Beyond One-Size-Fits-All: Tailoring Teicoplanin Regimens for Normal Renal Function Patients Using Population Pharmacokinetics and Monte Carlo Simulation.

In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK samples were obtained from 12 subjects and analyzed using a population approach. The derived parameters informed Monte Carlo simulations for dosing recommendations. The PK profile was best described using a three-compartment model, in which the estimated glomerular filtration rate calculated via the CKD-EPI equation and adjusted for body surface area was identified as a significant covariate affecting total clearance. For pathogens with a minimum inhibitory concentration of 1 mg/L, a loading dose (LD) of 14 mg/kg administered every 12 h for four doses, followed by a maintenance dose (MD) of 16 mg/kg administered every 24 h, is recommended. These findings indicate the need for dosage adjustments, such as increasing the LD and MD or decreasing the dosing interval of MD in patients with normal renal function. Because of the long half-life of teicoplanin and the requirement for long-term administration, therapeutic drug monitoring at strategic intervals is important to avoid nephrotoxicity associated with elevated trough concentrations.

Is the Availability of Biosimilar Adalimumab Associated with Budget Savings? A Difference-in-Difference Analysis of 14 Countries.

OBJECTIVE: The aim was to assess the influence of the presence of biosimilar adalimumab on adalimumab budget savings in 14 high- and upper-middle-income countries. METHODS: This study analyzed Multinational Integrated Data Analysis System (MIDAS)-IQVIA data from the fourth quarter (Q4) of 2018 to the Q4 of 2019, comparing adalimumab expenditure (in United States dollars) and consumption (in standard units [SU]) across 14 countries (Australia, Austria, Brazil, Canada, France, Germany, Italy, Japan, Korea, Singapore, South Africa, Spain, Sweden, and Taiwan). The countries were divided into two groups based on the availability of adalimumab biosimilars during the study period. A difference-in-difference design was employed to analyze the groups, focusing on changes from Q4 2018 to Q4 2019. Additionally, changes in adalimumab expenditure were decomposed into price, quantity, and drug mix during the study period. RESULTS: Among countries with adalimumab biosimilars, there was a significant decrease in expenditure (- $371.0 per gross domestic product per capita; p = 0.03) over four quarters, while the consumption significantly increased (1.0 SU per 1000 population; p = 0.02). This was consistent with visual observations and differed from countries without adalimumab biosimilar. Sensitivity analysis with a narrowed list of countries (12 high-income countries) showed a consistent trend. Adalimumab expenditure decreased by 14% during the study period in countries where adalimumab biosimilars were available, mainly due to the price changes (Pt = 0.85; - 15%) and the drug-mix effect (εt  = 0.88; - 12%). Yet, adalimumab expenditure (Et = 1.04; +4%) changed in a quantity-dependent manner (Qt = 1.06; +6%) in countries where adalimumab biosimilars were absent. CONCLUSION: The availability of biosimilars was associated with a decrease in adalimumab expenditure without compromising the consumption of adalimumab.

Population Pharmacokinetics and Monte Carlo Simulation of Cefepime in Critically Ill Patients with Hospital-Acquired/Ventilator-Associated Pneumonia.

BACKGROUND: This study aimed to investigate the population pharmacokinetics (PK) profile and determine the optimal dosage regimen of cefepime in critically ill adult patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). MATERIALS AND METHODS: Population-PK models for cefepime were developed using a nonlinear mixed-effect modeling approach. The percentage of time within 24 h in which the free concentration exceeded the minimum inhibitory concentration (MIC) at a steady state (50%fT>MIC, 100%fT>MIC, and 100%fT>4×MIC) for various combinations of dosage regimens and renal function was explored using Monte Carlo simulation. RESULTS: Twenty-one patients were prospectively enrolled in this study. Cefepime PK was best described using a two-compartment model in which creatinine clearance (CLCR) through Cockcroft-Gault (CG) was a significant covariate for the total clearance of cefepime. The simulation results to determine the optimal cefepime dosing regimen for 50%fT>MIC as treatment target with Cmin <20 mg/L as safety target showed that a dosage regimen of 2 g through intravenous (IV) infusion every 12 h administered over 4 h was optimal at an MIC of 4 mg/L, rather than the currently recommended dosage regimen of 2 g administered through IV infusion every 8 h, in patients with normal renal function (CLCR = 90 - 130 mL/min). For a treatment target of 100%fT>MIC with Cmin <35 mg/L as a safety target, a dosage regimen of 0.75 g administered through continuous infusion over 24 h would be sufficient at an MIC equal to or less than 8 mg/L in patients with renal dysfunction (CLCR = 10 - 30 mL/min). CONCLUSION: Our results suggest that clinicians should consider renal function and potential neurotoxicity when deciding the dosing regimen of cefepime in critically ill patients with HAP or VAP. Therapeutic drug monitoring (TDM) to adjust cefepime trough levels may be useful to improve clinical outcomes and reduce cefepime neurotoxicity.

Overall assessment for selected markers from high-throughput data.

Reproducibility, a hallmark of science, is typically assessed in validation studies. We focus on high-throughput studies where a large number of biomarkers is measured in a training study, but only a subset of the most significant findings is selected and re-tested in a validation study. Our aim is to get the statistical measures of overall assessment for the selected markers, by integrating the information in both the training and validation studies. Naive statistical measures, such as the combined P $$ P $$ -value by conventional meta-analysis, that ignore the non-random selection are clearly biased, producing over-optimistic significance. We use the false-discovery rate (FDR) concept to develop a selection-adjusted FDR (sFDR) as an overall assessment measure. We describe the link between the overall assessment and other concepts such as replicability and meta-analysis. Some simulation studies and two real metabolomic datasets are considered to illustrate the application of sFDR in high-throughput data analyses.

Pharmacokinetics and Monte Carlo Simulation of Meropenem in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation.

Objectives: There have been few clinical studies of ECMO-related alterations of the PK of meropenem and conflicting results were reported. This study investigated the pharmacokinetics (PK) of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and used Monte Carlo simulations to determine appropriate dosage regimens. Methods: After a single 0.5 or 1 g dose of meropenem, 7 blood samples were drawn. A population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment was evaluated using Monte Carlo simulation. The following treatment targets were evaluated: the cumulative percentage of time during which the free drug concentration exceeds the minimum inhibitory concentration of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4xMIC. Results: Meropenem PK were adequately described by a two-compartment model, in which creatinine clearance and ECMO flow rate were significant covariates of total clearance and central volume of distribution, respectively. The Monte Carlo simulation predicted appropriate meropenem dosage regimens. For a patient with a creatinine clearance of 50-130 ml/min, standard regimen of 1 g q8h by i. v. infusion over 0.5 h was optimal when a MIC was 4 mg/L and a target was 40% fT>MIC. However, the standard regimen did not attain more aggressive target of 100% fT>MIC or 100% fT>4xMIC. Conclusion: The population PK model of meropenem for patients on ECMO was successfully developed with a two-compartment model. ECMO patients exhibit similar PK with patients without ECMO. If more aggressive targets than 40% fT>MIC are adopted, dose increase may be needed.

Prospective Cohort Study of Population Pharmacokinetics and Pharmacodynamic Target Attainment of Vancomycin in Adults on Extracorporeal Membrane Oxygenation.

The aim of this study was to develop a population pharmacokinetics (PK) model for vancomycin and to evaluate its pharmacodynamic target attainment in adults on extracorporeal membrane oxygenation (ECMO). After a single 1,000-mg dose of vancomycin, samples were collected 9 times per patient prospectively. A population PK model was developed using a nonlinear mixed-effect model. The probability of target attainment (PTA) of vancomycin was evaluated for various dosing strategies using Monte Carlo simulation. The ratio of the area under the vancomycin concentration-time curve at steady state over 24 h to the MIC (AUC/MIC ratio) was investigated by applying the vancomycin breakpoint distribution of MICs for methicillin-resistant Staphylococcus aureus A total of 22 adult patients with 194 concentration measurements were included. The population PK was best described by a three-compartment model with a proportional residual error model. Vancomycin clearance and steady-state volume of distribution were 4.01 liters/h (0.0542 liters/h/kg) and 29.6 liters (0.400 liters/kg), respectively. If the treatment target AUC/MIC value was only ≥400, a total daily dose of 3 to 4 g would be optimal (PTA of ≥90%) for patients with normal renal function (estimated glomerular filtration rate [eGFR] = 60 to 120 ml/min/1.73 m2) when the MIC was presumed to be 1 mg/liter. However, AUC/MIC values of 400 to 600 were difficult to attain with any dosing strategy regardless of MIC and eGFR. Thus, it is hard to achieve efficacy and safety targets in patients on ECMO using the population dosing approach with Monte Carlo simulations, and therapeutic drug monitoring should be implemented in these patients.

A Meta-Regression Analysis of Utility Weights for Breast Cancer: The Power of Patients' Experience.

To summarize utility estimates of breast cancer and to assess the relative impacts of study characteristics on predicting breast cancer utilities. We searched Medline, Embase, RISS, and KoreaMed from January 1996 to April 2019 to find literature reporting utilities for breast cancer. Thirty-five articles were identified, reporting 224 utilities. A hierarchical linear model was used to conduct a meta-regression that included disease stages, assessment methods, respondent type, age of the respondents, and scale bounds as explanatory variables. The utility for early and late-stage breast cancer, as estimated by using the time-tradeoff with the scales anchored by death to perfect health with non-patients, were 0.742 and 0.525, respectively. The severity of breast cancer, assessment method, and respondent type were significant predictors of utilities, but the age of the respondents and bounds of the scale were not. Patients who experienced the health states valued 0.142 higher than did non-patients (P <0.001). Besides the disease stage, the respondent type had the highest impact on breast cancer utility.

The Burden of Cervical Cancer in Korea: A Population-Based Study.

This study used the Korean National Health Insurance (NHI) claims database from 2011 to 2017 to estimate the incidence and the incidence-based cost of cervical cancer and carcinoma in situ of cervix uteri (CIS) in Korea. The primary outcome was the direct medical cost per patient not diagnosed with cervical cancer (C53) or CIS (D06) 2 years prior to the index date in the first year after diagnosis. A regression analysis was conducted to adjust for relevant covariates. The incidence of cervical cancer tended to decrease from 2013 to 2016, while that of CIS increased. In particular, the incidence rate of CIS in women in their 20 s and 30 s increased by 56.8% and 28.4%, respectively, from 2013 to 2016. The incidence-based cost of cervical cancer and CIS was USD 13,058 and USD 2695 in 2016, respectively, which increased from 2013. Multivariate regression analysis suggested that age was the most influential variable of the cost in both patient groups, and the cost was highest in those aged over 60, i.e., the medical cost was significantly lower in younger women than their older counterparts. These findings suggest that targeting younger women in cervical cancer prevention is a reasonable option from both economic and public health perspectives.

Incidence, cost and gender differences of oropharyngeal and noncervical anogenital cancers in South Korea.

BACKGROUND: Human papillomavirus (HPV) is associated with a significant public health burden, yet few studies have been conducted in Asia, especially on noncervical cancers. We estimated the incidence and cost of oropharyngeal and noncervical anogenital (anal, vulvar, vaginal, penile) cancer in Korea. METHODS: We conducted a retrospective cohort study using Korea's National Health Insurance (NHI) claim database from 2013 to 2016. The main outcome measures were the number of respective cancer incidences during the study period and the annual costs per patient in the first year after diagnosis, which was adjusted by relevant variables based on the regression analysis. RESULTS: During the study period, 8022 patients with these cancers were identified, and oropharyngeal cancer comprised 46% of them. The crude incidence rate for male oropharyngeal cancer was significantly higher than that of females (3.1 vs. 0.7 per 100,000 as of 2016, respectively). Additionally, the crude incidence of male oropharyngeal cancer increased from 2.7 in 2013 to 3.1 in 2016, whereas that of female and other cancers was stable during the study period. The mean annual incidence-based cost per patient in 2016 was highest for oropharyngeal cancers (21,870 USD), and it was significantly higher in males than in females based on then regression analysis (p < .001). CONCLUSIONS: Oropharyngeal cancer comprises the highest number of HPV-associated noncervical cancer incidences in Korea, and the incidence and cost of oropharyngeal cancer was significantly higher among males than females. More aggressive public health policy toward males may decrease gender gap of oropharyngeal cancer.

Are Recently Evaluated Drugs More Likely to Receive Positive Reimbursement Recommendations in South Korea? 11-year Experience of the South Korean Positive List System.

PURPOSE: The South Korean government in 2014 introduced various policies to enhance accessibility of pharmaceuticals. This study sought to examine whether positive reimbursement recommendations of pharmaceuticals have increased since 2014. METHODS: Industry submissions evaluated from January 2007 to December 2018 were identified, and characteristics relevant to reimbursement recommendations were extracted. Logistic regression analyses with robust SEs were used to quantify the likelihood of positive recommendations for pharmaceuticals, after controlling for relevant factors influencing the recommendations. FINDINGS: During the study period, 355 (72.9%) of 487 submissions were positively recommended; the drugs evaluated after 2014 (77.8%) were significantly more likely to receive positive reimbursement recommendations than the drugs evaluated before 2014 (69.5%). In the multivariable logistic regression analysis, several factors (labeled a noncancer drug, priced less than alternatives, considered clinically superior, and having budget impact >10 billion South Korean won) were significantly associated with positive recommendations (P < 0.05). When considering interaction effects between evaluation year and other variables, only the interaction between comparative clinical benefit and evaluation year was significant. Specifically, clinically noninferior drugs evaluated after 2014 had 2.85 times the odds of receiving positive recommendations compared with the clinically noninferior drugs evaluated earlier. IMPLICATIONS: Recently evaluated drugs are more likely to receive positive reimbursement recommendations, especially those drugs whose comparative clinical benefits are noninferior.

Healthcare resource use and costs of diabetic macular oedema for patients with antivascular endothelial growth factor versus a dexamethasone intravitreal implant in Korea: a population-based study.

OBJECTIVES: To estimate the costs and healthcare resources of patients with diabetic macular oedema (DME) who received intravitreal antivascular endothelial growth factor (anti-VEGF) agents or a dexamethasone intravitreal implant (DEX-implant) in Korea. DESIGN: Retrospective cohort study. SETTING: The Korean National Health Insurance claim data from 1 January 2015 to 30 June 2017 were retrieved from the Health Insurance Review and Assessment Service. PARTICIPANTS: Adult patients with DME who were diagnosed with diabetic retinopathy or DME and received ranibizumab, aflibercept or a DEX-implant in conjunction with intravitreal injection were included. Patients whose primary diagnoses were age-related macular degeneration or retinal vein occlusion were excluded. MAIN OUTCOME MEASURES: Healthcare resource utilisation and costs related to DME in the 12-month postindex period. RESULTS: During the study period, 182 patients and 414 patients were identified in the anti-VEGF and DEX-implant groups, respectively, and there was no significant difference in the demographic characteristics between the two groups. The outpatient eye care-related medical costs were US$3002.33 for the anti-VEGF group vs US$2250.35 for the DEX-implant group (p<0.0001). After adjusting the relevant covariates based on the generalised linear model, the estimated outpatient eye care-related medical costs were 33% higher in the anti-VEGF group than in the DEX-implant group (p<0.0001, 95% CI 22% to 45%). The utilisation pattern of the two groups showed no significant difference except for the number of intravitreal injections, which was higher in the anti-VEGF group (2.69±2.29) than in the DEX-implant group (2.09±1.37, p<0.001). CONCLUSION: The average annual eye-related medical cost of the DEX-implant group was significantly lower than that of the anti-VEGF group during the study period, which was mainly due to decreased utilisation of eye care-related injections. Further long-term studies are needed.

Statistical analysis of the reproducibility and predictive capacity of MCTT HCE™ eye irritation test, a me-too test method for OECD TG 492.

We aimed to conduct additional statistical analysis of the reproducibility and predictive capacity of MCTT HCE™ eye irritation test (EIT), a me-too test method for OECD TG 492 with the data generated during the validation study in which 30 reference chemicals were tested in three repeated runs by three independent laboratories. We evaluated the within-laboratory reproducibility (WLR) and the between-laboratory reproducibility (BLR) through tabulation and graphs and presented the concordance of eye irritancy prediction with 95% Wilson's confidence intervals (CIs). Also, the analyses of the Intra-Class Correlation Coefficient (ICC) and Bland-Altman plot were applied to confirm the reproducibility and the comparability, referring to the validated methods of OECD TG 492. Kappa analysis was also performed to check the degree of agreement of the within- and between-laboratory reproducibility and agreement between MCTT HCE™ EIT and the reference methods. We calculated the predictive capacity via misprediction over total prediction method. The predictive capacity (sensitivity, specificity, and accuracy) was presented with 95% of Wilson's CIs. Also, bootstrap resampling was performed to express the 95% CI by the simple percentile methods for 30 chemicals and 141 reference chemicals additionally tested. Collectively, WLR (92.2%) and BLR (93.3%) met the criteria of the performance standards (WLR ≥ 90% and BLR ≥ 85%), and the results of ICC analysis and the Bland-Altman plot suggested an acceptable WLR and BLR and comparability to other validated methods of OECD TG 492. Also, the predictive capacity results for the 30 reference chemicals confirmed the good performance of the MCTT HCE™ EIT by satisfying the criteria of sensitivity, specificity, and the accuracy stated in the PS. The bootstrap resampling method showed a predictive capacity, sufficiently satisfying the criteria stated in the Performance Standards.

Effect of pharmacokinetic model misspecification on antibiotic probability of target attainment predicted by Monte Carlo simulation
.

OBJECTIVE: The first aim of this study was to compare the predictability of efficacy by Monte Carlo simulation between a true one-compartment model and a true two-compartment model for doripenem. The second aim was to explore how we can identify the usefulness of a one-compartment model when the pharmacokinetic/pharmacodynamic (PK/PD) indices between three misspecified one-compartment models and a true two-compartment model are compared. MATERIALS AND METHODS: The reported two-compartment model parameters of two doripenem studies and a vancomycin study were used to generate 200 virtual concentration-time profiles for each study. Sparse and dense sampling designs were selected to build the one- and two-compartment models, respectively. The probability of target attainment (PTA) for the PK/PD indices were compared between the one- and two-compartment models of the same drug, applying the clinical breakpoint distribution of minimum inhibitory concentrations (MICs). RESULTS: The simulated concentration-time profiles reproduced the original data well. In addition, PTAs were similar between the one- and two-compartment models when infusion time and MIC were the same in the doripenem studies. For vancomycin simulations, the maximum difference was 65.9% between a misspecified one-compartment model and the true two-compartment model. CONCLUSION: When a misspecified one-compartment model was established with sparse sampling data, the PTA was significantly different from that of the two-compartment model. Thus, a useful PK model must be verified through diagnostic plots and visual predictive checks and the range of sampling time should be sufficient to explain the PK of a drug.

Population Pharmacokinetic Analysis of Meropenem After Intravenous Infusion in Korean Patients With Acute Infections.

PURPOSE: The aim of this study was to investigate the population pharmacokinetic (PK) profile of meropenem in Korean patients with acute infections. METHODS: The study included 37 patients with a creatinine clearance ≤50 or >50 mL/min who received a 500- or 1000-mg dose of meropenem, respectively, infused intravenously over 1 hour every 8 hours. Blood samples were collected before and at 1, 1.5, and 5 hours after the start of the fourth infusion. The population PK analysis was conducted by using nonlinear mixed effect modeling software (NONMEM). Monte-Carlo simulations were performed to identify optimal dosing regimens. FINDINGS: Thirty-seven subjects completed the study. Meropenem PK variables were well described by using a one-compartment model. The typical values (relative SE) for weight-normalized clearance (CL) and Vd were 0.266 L/h/kg (12.29%) and 0.489 L/kg (11.01%), respectively. Meropenem CL was significantly influenced by the serum creatinine level, which explained 11% of the interindividual CK variability. The proposed equation to estimate meropenem CL in Korean patients was as follows: CL (L/h) = 0.266 × weight × [serum creatinine/0.74]-1.017. The simulation results indicate that the current meropenem dosing regimen may be suboptimal in patients infected with normal or augmented renal function. IMPLICATIONS: Prolonged infusions of meropenem over at least 2 hours should be considered, especially in patients with augmented renal function and those infected with pathogens for which the minimum inhibitory meropenem concentration is >1 µg/mL. Our results suggest an individualized meropenem dosing regimen for patients with abnormal renal function and those infected with pathogens with decreased in vitro susceptibility.

Pharmacokinetics of Doripenem in Healthy Koreans and Monte Carlo Simulations to Explore Optimal Dosage Regimens in Patients With Normal and Enhanced Renal Function.

BACKGROUND: Dose adjustment is often required in patients with normal or enhanced renal function. The aim of this study is to investigate the pharmacokinetic (PK) properties of doripenem and explore optimal dosing regimens in patients with normal or enhanced renal function according to various minimum inhibitory concentrations (MICs). METHODS: The authors conducted a clinical trial and analyzed PK samples in 11 healthy Korean subjects applying noncompartmental analysis and a population approach. The population PK parameter estimates were used in Monte Carlo simulations to explore optimal dosing regimens for a probability of target attainment of 90% at 40% fTMIC (free drug concentrations above MIC). RESULTS: The time course of doripenem concentrations was well described by a 2-compartment model. The population typical values of clearance and steady-state volume were 22.9 L/h and 19.1 L, respectively, and were consistent with our noncompartmental analysis results. When the MIC was greater than 1 mcg/mL, at least increasing the dose or prolonging the infusion time was essential in patients with normal or enhanced renal function. CONCLUSIONS: These results suggest that dosage adjustment such as increasing the dose or lengthening the infusion time should be considered in patients with normal or enhanced renal function.

Population Pharmacokinetic Analysis of Doripenem after Intravenous Infusion in Korean Patients with Acute Infections.

We investigated the population pharmacokinetics (PK) of doripenem in Korean patients with acute infections and determined an appropriate dosing regimen using a Monte Carlo simulation for predicting pharmacodynamics (PD). Patients (n = 37) with a creatinine clearance (CLCR) of 20 to 50 ml/min or >50 ml/min who received a 250-mg or 500-mg dose of doripenem over the course of 1 h every 8 h, respectively, were included in this study. Blood samples were taken predosing and 0 h, 0.5 h, and 4 to 6 h after the fourth infusion. A nonlinear mixed-effect modeling tool was used for the PK analysis and pharmacodynamic simulation; doripenem PK were well described by a one-compartment model. The population mean values of the body weight (WT)-normalized clearance (CL/WT) and the body weight-normalized volume of distribution (V/WT) were 0.109 liter/h/kg of body weight (relative standard error, 9.197%) and 0.280 liter/kg (relative standard error, 9.56%), respectively. Doripenem CL was significantly influenced by CLCR The proposed equation to estimate doripenem CL in Korean patients was CL/WT = 0.109 × WT × (CLCR/57)0.688, where CL/WT is in liters per hour per kilogram. CL in Korean patients was expected to be lower than that in Caucasian patients, regardless of renal function. The Monte Carlo simulation showed that 90% attainment of target PK/PD magnitudes could be achieved with the usual dosing regimens when the MIC was ≤1 mg/liter. However, prolonged infusions (4 h) should be considered, especially when patients have augmented renal function and for patients infected with pathogens with a high MIC. Our results provide an individualized doripenem dosing regimen for patients with various renal functions and for patients infected with bacteria with decreased susceptibility.

Assessment of impact of internal exposure to PBDEs on human thyroid function--comparison between congenital hypothyroidism and normal paired blood.

In this work, we investigated exposure levels, distribution patterns, and potential harmful impacts of polybrominated diphenyl ethers (PBDEs) on thyroid hormone activity in 26 children with congenital hypothyroidism and their mothers' pair and 12 normal control pairs. The average concentration of PBDEs in congenital hypothyroidism (median: 22.16 ng/g lipid) was higher than in normal controls (median: 14.76 ng/g lipid), but there was no statistical difference between the two groups. The BDE congeners were dominated by penta- to hepta-BDEs, but the greater brominated congeners (e.g., BDE 197, 196, 207, and 208) were relatively abundant in congenital hypothyroidism. BDE 138 was only observed in the congenital hypothyroidism cases. The maternal transfer and transport ratio of individual BDE congeners was shown for BDE 28 (0.588, p < 0.001), BDE 47 (0.564, p < 0.001), BDE 49 (0.712, p < 0.001) and BDE 119 (0.477, p = 0.002). The thyroid hormones were most obviously influenced by the internal exposure to PBDEs in normal mothers, showing a positive relationship with TSH (0.641 with BDE 154; 0.591 with BDE 153) and FT4 (0.584 with BDE 49; 0.572 with BDE 66) and a negative relationship with T3 (-0.577 with BDE 154) in the normal infants group. No significant correlations were observed in the congenital hypothyroidism cases.