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This study investigates the optimal meropenem (MEM) dosing regimen for critically ill pediatric patients, for which there is a lack of pharmacokinetic (PK) studies. We conducted a retrospective single-center PK and pharmacodynamic (PD) analysis of 34 pediatric intensive care unit patients who received MEM. Individual PK parameters were determined by a two-compartment analysis. The median (range) age and body weight were 1.4 (0.03–14.6) years old and 8.9 (2.7–40.9) kg, respectively, and eight (23.5%) patients received continuous renal replacement therapy (CRRT), of which three received extracorporeal membrane oxygenation. Renal function, systemic inflammatory response syndrome (SIRS) score, and the use of CRRT for central volumes of distribution (Vc) were identified as significant covariates. The mean clearance (CL), Vc, and peripheral volume of distribution (Vp) were 0.45 l/kg/h, 0.49 l/kg, and 0.34 l/kg, respectively. The mean population CL of MEM increased by 35% in patients with SIRS and Vc increased by 66% in patients on CRRT in the final model. Dosing simulations suggested that the standard dosing regimen provided insufficient PD exposures of 100% free time above the minimum inhibitory concentration, and higher doses (40–80 mg/kg/dose every 8 h) with a prolonged 3-h infusion were required to ensure the appropriate PD exposures for patients with SIRS. Our PK model indicated that critically ill pediatric patients are at risk of subtherapeutic exposure under the standard dosing regimen of MEM. A larger, prospective investigation confirming the safety and efficacy of higher concentrations and prolonged infusion of MEM is necessary.

Objectives In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. Methods A ‘meta-model’ with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0–24 of 400 mg·h/L at steady-state in at least 80% of neonates. Results A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0–24 target earlier than a standard ‘Blue Book’ dosage regimen in >89% of the treated patients. Conclusions The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.

A variant in the breast cancer resistance protein (BCRP) gene, 421C> A is a useful biomarker for describing large inter-individual differences in the pharmacokinetics of sulfasalazine (SASP), a BCRP substrate. However, large intra-genotypic variability still exists in spite of the incorporation of this variant into the pharmacokinetics of SASP. Since miR-328 negatively regulates BCRP expression in human tissues, we hypothesized that exosomal miR-328 in plasma, which leaks from the intestines, is a possible biomarker for estimating BCRP activity in the human intestines. We established an immunoprecipitation-based quantitative method for circulating intestine-derived miR-328 in plasma using an anti-glycoprotein A33 antibody. A clinical study was conducted with an open-label, non-randomized, and single-arm design involving 33 healthy participants. Intestine-derived exosomal miR-328 levels positively correlated (P < 0.05) with SASP AUC0-48, suggesting that subjects with high miR-328 levels have low intestinal BCRP activity, resulting in the high AUC of SASP. Circulating intestine-derived exosomal miR-328 in plasma has potential as a possible biomarker for estimating BCRP function in the human intestines.

BackgroundAtropine eye drops are indicated for juvenile myopia progression, cycloplegia, amblyopia, and strabismus. According to the package insert, 10 mg/mL atropine eye drops must be diluted for pediatric patients to prevent systemic adverse effects. Compounding units in hospital pharmaceutical departments or community pharmacies are compelled to prepare this essential medication; however, validated atropine stability data is limited and the shelf life after preparation is extremely short. As it is a long-term treatment, a longer shelf life is necessary to improve patient care. This study aimed to demonstrate the physical, chemical, and microbiological stability of diluted atropine eye drops over a period of six months.MethodsPreparation consists of dilution of a 10 mg/mL atropine solution (Nitten Atropine Ophthalmic Solution 1%; Nitten Pharmaceutical Co., Ltd.) in 0.9% NaCl to concentrations of 0.1, 1.0, 2.5, and 5.0 mg/mL, followed by a sterilizing filtration procedure and then an aseptic filling process of 5 mL in 5 mL polyethylene eyedropper bottles. The entire process is carried out in an overpressure isolator. All concentration products were kept for six months at 25 °C or 5 °C. Visual inspection was conducted and pH, osmolality, and atropine concentration were measured at day 0, day 14, day 28, and every month until six months. Atropine concentration was measured using liquid chromatography tandem mass spectrometry. The sterility was monitored using a method adapted from the Japanese Pharmacopoeia sterility assay.ResultsAtropine remained within ±5% of the target value in the six batches. Osmolality (285 mOsm/kg) as well as pH (5.88) were kept constant. No variations in solution characteristics (crystallization, discoloration) were noted. Sterility was maintained.ConclusionsThis study validated the physical, chemical, and microbiological stability of 0.1, 1.0, 2.5, and 5.0 mg/mL atropine sulfate eye drops conserved inside polyethylene eyedroppers for six months at 25 °C or 5 °C.

Aims: Tocilizumab (TCZ), a humanized anti-interleukin-6 receptor monoclonal antibody, is used to treat rheumatic diseases. There is limited information about the administration of TCZ during lactation. The dried spot method, a simple technique for processing biological samples which involves placement of a drop of specimen onto filter paper, has been used in clinical pharmacology to determine various drug concentrations. This study examined the feasibility of sample collection using the dried milk spot (DMS) method for obtaining data about the transfer of TCZ into breast milk. Methods:Concentrations of TCZ determined using DMSs prepared by patients were compared with those using liquid breast milk. Results:In an enzyme-linked immunosorbent assay of TCZ in DMSs, the accuracy ranged from 93.0% to 113.8% and the precision ranged from 0.3% to 8.4%. All concentrations of TCZ were within 15% of the reference value when analyzed on separate days. TCZ in DMSs at room temperature, 4°C, and −20°C were stable for 28 days.Extracted TCZ concentrations from patient-prepared DMSs were strongly correlated with those of liquid samples (r = 0.996). In a pharmacokinetic study, the median (range) maximum and minimum concentrations were 113 ng/mL (68-205) and 8.5 ng/ mL (4.8-13.4), respectively. The milk-to-serum ratio at the trough TCZ concentration of 3 lactating mothers were 0.0015, 0.00082 and 0.0014. Conclusions:The DMS method for measuring TCZ transfer into breast milk may be reliable and feasible, and should contribute to evaluating the safety of breast-fed infants whose mothers receive TCZ during lactation.

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