778 (12%) L/day and 2.32 (14%) L, respectively. Body weight was the only significant factor affecting the CL/F. There were no obvious differences in the PK properties of ropeginterferon alfa-2b, and predicted steady-state exposure was similar in the Chinese and Caucasian populations.Conclusion: No significant ethnic differences in ropeginterferon alfa-2b PKs were observed between the Chinese and Caucasian populations.

scholarly journals Tourism under the Early Phase of COVID-19 in Four APEC Economies: An Estimation with Special Focus on SARS Experiences

2020 ◽  
Vol 17 (20) ◽  
pp. 7543
Author(s):  
Bao-Linh Tran ◽  
Chi-Chung Chen ◽  
Wei-Chun Tseng ◽  
Shu-Yi Liao
Keyword(s):  
Hong Kong ◽  
New Zealand ◽  
Fixed Effects ◽  
Negative Impact ◽  
Asia Pacific ◽  
International Tourism ◽  
Special Focus ◽  
Tourism Demand ◽  
Data Set ◽  
The Impact

This study examines how experience of severe acute respiratory syndrome (SARS) influences the impact of coronavirus disease (COVID-19) on international tourism demand for four Asia-Pacific Economic Cooperation (APEC) economies, Taiwan, Hong Kong, Thailand, and New Zealand, over the 1 January–30 April 2020 period. To proceed, panel regression models are first applied with a time-lag effect to estimate the general effects of COVID-19 on daily tourist arrivals. In turn, the data set is decomposed into two nation groups and fixed effects models are employed for addressing the comparison of the pandemic-tourism relationship between economies with and without experiences of the SARS epidemic. Specifically, Taiwan and Hong Kong are grouped as economies with SARS experiences, while Thailand and New Zealand are grouped as countries without experiences of SARS. The estimation result indicates that the number of confirmed COVID-19 cases has a significant negative impact on tourism demand, in which a 1% COVID-19 case increase causes a 0.075% decline in tourist arrivals, which is a decline of approximately 110 arrivals for every additional person infected by the coronavirus. The negative impact of COVID-19 on tourist arrivals for Thailand and New Zealand is found much stronger than for Taiwan and Hong Kong. In particular, the number of tourist arrivals to Taiwan and Hong Kong decreased by 0.034% in response to a 1% increase in COVID-19 confirmed cases, while in Thailand and New Zealand, a 1% national confirmed cases increase caused a 0.103% reduction in tourism demand. Moreover, the effect of the number of domestic cases on international tourism is found lower than the effect caused by global COVID-19 mortality for the economies with SARS experiences. In contrast, tourist arrivals are majorly affected by the number of confirmed COVID-19 cases in Thailand and New Zealand. Finally, travel restriction in all cases is found to be the most influencing factor for the number of tourist arrivals. Besides contributing to the existing literature focusing on the knowledge regarding the nexus between tourism and COVID-19, the paper’s findings also highlight the importance of risk perception and the need of transmission prevention and control of the epidemic for the tourism sector.

scholarly journals Population Pharmacokinetics of Oseltamivir: Pediatrics through Geriatrics

2013 ◽  
Vol 57 (8) ◽  
pp. 3470-3477 ◽  
Author(s):  
Mohamed A. Kamal ◽  
Scott A. Van Wart ◽  
Craig R. Rayner ◽  
Vishak Subramoney ◽  
Daniel K. Reynolds ◽  
...  
Keyword(s):  
Steady State ◽  
Time Course ◽  
Demographic Data ◽  
Visual Predictive Check ◽  
Compartment Model ◽  
Plasma Drug ◽  
First Order ◽  
Drug Concentrations ◽  
Population Pk ◽  
The Impact

ABSTRACTOseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of oseltamivir and its active metabolite form, oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated by using the NONMEM software program, and subject covariates were assessed using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC and a one-compartment model with first-order elimination of OC were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent OC clearance (CLm/F) and central volume of distribution (Vcm/F). Creatinine clearance was a significant predictor of CLm/F, while Vcm/F also decreased linearly with age. A visual predictive check indicated that the final model described oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individualpost hocpredictions of maximum concentration of drug at steady state (Cmax) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC0–24) was high (r2= 0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone.

Firm-level agreements, employment strategies and temporary workers

2020 ◽  
Vol 42 (1) ◽  
pp. 194-212
Author(s):  
Saverio Minardi
Keyword(s):  
Fixed Effects ◽  
Selection Process ◽  
Temporary Employment ◽  
Least Square ◽  
Temporary Workers ◽  
Firm Level ◽  
Data Set ◽  
Content Type ◽  
Collective Agreements ◽  
The Impact

Purpose The purpose of this paper is to investigate the impact of two-tier firm-level collective agreements on firms’ propensity to use temporary employment, accounting for the process of self-selection of firms into different bargaining levels in the Italian context. It further examines which firm-level characteristics drive this process of selection. Design/methodology/approach The empirical analysis uses a panel data set of Italian firms for the years 2005, 2007, 2010 and 2015. Estimations are produced and compared through ordinary least square regression, random-effects and fixed-effects models. Findings Results show that enterprises adopting two-tier firm-level agreements (TTFA) are associated with lower levels of temporary workers. However, a longitudinal analysis suggests that introducing a TTFA does not impact firms’ propensity to employ temporary workers. This novel finding highlights the presence of a selection process based on firm-level time-constant characteristics. The paper argues that these characteristics refer to management orientation toward high-road rather than low-road employment strategies. Further evidence is brought in support of this claim, showing that firms’ propensity toward the provision of training for their labor force partially explain the process of selection. Originality/value The study is the first to analyze the impact of secondary-level collective agreements on firms’ reliance on temporary employment, offering new evidence on the causes of the expansion of temporary employment. It further highlights the relevance of employers’ strategies in shaping the impact of the bargaining structure.

scholarly journals Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: effect of elevated hepatic pressures

2015 ◽  
Vol 26 (2) ◽  
pp. 354-362 ◽  
Author(s):  
Kevin D. Hill ◽  
Mario R. Sampson ◽  
Jennifer S. Li ◽  
Robert D. Tunks ◽  
Scott R. Schulman ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Structural Model ◽  
Single Ventricle ◽  
Heart Defects ◽  
Model Development ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Mixed Effect ◽  
The Impact

AbstractAimsSildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures, which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects.MethodsA population pharmacokinetic model was developed using data from 20 single ventricle children receiving single-dose intravenous sildenafil during cardiac catheterisation. Non-linear mixed effect modelling was used for model development, and covariate effects were evaluated based on estimated precision and clinical significance.ResultsThe analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance=0.62 L/hour/kg); however, clearance of des-methyl-sildenafil (1.94×(hepatic pressure/9)−1.33 L/hour/kg) was predicted to decrease ~7-fold as hepatic pressure increased from 4 to 18 mmHg. Predicted drug exposure was increased by ~1.5-fold in subjects with hepatic pressures ⩾10 versus <10 mmHg (median area under the curve=533 versus 792 µg*h/L).DiscussionElevated hepatic pressure delays clearance of the sildenafil metabolite – des-methyl-sildenafil – and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessments in patients with unique cardiovascular physiology that may affect drug metabolism.

An Interim Evaluation of Systemic F-Ara-a Exposure in Pediatric Allogeneic Hematopoietic Cell Transplant (alloHCT) Recipients Using An Optimal Sampling Design

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1962-1962
Author(s):  
Janel R Long-Boyle ◽  
Shirley Yan ◽  
Christopher C. Dvorak ◽  
Biljana N. Horn ◽  
Morton Jerome Cowan ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Sampling Strategy ◽  
Volume Of Distribution ◽  
Exploratory Analysis ◽  
Accurate Estimation ◽  
Cell Transplant ◽  
Optimal Sampling ◽  
Exposure Response ◽  
Relative Standard ◽  
Population Pk

Abstract Abstract 1962 Background Fludarabine is a purine analogue used in the preparative regimens of pediatric alloHCT to enhance stem cell engraftment. Administered intravenously as a prodrug, fludarabine (f-ara-AMP) undergoes rapid dephosphorylation in the plasma to the systemically circulating compound, f-ara-a. Despite widespread use, there are no published pharmacokinetic-pharmacodynamic (PK-PD) studies of fludarabine in children undergoing alloHCT. Using an optimal sampling strategy (OSS), we designed a prospective study to evaluate the PK-PD of fludarabine in pediatric alloHCT recipients. We report the year-1 interim PK analysis of this 3-year exposure-response study. Methods Utilizing prior f-ara-a PK data available in adults and D-optimal sampling methods (PFIM software), we designed an OSS for f-ara-a in children. Based on the OSS, the relative standard errors (RSE), representing the precision of estimated PK parameters, were predicted to be less than 20% in a total of 45 children. An interim analysis was planned after year 1 to ensure the sample collection times selected by the OSS were sufficiently informative. Patients were eligible to participate in PK sampling if they were between 0 to 17 years of age, met protocol specific criteria for alloHCT, and would be receiving fludarabine as part of their preparative regimen. All patients underwent PK sampling with dose 1 of fludarabine. Fludarabine was infused per protocol over 30–60 minutes and 1 mL of whole blood was obtained at 2, 4, 8, and 24 h after the start of infusion. PK sampling was repeated following a subsequent dose of fludarabine (dose 2, 3, 4 or 5) at 2 and 24 h. Plasma samples were analyzed by LC-tandem MS and the assay was linear in the range of 5–500 ng/mL. PK model development using f-ara-a concentration-time data was carried out using standard population PK methodologies (NONMEM 7.2 software). Further development of a 2-compartment open model was based on exploratory analysis, diagnostic plots and changes in objective function value (OFV). The addition of allometric scaling, with weight built into the base model scaled to a reference patient having the median weight of the population, resulted in a significant drop in the OFV. No other covariates were tested based on exploratory analysis and plots. The model was parameterized in terms of clearance (CL), volume of distribution-central compartment (Vc), volume of distribution-peripheral compartment (Vp), and inter-compartmental clearance (Q). Residual unexplained variability was modeled as being proportional to the predicted concentrations. Area-under-the-curve (AUC) of f-ara-a was derived from the empirical Bayes estimates of individual CL. Results A total of 94 quantifiable concentrations from 16 subjects (10 male, 6 female) were available for interim PK modeling. Most patients received fludarabine 30–40mg/m2 daily over 3 to 5 days (n=13). In the 3 smallest children (<10kg), fludarabine was dosed at 1.33mg/kg/day for 3 to 4 days. Median age and weight of subjects was 6.5 years (range, 0.3–17) and 23.4kg (6.8-82.3), respectively. Markers for renal function were within normal age limits for all subjects. A 2-compartment model with linear elimination well described the PK of f-ara-a. The population PK estimates for CL, Vc, Vp, Q, and their RSE (%) were 9.0 (6.3%), 30 (8.9%), 34 (6.4%), and 7.7 (11%), respectively. The final model of this interim analysis estimated f-ara-a CL (L/h) = 9.0 * (WT/23.4)0.67. This model predicts f-ara-a CL (%CV) to be lower for children < 10kg (n=3), 3.8 L/h (11.3%) compared to those >10kg, 12.4 L/h (42%). Correspondingly, dose-normalized AUC was predicted to be approximately 2.8 times higher in patients < 10kg. Between-patient variability of CL was estimated to be 23% and the residual variability of concentrations 25%. Conclusion The optimal sampling strategy based on adult prior data allows for accurate estimation of f-ara-a population PK parameters in our study of 16 pediatric alloHCT recipients. These interim results suggest body weight may be used to predict f-ara-a clearance, as well as suggest the need for close evaluation of weight-based dosing to prevent over-exposure in very small children. Over the next 2 years we will continue to enroll children in this PK-PD study to confirm the interim PK results and identify exposure-response relationships to inform optimal dosing of fludarabine in pediatric alloHCT. Disclosures: Off Label Use: Fludarabine (Fludara) has no offical FDA indication for use in children.

scholarly journals Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation

2015 ◽  
Vol 59 (7) ◽  
pp. 3935-3943 ◽  
Author(s):  
Kevin M. Watt ◽  
Daniel Gonzalez ◽  
Daniel K. Benjamin ◽  
Kim L. R. Brouwer ◽  
Kelly C. Wade ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Mixed Effect ◽  
Final Model ◽  
Content Type ◽  
Membrane Oxygenation ◽  
Nonlinear Mixed Effect ◽  
Nonlinear Mixed Effect Modeling ◽  
Drug Pharmacokinetics

ABSTRACTCandidainfections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. The PK data were analyzed using nonlinear mixed-effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution (V). The final model included the effect of serum creatinine (SCR) level on CL and the effect of ECMO onVas follows: CL (in liters per hour) = 0.019 × weight × (SCR/0.4)−0.29× exp(ηCL) andV(in liters) = 0.93 × weight × 1.4ECMO× exp(ηV). The fluconazoleVwas increased in children supported by ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12 mg/kg of body weight) and treatment (35 mg/kg) paired with standard maintenance doses to achieve exposures similar to those of children not on ECMO.

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.

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