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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. [ABSTRACT FROM AUTHOR]

Objective: The elucidation of CYP2D6 developmental pharmacogenetics in children has improved, however, these findings have been largely limited to studies of Caucasian children. Given the clear differences in CYP2D6 pharmacogenetic profiles in people of different ancestries, there remains an unmet need to better understand the developmental pharmacogenetics in populations of different ancestries. We sought to use loratadine as a substrate drug to evaluate the effects of ontogeny and pharmacogenetics on the developmental pattern of CYP2D6 in Chinese pediatric patients. Methods: Chinese children receiving loratadine treatment were enrolled in the present study. The metabolite-to-parent ratio (M/P ratio), defined as the molar ratio of desloratadine to loratadine of trough concentrations samples at steady-state condition, was used as a surrogate of CYP2D6 activity. Loratadine and desloratadine were determined by LC/MS/MS method. Variants of CYP2D6 were genotyped by polymerase chain reaction for CYP2D6 *4, *10, *41 and long polymerase chain reaction for CYP2D6 *5. Results: A total of 40 patients were available for final analysis. The mean age was 4.50 (range 0.50–9.00) years and the mean weight was 19.64 (range 7.00–42.00) kg. The M/P ratio was significantly lower in intermediate metabolizers (IMs) compared to normal metabolizers (NMs) (10.18 ± 7.97 vs. 18.80 ± 15.83, p = 0.03). Weight was also found to be significantly associated with M/P ratio (p = 0.03). Conclusion: The developmental pharmacogenetics of CYP2D6 in Chinese children was evaluated using loratadine as a substrate drug. This study emphasizes the importance of evaluating the developmental pharmacogenetics in populations of different ancestries. [ABSTRACT FROM AUTHOR]

Aims: Nephrotic syndrome (NS) is the most common clinical manifestation of glomerular disease in children. Currently, tacrolimus (TAC) is widely used in children with NS. However, pharmacokinetic data in children with nephrotic syndrome is limited. This study was intended to evaluate the population pharmacokinetics (PPK) of TAC in paediatric NS and to optimize dosing regimen. Methods: Blood samples from NS children treated with TAC were collected and the blood concentrations of TAC were detected using HPLC‐MS/MS. A PPK model was developed using NONMEM software. Pharmacogenetic analysis was carried out in the CYP3A5 gene. Results: The data from 28 children were used for PPK analysis. A one‐compartment model and first‐order elimination were accorded with the TAC data in paediatric NS. A covariate analysis showed that body weight and CYP3A5 genotype significantly affected TAC pharmacokinetics. Monte Carlo simulation indicated that NS children with CYP3A5*3/*3 receiving 0.10 mg kg−1 dose−1 twice daily and NS children with CYP3A5*1 receiving 0.25 mg kg−1 dose−1 twice daily TAC could achieve the target concentrations of 5–10 ng ml−1. Conclusion: The PPK of TAC was estimated in children with NS and a CYP3A5 genotype‐based dosing regimen was set up based on simulations. [ABSTRACT FROM AUTHOR]

Abstract: A rapid, accurate and specific high‐performance liquid chromatography–tandem mass spectrometry method has been validated for the simultaneous determination of cefoperazone and sulbactam in a small volume sample for children. A Shim‐pack XR‐ODS C18 column with gradient elution of water (0.1% formic acid) and acetonitrile (0.1% formic acid) solution was used for separation at a flow rate of 0.3 mL/min. The calibration curves of two analytes in serum showed excellent linearity over the concentration ranges of 0.03–10 μg/mL for cefoperazone, and 0.01–3 μg/mL for sulbactam, respectively. This method involves simple sample preparation steps and was validated according to standard US Food and Drug Administration and European Medicines Agency guidelines in terms of selectivity, linearity, detection limits, matrix effects, accuracy, precision, recovery and stability. This assay can be easily implemented in clinical practice to determine concentrations of cefoperazone and sulbactam in children. [ABSTRACT FROM AUTHOR]

• Free cefoperazone in plasma ultrafiltrate was analyzed by LC-MS/MS. • A small sample volume (20 μl of ultrafiltrate) was used for the detection. • The sensitive method was applied to determining free cefoperazone in pediatric patients. • Age and albumin had significant effects on the protein binding of cefoperazone. Antimicrobial activity of cefoperazone, a high protein bound cephalosporin, depends on its unbound concentration. However, the protein binding data of cefoperazone in children is limited, making it challenging to optimize antimicrobial therapy in pediatric clinical practice. Furthermore, a validated method to measure the free part in children is unavailable with the small volume of samples that can be obtained. Therefore, in the present study, we developed and validated an LC-MS/MS method for the determination of free cefoperazone in children. In this study, 70 μL of plasma was used to prepare the ultrafiltrate (only containing the free drug). Chromatographic separation of the analyte was achieved on a C18 column using gradient elution with a mobile phase of acetonitrile and water (0.1% formic acid). Negative electrospray ionisation in the multiple reaction monitoring mode was applied for the detection of cefoperazone and ceftiofur (internal standard). The calibration curve was prepared in the range of 5–5000 ng/mL with excellent linearity. For each level of quality control samples, the intra- and inter-day precision (CV) was below 9.0%, and the accuracy ranged from 91.5% to 105.0%. The matrix effect was less than 11.7%, and the recovery was between 92.9% and 95.9% of cefoperazone. The validated method has been successfully applied to the determination of free plasma concentration of cefoperazone in pediatric patients. The results of the unbound fraction showed considerable individual variability (range: 8.1–48.0%). The correlation analysis showed that age and albumin had significant effects on the protein binding of cefoperazone. [ABSTRACT FROM AUTHOR]