Measurement of Carbon Dioxide Isotopes with Air-Lasing-Based Coherent Raman Spectroscopy.

Isotope detection is crucial for geological research, medical diagnostics, industrial production, and environmental monitoring. Various spectroscopic techniques are continually emerging for isotopic identification and accurate measurement. Herein, coherent Raman scattering (CRS) spectroscopy is developed for the quantitative detection of carbon dioxide isotopes, in which the N2+ air lasing coherently created in the interaction region is used as the probe. Benefiting from the narrow spectral width of air lasing, the Raman peaks of 12CO2 and 13CO2 can be well discerned, although their spectra partially overlap. The overlapped signals were proven to be the result of the coherent superposition of individual Raman signals. Based on that fact, a deconvolution algorithm was designed to retrieve the concentration ratio of the two isotopes. The relative error of the measurement is less than 6%. The CRS technique based on air lasing offers a potential approach for the quantitative characterization of molecular isotopes, especially in application scenarios of remote sensing or in situ detection.

Is the current therapeutic dosage of nadroparin adequate for neonates and infants under 8 months with thromboembolic disease? a population pharmacokinetic study from a national children's medical center.

Objectives: Nadroparin, a low-molecular-weight-heparin is commonly used off-label in neonates and infants for thromboembolic events prevention. However, the recommended dosing regimen often fails to achieve therapeutic target ranges. This study aimed to develop a population pharmacokinetic (PK) model of nadroparin to determine an appropriate dosing regimen for neonates and infants less than 8 months. Methods: A retrospective chart review was conducted on patients treated with nadroparin at Children's Hospital of Fudan University between July 2021 and December 2023. A population PK model was developed using anti-Xa levels, and its predictive performance was evaluated internally. Monte Carlo simulations were performed to design an initial dosing schedule targeting anti-Xa levels between 0.5 and 1 IU/mL. Results: A total of 40 neonates and infants aged less than 8 months with gestational age ranging from 25 to 41 weeks treated with nadroparin were enrolled in the study for analysis. A one-compartment PK model with first order absorption and elimination was adequately fitted to the data. Creatinine clearance was identified as a significant factor contributing to inter-individual variability in clearance. The typical population parameter estimates of clearance, distribution volume and absorption rate in this population were 0.211 L/h, 1.55 L and 0.495 h-1, respectively. Our findings suggest that current therapeutic doses of nadroparin (150-200 IU/kg q12 h) may result in subtherapeutic exposure, thus higher doses might be required. Conclusion: The present study offers the first estimation of PK parameters for nadroparin in preterm or term neonates and infants less than 8 months utilizing the model. Our findings have potential implications for recommending initial personalized dosages, particularly among patient populations exhibiting similar characteristics.

Enantioselective Palladium-Catalyzed Directed Migratory Allylation of Remote Dienes.

Chain walking has been an efficient route to realize the functionalization of inert C(sp3 )-H bonds, but this strategy is limited to mono-olefin migration and functionalization. Herein, we demonstrate the feasibility of tandem directed simultaneous migrations of remote olefins and stereoselective allylation for the first time. The adoption of palladium hydride catalysis and secondary amine morpholine as solvent is critical for achieving high substrate compatibility and stereochemical control with this method. The protocol is also applicable to the functionalization of three vicinal C(sp3 )-H bonds and thus construct three continuous stereocenters along a propylidene moiety via a short synthetic process. Preliminary mechanistic experiments corroborated the design of simultaneous walking of remote dienes.

Analyzing and Predicting the Viscosity of Polymer Nanocomposites in the Conditions of Temperature, Shear Rate, and Nanoparticle Loading with Molecular Dynamics Simulations and Machine Learning.

Predicting the viscosity (η) of polymer nanocomposites (PNCs) is of critical importance as it governs a dominant role in PNCs' processing and application. Machine-learning (ML) algorithms, enabled by pre-existing experimental and computational data, have emerged as robust tools for the prediction of quantitative relationships between feature parameters and various physical properties of materials. In this work, we employed nonequilibrium molecular dynamics (NEMD) simulation with ML models to systematically investigate the η of PNCs over a wide range of nanoparticle (NP) loadings (φ), shear rates (γ̇), and temperatures (T). With the increase in γ̇, shear thinning takes place as the value of η decreases on the orders of magnitude. In addition, the φ dependence and T dependence reduce to the extent that it is not visible at high γ̇. The value of η for PNCs is proportional to φ and inversely proportional to T below the intermediate γ̇. Using the obtained NEMD results, four machine-learning models were trained to provide effective predictions for the η. The extreme gradient boosting (XGBoost) model yields the best accuracy in η prediction under complex conditions and is further used to evaluate feature importance. This quantitative structure-property relationship (QSPR) model used physical views to investigate the effect of process parameters, such as T, φ, and γ̇, on the η of PNCs and paves the path for theoretically proposing reasonable parameters for successful processing.

A convergence analysis for projected fast iterative soft-thresholding algorithm under radial sampling MRI.

Radial sampling is a fast magnetic resonance imaging technique. Further imaging acceleration can be achieved with undersampling but how to reconstruct a clear image with fast algorithm is still challenging. Previous work has shown the advantage of removing undersampling image artifacts using the tight-frame sparse reconstruction model. This model was further solved with a projected fast iterative soft-thresholding algorithm (pFISTA). However, the convergence of this algorithm under radial sampling has not been clearly set up. In this work, the authors derived a theoretical convergence condition for this algorithm. This condition was approximated by estimating the maximal eigenvalue of reconstruction operators through the power iteration. Based on the condition, an optimal step size was further suggested to allow the fastest convergence. Verifications were made on the prospective in vivo data of static brain imaging and dynamic contrast-enhanced liver imaging, demonstrating that the recommended parameter allowed fast convergence in radial MRI.

Using real-world data to inform dosing strategies of rituximab for pediatric patients with frequent-relapsing or steroid-dependent nephrotic syndrome: a prospective pharmacokinetic-pharmacodynamic study.

Objectives: Rituximab is frequently used off-label for the treatment of frequent-relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). However, the optimal dosing schedules remain undetermined. The objective of this study was to establish a population pharmacokinetic-pharmacodynamic (PK-PD) model in pediatric patients with FRNS/SDNS, and to investigate dosing regimens that provide adequate suppression of B lymphocytes. Methods: A prospective, open-label, single-center study was conducted in Nephrology Department at Children's Hospital of Fudan University, and a two-compartment PK model of rituximab in pediatric FRNS/SDNS has been developed previously by our group. CD19+ lymphocyte count profiles were obtained from these patients. The presence of anti-rituximab antibodies was assessed prior to medication in children who had previously received rituximab or during follow-up at the last sampling point for PK analysis. PK-PD analyses were performed to describe the changes of CD19+ lymphocytes, with rituximab assumed to increase their death rate. Monte Carlo simulation was conducted to evaluate different dosing regimens. Results: In total, 102 measurements of CD19+ lymphocyte counts were available for PK-PD analysis. No detectable levels of anti-rituximab antibodies were observed during the PK follow-up period. A turnover model with saturable stimulatory action of rituximab on the removal of lymphocytes best characterized the relationship between rituximab concentration and CD19+ lymphocyte counts, where the Emax and EC50 were estimated to be 99.6*106/L and 5.87 µg/mL, respectively. Simulations indicated that a single infusion of 750 mg/m2 and 2 infusions of 375 mg/m2 both yielded a 10-week suppression of CD19+ lymphocytes. Conclusion: This study represents a first attempt to quantitatively describe the PK-PD relationship of rituximab in pediatric patients with FRNS/SDNS, and provide a potential pathway for future precision dosing strategy for rituximab therapy. Further clinical studies are warranted to evaluate the efficacy and safety of different dosing schemes.

Population Pharmacokinetics of Rituximab in Pediatric Patients With Frequent-Relapsing or Steroid-Dependent Nephrotic Syndrome.

Objectives: Rituximab is frequently used off-label for the treatment of frequent-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS), but the relapse rate remained high and the dosing regimen varied widely. The objective of this study was to characterize rituximab pharmacokinetics (PK) in pediatric patients with FRNS/SDNS, and to investigate the differences in rituximab PK between patients with FRNS/SDNS and other disease populations. Methods: Fourteen pediatric patients received rituximab for FRNS/SDNS treatment were enrolled in a prospective, open-label, single-center PK study. A population PK model of rituximab was developed and validated, and PK parameters were derived for quantitative evaluation. Results: A two-compartment PK model best described the data. Body surface area was the most significant covariate for both central clearance (CL) and apparent central volume of distribution (V1). Patients with FRNS/SDNS exhibited a clinically relevant increase in rituximab CL compared to patient population with non-Hodgkin's lymphoma (NHL). Conclusion: This pilot study indicated that higher doses or more frequent regimens of rituximab may be required for optimal therapeutic effects in patients with FRNS/SDNS. Further clinical studies with more patients are warranted to confirm this result.

Palladium-catalyzed regio- and enantioselective migratory allylic C(sp3)-H functionalization.

Transition metal-catalyzed asymmetric allylic substitution with a suitably pre-stored leaving group in the substrate is widely used in organic synthesis. In contrast, the enantioselective allylic C(sp3)-H functionalization is more straightforward but far less explored. Here we report a catalytic protocol for the long-standing challenging enantioselective allylic C(sp3)-H functionalization. Through palladium hydride-catalyzed chain-walking and allylic substitution, allylic C-H functionalization of a wide range of acyclic nonconjugated dienes is achieved in high yields (up to 93% yield), high enantioselectivities (up to 98:2 er), and with 100% atom efficiency. Exploring the reactivity of substrates with varying pKa values uncovers a reasonable scope of nucleophiles and potential factors controlling the reaction. A set of efficient downstream transformations to enantiopure skeletons showcase the practical value of the methodology. Mechanistic experiments corroborate the PdH-catalyzed asymmetric migratory allylic substitution process.

Hypertension in 172 Chinese Children: An 8-Year Retrospective Study.

BACKGROUND: We evaluated children with hypertension and compared those with essential and secondary (including renal and non-renal) hypertension. METHODS: This retrospective study analyzed data from hypertensive children (age, 0-18 years) referred for treatment between January 2008 and December 2015. Demographic factors, causative factors, and medical treatments were evaluated. Treatment failure was defined as a systolic or diastolic blood pressure ≥95th percentile for age, gender, and height on three separate occasions, despite treatment. All patients not meeting the failure criteria were considered to have controlled hypertension. The control rate was defined as the proportion of patients with controlled blood pressure. RESULTS: Among 172 consecutive patients, 28% had essential hypertension and 72% had secondary hypertension. As compared with children with secondary hypertension, those with essential hypertension had a higher frequency of family history of hypertension (P<0.001), a higher body mass index (BMI) (P=0.001), lower frequency of proteinuria (P=0.003), lower uric acid (P=0.04), and lower triglyceride (P=0.048). The medications used in the controlled group were similar to those used in the uncontrolled group. Angiotensin-converting enzyme inhibitors (ACEIs) were only used in nephrogenic patients, and a higher rate of ACEI use seemed to increase control rates. Control rates did not significantly differ by age, number of drugs, or cause of hypertension. CONCLUSIONS: As compared with children with secondary hypertension, those with essential hypertension were more likely to have a family history of hypertension and had a higher BMI, lower frequency of proteinuria, and lower uric acid and triglyceride concentrations. Treatment guidelines for essential and secondary hypertension should be established for children of all ages.

Ppb-level detection of methane based on an optimized T-type photoacoustic cell and a NIR diode laser.

This paper presents an optimized T-type resonant photoacoustic (PA) cell for methane (CH4) gas detection. The noise transmission coefficients and PA field distributions of the T-type resonant PA cell have been evaluated using the finite element method and thermoviscous acoustic theory. The optimized T-type resonant PA cell, together with a near-infrared (NIR) distributed feedback (DFB) laser source, a high-speed spectrometer and a fiber-optic acoustic sensor constitutes a PAS system for CH4 detection. The sensitivity is measured to be 1.8 pm/ppm and a minimum detectable limit (MDL) of 9 parts per billion (ppb) can be achieved with an averaging time of 500 s. The optimized T-type longitudinal resonant PA cell features of high PA cell constant, fast response time and simple manufacturing process.

High-sensitivity photoacoustic gas detector by employing multi-pass cell and fiber-optic microphone.

A high-sensitivity photoacoustic (PA) spectroscopy (PAS) system is proposed for dual enhancement from both PA signal excitation and detection by employing a miniaturized Herriott cell and a fiber-optic microphone (FOM). The length of the optical absorption path of the PA cell is optimized to ∼374 mm with 17 reflections. The volume of the PA cell is only 622 µL. The FOM is a low-finesse fiber-optic Fabry-Pérot (FP) interferometer. The two reflectors of the FP cavity are formed by a fiber endface and a circular titanium diaphragm with a radius of 4.5 mm and a thickness of 3 µm. A fast demodulated white-light interferometer (WLI) is utilized to measure the absolute FP cavity length. The acoustic responsivity of the FOM reaches 126.6 nm/Pa. Several representative PA signals of trace acetylene (C2H2) are detected to evaluate the performance of the trace gas detector in the near-infrared region. Experimental results show that the minimum detectable pressure (MDP) of the FOM is 3.8 µPa/Hz1/2 at 110 Hz. The noise equivalent minimum detection concentration is measured to be 8.4 ppb with an integration time of 100 s. The normalized noise equivalent absorption (NNEA) coefficient is calculated as 1.4×10-9 cm-1·W·Hz-1/2.

Highly Sensitive Photoacoustic Microcavity Gas Sensor for Leak Detection.

A highly sensitive photoacoustic (PA) microcavity gas sensor for leak detection is proposed. The miniature and low-cost gas sensor mainly consisted of a micro-electro-mechanical system (MEMS) microphone and a stainless-steel capillary with two small holes opened on the side wall. Different from traditional PA sensors, the designed low-power sensor had no gas valves and pumps. Gas could diffuse into the stainless-steel PA microcavity from two holes. The volume of the cavity in the sensor was only 7.9 µL. We use a 1650.96 nm distributed feedback (DFB) laser and the second-harmonic wavelength modulation spectroscopy (2f-WMS) method to measure PA signals. The measurement result of diffused methane (CH4) gas shows a response time of 5.8 s and a recovery time of 5.2 s. The detection limit was achieved at 1.7 ppm with a 1-s lock-in integral time. In addition, the calculated normalized noise equivalent absorption (NNEA) coefficient was 1.2 × 10-8 W·cm-1·Hz-1/2. The designed PA microcavity sensor can be used for the early warning of gas leakage.

PK/PD Study of Mycophenolate Mofetil in Children With Systemic Lupus Erythematosus to Inform Model-Based Precision Dosing.

Objectives: To evaluate the mycophenolic acid [MPA, the active form of mycophenolate mofetil (MMF)] pharmacokinetic parameters in relation to clinical response to identify target exposure ranges in pediatric patients with systemic lupus erythematosus (SLE). Methods: This was a retrospective study using pharmacokinetic data collected in 67 pediatric patients aged 4-18 years with SLE. Target MPA exposures for effective inhibition of SLE activity (as measured by SLE disease Activity Index (SLEDAI), active SLE was defined as a SLEDAI score of ≥6, and a controlled disease was defined as a SLEDAI score of ≤4) were assessed by receiver operating characteristic (ROC) curve and logistic regression. Exposure-response models were developed to quantitatively describe the relationship between SLEDAI score and AUC0-12 or Ctrough, respectively. Results: The MPA AUC0-12 in patients with active SLE was significantly lower than that in patients with inactive SLE. ROC analysis revealed that an AUC0-12 threshold of 39 µg h/ml or a Ctrough of 1.01 µg/ml was associated with the lowest risk of active SLE. Logistic regression analysis revealed that an AUC0-12 of less than 34 µg h/ml or a Ctrough of less than 1.2 µg/ml probably is associated with active SLE. The results of the exposure-response modeling also indicated that an AUC0-12 less than 32 µg h/ml or a Ctrough less than 1.1 µg/ml was associated with suboptimal clinical outcome. An AUC0-12 above 50 µg h/ml or a Ctrough above 1.7 ug/ml was associated with disease control. Conclusion: Both AUC0-12 and Ctrough of MPA are predictive of the likelihood of active SLE in pediatric patients receiving MMF. An individualized dosing regimen of MMF, with a target AUC0-12 or Ctrough, should be considered for SLE patients.

An auto-correction laser photoacoustic spectrometer based on 2f/1f wavelength modulation spectroscopy.

An auto-correction laser photoacoustic (PA) spectrometer based on 2f/1f wavelength modulation spectroscopy (WMS) has been proposed and demonstrated for trace gas detection to eliminate concentration measurement errors due to light power variations. A 1.53 µm distributed feedback (DFB) laser is used as a light source to excite the 2f PA signal that is generated by gas absorption. Meanwhile, a multilayer graphene sheet is employed as a highly efficient photothermal conversion unit for adding a 1f PA background signal, whose amplitude at the absorption center of the traditional PAS system is almost zero. The experimental results show that the gas concentration measured from the 2f/1f WMS signal is almost independent of the laser power. A detection limit of 416 ppb has been achieved for the 1 s measurement interval and could be further improved to 65 ppb with 100 s averaging, according to the Allan deviation analysis.

Integration of T-type half-open photoacoustic cell and fiber-optic acoustic sensor for trace gas detection.

We present a novel T-type half-open resonant photoacoustic (PA) cell for trace gas detection. The T-type PA cell has just one buffer volume, and a fiber-optic acoustic sensor is placed at one end of the resonator. Compared with the conventional H-type PA cell, the first-order resonant frequency of the T-type PA cell is reduced by half and the PA signal is enhanced with the same resonator. The T-type resonant PA cell was used in acetylene (C2H2) gas detection system based on PA spectroscopy. Experimental results show that the minimum detectable limit of C2H2 is calculated to be 0.70 parts per billion (ppb), which is lower than the traditional H-type PA cell.

Fiber-optic photoacoustic sensor for remote monitoring of gas micro-leakage.

We present a fiber-optic photoacoustic (PA) sensor for remote monitoring of gas micro-leakage. The gas sensing head is a miniature ferrule-top PA cavity with a cantilever beam. Gas diffuses into the cavity from the gap around the cantilever beam, and a small hole opens on the side wall. The volume of the optimized PA cavity is only 70 µL. An erbium-doped fiber amplified laser is used as a light source of acoustic excitation. The PA pressure signal is obtained by measuring the deflection of the cantilever beam with a fiber-optic white-light interferometric readout. The experimental result of leaking acetylene (C2H2) gas measurement shows a real-time response of 11.2 s. A detection limit is achieved to be 20 ppb with a 1 s lock-in integration time and a 1 km conductive fiber. Since both the excitation light and probe light are transmitted by the optical fiber, the designed sensing system has the advantages of remote detection and intrinsic safety.

Population pharmacokinetics of vancomycin and AUC-guided dosing in Chinese neonates and young infants.

OBJECTIVES: To develop a population pharmacokinetic (PK) model for vancomycin in Chinese neonates and infants less than 2 months of age (young infants) with a wide gestational age range, in order to determine the appropriate dosing regimen for this population. METHODS: We performed a retrospective chart review of patients from the neonatal intensive care unit (NICU) at Children's Hospital of Fudan University to identify neonates and young infants treated with vancomycin from May 2014 to May 2017. Vancomycin concentrations and covariates were utilized to develop a one-compartment model with first-order elimination. The predictive performance of the final model was assessed by both internal and external evaluation, and the relationship between trough concentration and AUC0-24 was investigated. Monte Carlo simulations were performed to design an initial dosing schedule targeting an AUC0-24 ≥ 400. RESULTS: The analysis included a total of 330 concentration-time data points from 213 neonates and young infants with gestational age (GA) and body weight of 25-42 weeks and 0.88-5.1 kg, respectively. Body weight, postmenstrual age (PMA) and serum creatinine level were found to be important factors explaining the between-subject variability in vancomycin PK parameters for this population. Both internal and external evaluation supported the prediction of the final vancomycin PK model. The typical population parameter estimates of clearance and distribution volume for an infant weighing 2.73 kg with a PMA of 39.8 weeks and serum creatinine of 0.28 mg/dL were 0.103 L/h/kg and 0.58 L/kg, respectively. Although vancomycin serum trough concentrations were predictive of the AUC, considerable variability was observed in the achievement of an AUC0-24/MIC of ≥400. For MIC values of ≤0.5 mg/L, AUC0-24/MIC ≥400 was achieved for 95% of the newborn infants with vancomycin troughs of 5-10 mg/L. When the MIC increased to 1 mg/L, only 15% of the patients with troughs of 5-10 mg/L achieved AUC0-24/MIC ≥400. For MIC values of 2 mg/L, no infants achieved the target. Simulations predicted that a dose of at least 14 and 15 mg/kg every 12 h was required to attain the target AUC0-24 ≥ 400 in 90% of infants with a PMA of 30-32 and 32-34 weeks, respectively. This target was also achieved in 93% of simulated infants in the oldest PMA groups (36-38 and 38-40 weeks, respectively) when the dosing interval was extended to 8 h. For infants with a PMA ≥44 weeks, a dose increase to 18 mg/kg every 8 h was needed. The trough concentrations of 5-15 mg/L were highly predictive of an AUC0-24 of ≥400 when treating invasive MRSA infections with an MIC of ≤1 mg/L. CONCLUSIONS: The PK parameters for vancomycin in Chinese infants younger than 2 months of age were estimated using the model developed herein. This model has been used to predict individualized dosing regimens in this vulnerable population in our hospital. A large external evaluation of our model will be conducted in future studies.

Target attainment analysis and optimal sampling designs for population pharmacokinetic study on piperacillin/tazobactam in neonates and young infants.

OBJECTIVES: Population pharmacokinetic (popPK) analyses for piperacillin/tazobactam in neonates and infants of less than 2 months of age have been performed by our group previously. The results indicate that a dose of 44.44/5.56 mg/kg piperacillin/tazobactam every 8 or 12 h may not be enough for controlling infection in this population. In order to determine the appropriate dosing regimen and to provide a rationale for the development of dosing guidelines suitable for this population, further popPK studies of piperacillin/tazobactam would need to be conducted. The aim of the present study was to determine the appropriate dosing regimen and optimal sampling schedules in neonates and infants of less than 2 months of age. METHODS: Pharmacodynamic profiling of piperacillin using Monte Carlo simulation was performed to explore the target attainment probability of different dosing regimens for infections caused by different isolated pathogens. D-optimal designs for piperacillin and tazobactam were conducted separately, and the times that overlapped were chosen as the final sampling scheme for future popPK studies in neonates and young infants of less than 2 months of age. RESULTS: Our findings revealed that compared to the current empirical piperacillin/tazobactam dose regimen (50 mg/kg every 12 h by 5-min infusion in our hospital), the clinical outcome could be improved by increasing doses, increasing administration frequency, and prolonging intravenous infusion in neonates and infants of less than 2 months of age. The following optimal sampling windows were chosen as the final sampling scheme: 0.1-0.11, 0.26-0.29, 0.97-2.62, and 7.95-11.9 h administered every 12 h with 5-min infusion; 0.1-0.12, 0.39-0.56, 2.86-4.95, and 8.91-11.8 h administered every 12 h with 3-h infusion; 0.1-0.11, 0.22-0.29, 0.91-1.96, and 5.56-7.93 h administered every 8 h with 5-min infusion; 0.1-0.11, 0.38-0.48, 2.54-3.82, and 6.86-7.93 h administered every 8 h with 3-h infusion; 0.1-0.11, 0.25-0.28, 0.84-1.69, and 4.55-5.94 h administered every 6 h with 5-min infusion; and 0.1-0.11, 0.37-0.54, 3.13-3.72, and 5.57-5.99 h administered every 6 h with 3-h infusion. CONCLUSIONS: The dosing regimen and sampling schedules proposed in this study should be evaluated in future popPK studies of piperacillin/tazobactam in neonates and infants. To the best of our knowledge, this is the first study that combined optimal sampling design with Monte Carlo simulation for designing popPK studies of piperacillin/tazobactam.

Population pharmacokinetic analysis of digoxin in Chinese neonates and infants.

To obtain more information regarding the influence of various covariates on the disposition of digoxin in Chinese neonates and infants, routine clinical pharmacokinetic data were retrospectively collected from 131 hospitalized patients. A nonlinear mixed effects modeling (NONMEM) method was applied to the data. A one-compartment/first-order absorption model was employed to estimate the influence of total body weight (allometric power model), postnatal age, serum creatinine, gender, presence of heart congestive failure, and concomitant medications on apparent total clearance and apparent drug distribution of digoxin. Pharmacokinetic parameter estimates for CL/F and V/F were 0.147 L∙h(-1)∙kg(-1) and 15.7 L/kg, respectively. Total body weight and postnatal age were identified as the important factors affecting total clearance of digoxin; total body weight was the covariate identified to influence the apparent distribution volume. Both internal (bootstrap method, visual predictive checks, and normalized prediction distributed error) and external validation supported the stable and predictive performance of the final model. We concluded that the model can be used to choose an appropriate dose regimen in Chinese neonates and infants.

Population pharmacokinetics of piperacillin/tazobactam in neonates and young infants.

OBJECTIVES: To develop population pharmacokinetic (PK) models for piperacillin/tazobactam in neonates and infants of less than 2 months of age in order to determine the appropriate dosing regimen and provide a rational basis for the development of preliminary dosing guidelines suitable for this population. METHODS: A two-stage, open-label study was conducted in neonates and infants less than 2 months of age in the neonatal intensive care unit (NICU). A total of 207 piperacillin and 204 tazobactam concentration-time data sets from 71 patients were analyzed using a nonlinear mixed-effect modeling approach (NONMEM VII). PK models were developed for piperacillin and tazobactam. The final models were evaluated using both bootstrap and visual predictive checks. External model evaluations were made in 20 additional patients. RESULTS: For neonates and young infants less than 2 months of age, the median central clearance was 0.133 and 0.149 L/h/kg for piperacillin and tazobactam, respectively. Postmenstrual age (PMA) was identified as the most significant covariate on central clearance of piperacillin and tazobactam. However, the combination of current bodyweight (BW) and postnatal age proved to be superior to PMA alone. BW was the most important covariate for apparent central volume of distribution. Both internal and external evaluations supported the prediction of the final piperacillin and tazobactam PK models. The dosing strategy 44.44/5.56 mg/kg/dose piperacillin/tazobactam every 8 or 12 h evaluated in this study achieved the pharmacodynamic target (free piperacillin concentrations >4 mg/L for more than 50 % of the dosing interval) in about 67 % of infants. CONCLUSIONS: Population PK models accurately described the PK profiles of piperacillin/tazobactam in infants less than 2 months of age. The results indicated that higher doses or more frequent dosing regimens may be required for controlling infection in this population in NICU.