Population pharmacokinetics of daptomycin in critically ill patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are  ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.

A machine learning-based choledocholithiasis prediction tool to improve ERCP decision making: a proof-of-concept study.

BACKGROUND: Previous studies demonstrated limited accuracy of existing guidelines for predicting choledocholithiasis, leading to overutilization of endoscopic retrograde cholangiopancreatography (ERCP). More accurate stratification may improve patient selection for ERCP and allow use of lower-risk modalities. METHODS: A machine learning model was developed using patient information from two published cohort studies that evaluated performance of guidelines in predicting choledocholithiasis. Prediction models were developed using the gradient boosting model (GBM) machine learning method. GBM performance was evaluated using 10-fold cross-validation and area under the receiver operating characteristic curve (AUC). Important predictors of choledocholithiasis were identified based on relative importance in the GBM. RESULTS: 1378 patients (mean age 43.3 years; 61.2% female) were included in the GBM and 59.4% had choledocholithiasis. Eight variables were identified as predictors of choledocholithiasis. The GBM had accuracy of 71.5% (SD 2.5%) (AUC 0.79 [SD 0.06]) and performed better than the 2019 American Society for Gastrointestinal Endoscopy (ASGE) guidelines (accuracy 62.4% [SD 2.6%]; AUC 0.63 [SD 0.03]) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines (accuracy 62.8% [SD 2.6%]; AUC 0.67 [SD 0.02]). The GBM correctly categorized 22% of patients directed to unnecessary ERCP by ASGE guidelines, and appropriately recommended as the next management step 48% of ERCPs incorrectly rejected by ESGE guidelines. CONCLUSIONS: A machine learning-based tool was created, providing real-time, personalized, objective probability of choledocholithiasis and ERCP recommendations. This more accurately directed ERCP use than existing ASGE and ESGE guidelines, and has the potential to reduce morbidity associated with ERCP or missed choledocholithiasis.

Differences in functional connectivity distribution after transcranial direct-current stimulation: A connectivity density point of view.

In this manuscript, we consider the problem of relating functional connectivity measurements viewed as statistical distributions to outcomes. We demonstrate the utility of using the distribution of connectivity on a study of resting-state functional magnetic resonance imaging association with an intervention. The method uses the estimated density of connectivity between nodes of interest as a functional covariate. Moreover, we demonstrate the utility of the procedure in an instance where connectivity is naturally considered an outcome by reversing the predictor/response relationship using case/control methodology. The method utilizes the density quantile, the density evaluated at empirical quantiles, instead of the empirical density directly. This improved the performance of the method by highlighting tail behavior, though we emphasize that by being flexible and non-parametric, the technique can detect effects related to the central portion of the density. To demonstrate the method in an application, we consider 47 primary progressive aphasia patients with various levels of language abilities. These patients were randomly assigned to two treatment arms, transcranial direct-current stimulation and language therapy versus sham (language therapy only), in a clinical trial. We use the method to analyze the effect of direct stimulation on functional connectivity. As such, we estimate the density of correlations among the regions of interest and study the difference in the density post-intervention between treatment arms. We discover that it is the tail of the density, rather than the mean or lower order moments of the distribution, that demonstrates a significant impact in the classification. The new approach has several benefits. Among them, it drastically reduces the number of multiple comparisons compared with edge-wise analysis. In addition, it allows for the investigation of the impact of functional connectivity on the outcomes where the connectivity is not geometrically localized.

Epithelial lining fluid concentrations of ceftriaxone in children with community-acquired pneumonia.

Ceftriaxone is widely used in children with community-acquired pneumonia. Currently, there are no available data regarding epithelial lining fluid (ELF) concentrations of ceftriaxone in children. Thus, blood and bronchoalveolar lavage fluids samples were collected by using an opportunistic sampling design, then we determined plasma and ELF concentrations in 22 children (0.5-11.7 years), with a total of 36 plasma and 22 ELF samples available for analysis. Ceftriaxone plasma and ELF concentrations ranged from 1.07 to 138.71 mg/L and from 0.61 to 26.69 mg/L, respectively. Ceftriaxone concentration in ELF was 12.18 ± 5.15 (mean ± standard deviation) times higher than that in plasma, ranging from 1.29 to 20.44.

Clinical utility of a model-based amoxicillin dosage regimen in neonates with early-onset sepsis.

Early-onset sepsis (EOS) is one of the most significant causes of morbidity and mortality in neonates. Currently, amoxicillin is empirically used to treat neonates with EOS. However, data on its effectiveness in neonates with EOS are still limited. Therefore, we aimed to evaluate the pharmacodynamics (PD) target attainment and effectiveness of a model-based amoxicillin dosage regimen in these neonates. We used a previously developed model and collected additional clinical data from the EOS neonates who used the model-based dosage regimen (25 mg/kg every 12 h). The primary outcomes were PD target attainment (free drug concentration above minimum inhibitory concentration during 70% of the dosing interval) and treatment failure rate. The secondary endpoints were length of amoxicillin treatment, duration of hospitalization etc. Seventy-five neonates (postmenstrual age 28.4-41.6 wk) were enrolled. A total of 70 (93.3%) neonates reached their PD target using 1 mg/L as the minimum inhibitory concentration breakpoint. The treatment failure rate was 10.7%.

Clinical utiliy of a model-based piperacillin dose in neonates with early-onset sepsis.

AIMS: Early-onset sepsis (EOS) is a common disease in neonates with a high morbidity and mortality rate. Piperacillin/tazobactam has been used extensively and empirically for EOS treatment without clinically validated dosing regimens, although the population pharmacokinetics (PPK) of piperacillin in neonates has been reported. Therefore, we wanted to study the effectiveness and tolerance of a PPK model-based dosing regimen of piperacillin/tazobactam in EOS patients. METHODS: A prospective, single-centre, phase II clinical study of piperacillin/tazobactam in neonates with EOS was conducted. The dosing regimen (90 mg·kg-1 , q8h) was determined based on a previous piperacillin PPK model in young infants using NONMEM v7.4. The pharmacodynamics (PD) target (70%fT > MIC, free drug concentration above MIC during 70% of the dosing interval) attainment was calculated using NONMEM combined with an opportunistic sampling design. The clinical treatment data were collected. RESULTS: A total of 52 neonates were screened and 49 neonates completed their piperacillin/tazobactam treatment course and were included in this analysis. The median (range) values of postmenstrual age were 33.57 (range 26.14-41.29) weeks. Forty-seven (96%) neonates reached their PD target. Eight (16%) neonates experienced treatment failure clinically. The mean (SD, range) duration of treatment and length of hospitalization were 100.1 (62.2, 36.2-305.8) hours and 31 (30, 5-123) days. There were no obvious adverse events and no infection-related deaths occurred in the first month of life. CONCLUSIONS: A model-based dosing regimen of piperacillin/tazobactam was evaluated clinically, was tolerated well and was determined to be effective for EOS treatment.

Effect of drug combination on tacrolimus target dose in renal transplant patients with different CYP3A5 genotypes.

Various factors, including genetic polymorphisms, drug-drug interactions, and patient characteristics influence the blood concentrations of tacrolimus in renal transplant patients. In the present study, we established a population pharmacokinetic model to explore the effect of combined use of Wuzhi capsules/echinocandins and the patients' biochemical parameters such as haematocrit on blood concentrations and target doses of tacrolimus in renal transplant patients with different CYP3A5 genotypes. The aim of the study was to propose an individualised tacrolimus administration regimen for early renal transplant recipients.In this retrospective cohort study, we included 240 renal transplant recipients within 21 days of surgery (174 males and 66 females, mean age 39.4 years), who received tacrolimus alone (n = 54), in combination with Wuzhi capsules (99) or caspofungin (57) or micafungin (30). We collected demographic characteristics, clinical indicators, CYP3A5 genotypes, and 1950 steady-state concentrations of tacrolimus and included them in population pharmacokinetic model. An additional 110 renal transplant recipients and 625 steady-state concentrations of tacrolimus were included for external validation of the model. The population pharmacokinetic model was established and Monte Carlo was used to simulate probabilities for achieving the target concentration for individual tacrolimus administration.A two-compartment model of first-order absorption and elimination was developed to describe the population pharmacokinetics of tacrolimus. CYP3A5 genotypes and co-administration of Wuzhi capsules, as well as time after renal transplantation and haematocrit, were important factors affecting the clearance of tacrolimus. We found no obvious change in trend in the scatter plot of tacrolimus clearance rate vs. haematocrit. The Monte Carlo simulation indicated the following recommended doses of tacrolimus alone: 0.14 mg⋅kg-1⋅d-1 for genotype CYP3A5*1*1, 0.12 mg⋅kg-1⋅d-1 for CYP3A5*1*3, and 0.10 mg⋅kg-1⋅d-1 for CYP3A5*3*3. For patients receiving the combination with Wuzhi capsules, the recommended doses of tacrolimus were 0.10 mg⋅kg-1⋅d-1 for CYP3A5*1*1, 0.08 mg⋅kg-1⋅d-1 for CYP3A5*1*3, and 0.06 mg⋅kg-1⋅d-1 for CYP3A5*3*3 genotypes. Caspofungin or micafungin had no effect on the clearance of tacrolimus in renal transplant recipients.The population pharmacokinetics of tacrolimus in renal transplant patients was evaluated and the individual administration regimen of tacrolimus was simulated. For early kidney transplant recipients receiving tacrolimus treatment, not only body weight, but also CYP3A5 genotypes and drugs used in combination should be considered when determining the target dose of tacrolimus.

Population pharmacokinetics and dosing optimization of azlocillin in neonates with early-onset sepsis: a real-world study.

OBJECTIVES: Nowadays, real-world data can be used to improve currently available dosing guidelines and to support regulatory approval of drugs for use in neonates by overcoming practical and ethical hurdles. This proof-of-concept study aimed to assess the population pharmacokinetics of azlocillin in neonates using real-world data, to make subsequent dose recommendations and to test these in neonates with early-onset sepsis (EOS). METHODS: This prospective, open-label, investigator-initiated study of azlocillin in neonates with EOS was conducted using an adaptive two-step design. First, a maturational pharmacokinetic-pharmacodynamic model of azlocillin was developed, using an empirical dosing regimen combined with opportunistic samples resulting from waste material. Second, a Phase II clinical trial (ClinicalTrials.gov: NCT03932123) of this newly developed model-based dosing regimen of azlocillin was conducted to assure optimized target attainment [free drug concentration above MIC during 70% of the dosing interval ('70% fT>MIC')] and to investigate the tolerance and safety in neonates. RESULTS: A one-compartment model with first-order elimination, using 167 azlocillin concentrations from 95 neonates (31.7-41.6 weeks postmenstrual age), incorporating current weight and renal maturation, fitted the data best. For the second step, 45 neonates (30.3-41.3 weeks postmenstrual age) were subsequently included to investigate target attainment, tolerance and safety of the pharmacokinetic-pharmacodynamic model-based dose regimen (100 mg/kg q8h). Forty-three (95.6%) neonates reached their pharmacokinetic target and only two neonates experienced adverse events (feeding intolerance and abnormal liver function), possibly related to azlocillin. CONCLUSIONS: Target attainment, tolerance and safety of azlocillin was shown in neonates with EOS using a pharmacokinetic-pharmacodynamic model developed with real-world data.

Pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor in children with acute leukaemia.

AIMS: This open-label, phase I study evaluated the pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for the treatment of chemotherapy-induced neutropenia in children with acute leukaemia. METHODS: PEG-rhG-CSF was administered as a single 100 mcg/kg (3 mg maximum dose) subcutaneous injection at the end of each chemotherapy period when neutropenia occurred. Blood samples were obtained from patients treated with PEG-rhG-CSF. PEG-rhG-CSF serum concentrations were determined by an enzyme-linked immunosorbent assay. Population pharmacokinetic (PPK) analysis was implemented using the nonlinear mixed-effects model. Short-term safety was evaluated through adverse events collection (registered at clinicaltrials.gov identifier: 03844360). RESULTS: A total of 16 acute leukaemia patients (1.8-13.6 years) were included, of whom two (12.5%) had grade 3 neutropenia, six (37.5%) had grade 4 neutropenia, and eight (50.0%) had severe neutropenia. For PPK modelling, 64 PEG-rhG-CSF serum concentrations were obtainable. A one-compartment model with first-order elimination was used for pharmacokinetic data modelling. The current weight was a significant covariate. The median (range) of clearance (CL) and area under the serum concentration-time curve (AUC) were 5.65 (1.49-14.45) mL/h/kg and 16514.75 (6632.45-54423.30) ng·h/mL, respectively. Bone pain, pyrexia, anaphylaxis and nephrotoxicity were not observed. One patient died 13 days after administration, and the objective assessment of causality was that an association with PEG-rhG-CSF was "possible". CONCLUSIONS: The AUC of PEG-rhG-CSF (100 mcg/kg, 3 mg maximum dose) in paediatric patients with acute leukaemia were similar to those of PEG-rhG-CSF (100 mcg/kg) in children with sarcoma. PEG-rhG-CSF is safe, representing an important therapeutic option for chemotherapy-induced neutropenia in paediatric patients with acute leukaemia.

Population Pharmacokinetic Analysis of Isoniazid among Pulmonary Tuberculosis Patients from China.

The blood concentration of isoniazid (INH) is evidently affected by polymorphisms in N-acetyltransferase 2 (NAT2), an enzyme that is primarily responsible for the trimodal (i.e., fast, intermediate, and slow) INH elimination. The pharmacokinetic (PK) variability, driven largely by NAT2 activity, creates a challenge for the deployment of a uniform INH dosage in tuberculosis (TB) patients. Although acetylator-specific INH dosing has long been suggested, well-recognized dosages according to acetylator status remain elusive. In this study, 175 blood samples were collected from 89 pulmonary TB patients within 0.5 to 6 h after morning INH administration. According to their NAT2 genotypes, 32 (36.0%), 38 (42.7%), and 19 (21.3%) were fast, intermediate, and slow acetylators, respectively. The plasma INH concentration was detected by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic (PPK) analysis was conducted using NONMEM and R software. A two-compartment model with first-order absorption and elimination well described the PK parameters of isoniazid. Body weight and acetylator status significantly affected the INH clearance rate. The dosage simulation targeting three indicators, including the well-recognized efficacy-safety indicator maximum concentration in serum (Cmax; 3 to 6 µg/ml), the reported area under the concentration-time curve from 0 h to infinity (AUC0-∞; ≥10.52 µg·h/ml), and the 2-h INH serum concentrations (≥2.19 µg/ml), was associated with the strongest early bactericidal activity. The optimal dosages targeting the different indicators varied from 700 to 900 mg/day, 500 to 600 mg/day, and 300 mg/day for the rapid, intermediate, and slow acetylators, respectively. Furthermore, a PPK model for isoniazid among Chinese tuberculosis patients was established for the first time and suggested doses of approximately 800 mg/day, 500 mg/day, and 300 mg/day for fast, intermediate, and slow acetylators, respectively, after a trade-off between efficacy and the occurrence of side effects.

Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis.

Data of developmental pharmacokinetics (PK) of meropenem in critically ill infants and children with severe infections are limited. We assessed the population PK and defined the appropriate regimen to optimize treatment in this population based on developmental PK-pharmacodynamic (PD) analysis. Blood samples were collected from pediatric intensive care unit patients with severe infection treated with standard dosage regimens for meropenem. Population PK data were analyzed using NONMEM software. Fifty-seven patients (mean age, 2.96 years [range, 0.101 to 14.4]; mean body weight, 15.8 kg [range, 5.0 to 65.0]) were included. A total of 135 meropenem concentrations were obtainable for population PK modeling. The median number of samples per patients was 2 (range, 1 to 4). A two-compartment model with first-order elimination was optimal for PK modeling. Weight and creatinine clearance (estimated by the Schwartz formula) were significantly correlated with the PK parameters of meropenem. The probabilities of target attainment for pathogens with low MICs of 1 and 2 µg/ml were 87.5% and 68.6% following administration of 40 mg/kg/dose (every 8 h [q8h]) as a 4-h infusion and 98.0% and 73.3% with high MICs of 4 and 8 µg/ml following administration of 110 mg/kg/day as a continuous infusion in critically ill infants and children under 70% fT>MIC (the free time during which the plasma concentration of meropenem exceeds the MIC), respectively. The standard dosage regimens for meropenem did not meet an appropriate PD target, and an optimal dosing regimen was established in critically ill infants and children. (This study has been registered at ClinicalTrials.gov under identifier NCT03643497.).

Optimal Dosing of Ceftriaxone in Infants Based on a Developmental Population Pharmacokinetic-Pharmacodynamic Analysis.

Ceftriaxone is a third-generation cephalosporin used to treat infants with community-acquired pneumonia. Currently, there is a large variability in the amount of ceftriaxone used for this purpose in this particular age group, and an evidence-based optimal dose is still unavailable. Therefore, we investigated the population pharmacokinetics of ceftriaxone in infants and performed a developmental pharmacokinetic-pharmacodynamic analysis to determine the optimal dose of ceftriaxone for the treatment of infants with community-acquired pneumonia. A prospective, open-label pharmacokinetic study of ceftriaxone was conducted in infants (between 1 month and 2 years of age), adopting an opportunistic sampling strategy to collect blood samples and applying high-performance liquid chromatography to quantify ceftriaxone concentrations. Developmental population pharmacokinetic-pharmacodynamic analysis was conducted using nonlinear mixed effects modeling (NONMEM) software. Sixty-six infants were included, and 169 samples were available for pharmacokinetic analysis. A one-compartment model with first-order elimination matched the data best. Covariate analysis elucidated that age and weight significantly affected ceftriaxone pharmacokinetics. According to the results of a Monte Carlo simulation, with a pharmacokinetic-pharmacodynamic target of a free drug concentration above the MIC during 70% of the dosing interval (70% fT>MIC), regimens of 20 mg/kg of body weight twice daily for infants under 1 year of age and 30 mg/kg twice daily for those older than 1 year of age were suggested. The population pharmacokinetics of ceftriaxone were established in infants, and evidence-based dosing regimens for community-acquired pneumonia were suggested based on developmental pharmacokinetics-pharmacodynamics.

Developmental population pharmacokinetics-pharmacodynamics and dosing optimization of cefoperazone in children.

OBJECTIVES: To evaluate the population pharmacokinetics of cefoperazone in children and establish an evidence-based dosing regimen using a developmental pharmacokinetic-pharmacodynamic approach in order to optimize cefoperazone treatment. METHODS: A model-based, open-label, opportunistic-sampling pharmacokinetic study was conducted in China. Blood samples from 99 cefoperazone-treated children were collected and quantified by HPLC/MS. NONMEM software was used for population pharmacokinetic-pharmacodynamic analysis. This study was registered at ClinicalTrials.gov (NCT03113344). RESULTS: A two-compartment model with first-order elimination agreed well with the experimental data. Covariate analysis showed that current body weight had a significant effect on the pharmacokinetics of cefoperazone. Monte Carlo simulation showed that for bacteria for which cefoperazone has an MIC of 0.5 mg/L, 78.1% of hypothetical children treated with '40 mg/kg/day, q8h, IV drip 3 h' would reach the pharmacodynamic target. For bacteria for which cefoperazone has an MIC of 8 mg/L, 88.4% of hypothetical children treated with 80 mg/kg/day (continuous infusion) would reach the treatment goal. A 160 mg/kg/day (continuous infusion) regimen can cover bacteria for which cefoperazone has an MIC of 16 mg/L. Nevertheless, even if using the maximum reported dose of 160 mg/kg/day (continuous infusion), the ratio of hypothetical children reaching the treatment target was only 9.9% for bacteria for which cefoperazone has an MIC of 32 mg/L. CONCLUSIONS: For cefoperazone, population pharmacokinetics were evaluated in children and an appropriate dosing regimen was developed based on developmental pharmacokinetics-pharmacodynamics. The dose indicated in the instructions (20-160 mg/kg/day) can basically cover the clinically common bacteria for which cefoperazone has an MIC of ≤16 mg/L. However, for bacteria for which the MIC is >16 mg/L, cefoperazone is not a preferred choice.

Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration.

PURPOSE: Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters. METHODS: ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively. CONCLUSIONS: The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

Population pharmacokinetics and dose optimization of ceftriaxone for children with community-acquired pneumonia.

PURPOSE: To assess ceftriaxone population pharmacokinetics in a large pediatric population and describe the proper dose for establishing an optimized antibiotic regimen. METHODS: From pediatric patients using ceftriaxone, blood samples were obtained and the concentration was measured using high-performance liquid chromatography ultraviolet detection. The NONMEM software program was used for population pharmacokinetic analysis, for which data from 99 pediatric patients (2 to 12 years old) was collected and 175 blood concentrations were obtained. RESULTS: The best fit with the data was shown by the one-compartment model with first-order elimination. According to covariate analysis, weight had a significant impact on the clearance of ceftriaxone. Using Monte Carlo simulation, in a pediatric population with community-acquired pneumonia, a dose regimen of 100 mg/kg every 24 h produced satisfactory target attainment rates while remaining within the required minimum inhibitory concentration (2 mg/L). CONCLUSION: Population pharmacokinetics of ceftriaxone was evaluated in children and an optimum dosing regimen was constructed on the basis of the pharmacokinetics-pharmacodynamics model-based approach.

First dose in neonates: pharmacokinetic bridging study from juvenile mice to neonates for drugs metabolized by CYP3A.

First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A. We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK parameters in neonates using different correction methods. The bridging results were evaluated by the fold-error of 0.5- to 1.5-fold. Simple allometry with and without a correction factor for maximum lifespan potential could be used for a bridging of clearance (CL) and volume of distribution (Vd), respectively, from juvenile mice to neonates. Simulation results demonstrated that for midazolam, 100% of clinical studies for which both the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. For clindamycin, 75% and 100% of clinical studies for which the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. A PK bridging of drugs metabolized by CYP3A is feasible from juvenile mice to neonates. It could be a complement to the ADE and PBPK models to support the first dose in neonates.

Population Pharmacokinetics and Dosing Optimization of Imipenem in Children with Hematological Malignancies.

Imipenem is widely used for the treatment of children with serious infections. Currently, studies on the pharmacokinetics of imipenem in children with hematological malignancies are lacking. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population. After children were treated with imipenem-cilastatin (IMP-CS), blood samples were collected from the children and the concentrations of imipenem were quantified using high-performance liquid chromatography with UV detection. Then, a population-level pharmacokinetic analysis was conducted using NONMEM software. Data were collected from 56 children (age range, 2.03 to 11.82 years) with hematological malignancies to conduct a population pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be the most suitable. The parameters of current weight, age, and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 41.4%, 56.1%, and 67.1% of the children reached the pharmacodynamic target (the percentage of the time during the total dosing interval that the free drug concentration remains above the MIC of 70%) against sensitive pathogens with an MIC of 0.5 mg/liter with imipenem at 15, 20, and 25 mg/kg of body weight every 6 h (q6h), respectively. However, only 11.1% of the children achieved the pharmacodynamic target against Pseudomonas aeruginosa isolates with an MIC of 2 mg/liter at a dose of 25 mg/kg q6h. The population pharmacokinetics of imipenem were assessed in children. The current dosage regimens of imipenem result in underdosing against resistant pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h. (The study discussed in this paper has been registered at ClinicalTrials.gov under identifier NCT03113344.).

Population Pharmacokinetics and Dosing Optimization of Amoxicillin in Neonates and Young Infants.

Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable intercenter variability in dosage regimens of antibiotics exists in clinical practice. The pharmacokinetics of amoxicillin has been described in only a few preterm neonates. Thus, we aimed to evaluate the population pharmacokinetics of amoxicillin through a large sample size covering the entire age range of neonates and young infants and to establish evidence-based dosage regimens based on developmental pharmacokinetics-pharmacodynamics. This is a prospective, multicenter, pharmacokinetic study using an opportunistic sampling design. Amoxicillin plasma concentrations were determined using high-performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM. A total of 224 pharmacokinetic samples from 187 newborns (postmenstrual age range, 28.4 to 46.3 weeks) were available for analysis. A two-compartment model with first-order elimination was used to describe population pharmacokinetics. Covariate analysis showed that current weight, postnatal age, and gestational age were significant covariates. The final model was further validated for predictive performance in an independent cohort of patients. Monte Carlo simulation demonstrated that for early-onset sepsis, the currently used dosage regimen (25 mg/kg twice daily [BID]) resulted in 99.0% of premature neonates and 87.3% of term neonates achieving the pharmacodynamic target (percent time above MIC), using a MIC breakpoint of 1 mg/liter. For late-onset sepsis, 86.1% of premature neonates treated with 25 mg/kg three times a day (TID) and 79.0% of term neonates receiving 25 mg/kg four times a day (QID) reached the pharmacodynamic target, using a MIC breakpoint of 2 mg/liter. The population pharmacokinetics of amoxicillin was assessed in neonates and young infants. A dosage regimen was established based on developmental pharmacokinetics-pharmacodynamics.

Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia.

Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population. This was a prospective, multicenter, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPK analysis was conducted using NONMEM software. The pharmacokinetic data from 95 pediatric patients (age range, 2.1 to 11.7 years) were available for analysis. The PPK was best fitted by a two-compartment model with linear elimination. Covariate analysis verified that body weight and alanine aminotransferase (ALT) had significant effects on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT of >40. Monte Carlo simulation showed that for children with normal liver function, a loading-dose strategy (a loading dose of 15 mg/kg of body weight followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 h (fAUC) to MIC90 (fAUC/MIC) target of 3 h in 53.2% of hypothetical patients, using a normative MIC susceptibility breakpoint of 2 mg/liter. For children with ALT of >40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%. In conclusion, the PPK of azithromycin was evaluated in children with CAP and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation.

Early target attainment of azithromycin therapy in children with lower respiratory tract infections.

Objectives: Early target attainment is the key factor influencing the outcome of antimicrobial therapy. The objective of the present study was to evaluate the relationship between azithromycin concentrations during the first 24-48 h of therapy and the clinical outcome in order to optimize antimicrobial therapy. Methods: All children with lower respiratory tract infections receiving intravenous azithromycin monotherapy were included. The relationship between azithromycin trough concentrations during the first 24-48 h and the effectiveness and safety was explored. Results: Data from 44 children [mean (SD) age = 5.25 (3.72) years] were available for final analysis. Children with trough concentrations >0.25 mg/L (n = 8) had a more significant improvement in antibacterial efficacy in terms of decreased C-reactive protein (P = 0.006) and the percentage of neutrophils (P = 0.043) compared with children with trough concentrations ≤0.25 mg/L (n = 36). No drug-related adverse events were shown to have a causal association with azithromycin therapy. Conclusions: Our study showed the clinical benefits of early target attainment of azithromycin therapy. A target trough concentration of 0.25 mg/L in the first 24-48 h of hospitalization was required to ensure better antibacterial efficacy.