The PPK of TAC was estimated in children with NS and a CYP3A5 genotype-based dosing regimen was set up based on simulations.

Aims: Chinese children are more susceptible to the development of thiopurineinduced leukopenia compared with Caucasian populations. The aim of our study was to establish a 6-mercaptopurine (6-MP) dose-concentration-response relationship through exploration of pharmacogenetic factors involved in the thiopurine-induced toxicities in Chinese paediatric patients afflicted by acute lymphoblastic leukaemia (ALL).Methods: Blood samples were obtained from ALL children treated with 6-MP. We determined the metabolite steady-state concentrations of 6-MP in red blood cells (RBCs) by using high-performance liquid chromatography. Pharmacogenetic analysis was carried out on patients' genomic DNA using the MassArray genotyping platform.Results: Sixty children afflicted by ALL who received 6-MP treatment were enrolled in this study. The median concentration of 6-thioguanine in patients afflicted by leukopenia was 235.83 pmol/8 × 10 8 RBCs, which was significantly higher than for patients unafflicted by leukopenia (178.90 pmol/8 × 10 8 RBCs; P = 0.029). We determined the population special target 6-thioguanine threshold to have equalled 197.50 pmol/8 × 10 8 RBCs to predict leukopenia risk in Chinese paediatric patients afflicted by ALL. Among 36 candidate single nucleotide polymorphisms, our results indicated that NUDT15 (rs116855232) and IMPDH1 (rs2278293) were correlated with a 5.50-fold and 5.80-fold higher risk of leukopenia, respectively. MTHFR rs1801133 Tian-You Wang and Wei Zhao contributed equally.The authors confirm that the Principal Investigator for this paper is Wei Zhao and that he had direct clinical responsibility for patients.

No abstract

Objective: Cefepime is used to treat severe infections in neonates. Pharmacokinetic data have only been evaluated among preterm neonates and population pharmacokinetic model lacked external validation. Hence, our aim is to obtain the population pharmacokinetic parameters of cefepime with large sampling and optimize the cefepime dosage regimen for neonatal infection based on developmental pharmacokinetics-pharmacodynamics.Methods: Blood samples from neonates and young infants treated with cefepime were collected using the opportunistic sampling design. The concentration of cefepime was determined using high performance liquid chromatography with ultraviolet detection. The population pharmacokinetic model was established using NONMEM software. Results:One hundred blood samples from eighty-five neonates were analyzed. The population pharmacokinetics of cefepime were described by a one-compartment model with first-order elimination. Covariate analysis indicated that serum creatinine concentration, postmenstrual age and current weight had significant impact on the pharmacokinetic parameters of cefepime. Monte Carlo simulation results showed that the current dosage regimen (30 mg/kg, q12 h) had a high risk of insufficient dose. For 70% of neonates to obtain a higher free drug concentration than the minimum inhibitory concentration during 70% of the dosing interval, 50 mg/kg q12 h was needed with a susceptibility breakpoint of 4 mg/l. For a minimum inhibitory concentration of 8 mg/l, 40 mg/kg q8 h was recommended for all neonates.Conclusion: A population pharmacokinetic model of cefepime in neonates and young infants was established. According to simulation results based on the developmental Frontiers in Pharmacology | www.frontiersin.org

No study has evaluated the impact of different iodinated contrast media on coronary contrast enhancement, using an injection protocol according to body surface area (BSA). Thus, the present study aimed to examine the usefulness and safety of personalized application of different iodine concentrations of contrast media in coronary computed tomographic (CT) angiography with a 2nd dual‐source CT scanner in eliminating differences in coronary contrast enhancement based on a BSA‐adapted injection protocol of contrast media. A total of 270 enrolled participants were randomly assigned to three groups: ioversol 320, ioversol 350 and iopromide 370 (n = 90 per group). The three groups were administered contrast media at a BSA‐adjusted volume and flow rate with a fixed injection time of 15 seconds, and they subsequently received a 30‐mL saline flush. All patients were scanned with a prospective electrocardiogram‐gated protocol in a craniocaudal direction using a second‐generation 128‐slice dual‐source CT system. The three iodinated contrast media used in coronary CT angiography exhibited similar diagnostic quality and safety. No significant differences were found in the contrast enhancement degrees, image quality scores, radiation doses and incidences of adverse effects among the three groups. The three contrast media used in coronary CT angiography with 320, 350 and 370 mg/mL iodine, respectively, have comparable diagnostic quality and safety. However, more large‐scale, multinational, multi‐centre and prospective trials are warranted.