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What Is Known and Objective: Midazolam is a drug that is metabolized by cytochrome P450 (CYP450) enzymes, particularly CYP3A4 and CYP3A5. The presence of single-nucleotide polymorphisms (SNPs) in the genes encoding these enzymes, such as CYP3A4*1B which is associated with low enzyme expression and activity and CYP3A5*3, has been associated with decrease in enzymatic activity and reduced drug clearance, with potential effects on drug levels and/or toxicity. The present study was conducted to determine the frequencies of the allelic variants of the CYP3A4 (rs2740574) and CYP3A5 (rs776746) genes and their effects on the plasma levels and clearance of intravenous midazolam in critically ill Mexican paediatric patients., Methods: Seventy-two DNA samples were genotyped by real-time PCR with TaqMan probes. Plasma midazolam levels were determined at 3 and 24 h post infusion by high-performance liquid chromatography., Results and Discussion: The allelic variant rs776746 (CYP3A5*3) was associated with high midazolam plasma levels; the median concentration in patients with the normal genotype (CC) <0.01 ng/ml (Q 25 0.01-Q 75 196.09), whereas patients with the allelic variant (TT+TC) had a median midazolam concentration of 320.3 ng/ml (Q 25 37.51-Q 75 529.51), p = 0.001. The median pharmacokinetic clearance rates were 0.10 L/kg/h (Q 25 0.01-Q 75 0.34) in patients with the allelic variant (TT+TC) and 0.03 L/kg/h (Q 25 0.002-Q 75 0.13) in patients with the normal genotype (CC), p = 0.042., What Is New and Conclusion: This is the first study that reports the frequency of the rs776746 polymorphism in critically ill paediatric patients, which is relevant, since carriers of the *1 allele synthesizing a functional enzyme may need higher doses to achieve adequate sedation. Our results show that compared with carriers of the normal allele, patients with the CYP3A5*3 allelic variant (rs776746) had increased plasma midazolam levels at 3 h after infusion discontinuation (320.3 ng/ml) and greater clearance (0.10 L/kg/h) of the drug., (© 2021 John Wiley & Sons Ltd.)

Midazolam (MDZ) is used for sedation in surgical procedures; its clinical effect is related to its receptor affinity and the dose administered. Therefore, a pharmacokinetic–pharmacodynamic (PK-PD) population model of MDZ in pediatric patients undergoing minor surgery is proposed. A descriptive, observational, prospective, and longitudinal, study that included patients of both sexes, aged 2–17 years, ASA I/II, who received MDZ in IV doses (0.05 mg/kg) before surgery. Three blood samples were randomly taken between 5–120 min; both sedation by the Bispectral Index Scale (BIS) and its adverse effects were recorded. The PK-PD relationship was determined using a nonlinear mixed-effects, bicompartmental first-order elimination model using Monolix Suite™. Concentrations and the BIS were fitted to the sigmoid Emax PK-PD population and sigmoid Emax PK/PD indirect binding models, obtaining drug concentrations at the effect site (biophase). The relationship of concentrations and BIS showed a clockwise hysteresis loop, probably indicating time-dependent protein binding. Of note, at half the dose used in pediatric patients, adequate sedation without adverse effects was demonstrated. Further PK-PD studies are needed to optimize dosing schedules and avoid overdosing or possible adverse effects. [ABSTRACT FROM AUTHOR]

Whether age and sex influence the depth of sedation and the pharmacokinetics of midazolam is currently unknown. The influence of age and sex was investigated in 117 children (2 to 17 years) who required intravenous sedation for minor surgery (0.05 mg/kg). Plasma concentrations and sedation effects were simultaneously measured. The measured concentrations were analyzed using a two-compartment model with first-order elimination. Among the age ranges, significant differences were found (p < 0.05) between the volume of distribution (Vd) of the first compartment (V1) and that of the second (V2). With respect to sex, differences in V2 were found between age groups. At the administered dose, in patients younger than 6 years, a profound sedative effect (40–60 BIS) was observed for up to 120 min, while in older children, the effect lasted only half as long. The differences found in the Vd and bispectral index (BIS) in patients younger than 6 years compared to older patients may be due to immature CYP3A activity and body fat content; furthermore, the Vd varies with age due to changes in body composition and protein binding. Patients younger than 6 years require intravenous (IV) doses <0.05 mg/kg of midazolam for deep sedation. Dosage adjustments according to age group are suggested. [ABSTRACT FROM AUTHOR]

Midazolam (MDZ) is a short-acting benzodiazepine that is widely used to induce and maintain general anesthesia during diagnostic and therapeutic procedures in pediatric patients due to its sedative properties. The aim of this study was to perform a systematic review without a meta-analysis to identify scientific articles and clinical assays concerning MDZ-induced sedation for a pediatric surgery approach. One hundred and twenty-eight results were obtained. After critical reading, 37 articles were eliminated, yielding 91 publications. Additional items were identified, and the final review was performed with a total of 106 publications. In conclusion, to use MDZ accurately, individual patient characteristics, the base disease state, comorbidities, the treatment burden and other drugs with possible pharmacological interactions or adverse reactions must be considered to avoid direct alterations in the pharmacokinetics and pharmacodynamics of MDZ to obtain the desired effects and avoid overdosing in the pediatric population. [ABSTRACT FROM AUTHOR]

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Background: The lack of pediatric drug formulations is a problem that has limited the prescription in that population in the long term, resulting errors in drug administration by patients. Objetive: To determine the frequency of drug consumption at a National Pediatrics Institute in a six year-period, and identify those medications for which there is no available pediatric formulation. Methods: The frequency of consumption of medications was investigated, using the data base at the Pharmacy of the National Pediatrics Institute during the period from January 2001 to June 2006. Drugs were grouped according to their frequency, identifying those not available for pediatric use which are nevertheless prescribed. Results:. About 85 different drugs were used to attend hospital demands, which were prescribed on 7514 occasions within the period of study. The most frequently used drugs were: ranitidine (4.7%), paracetamol (3.8%) and midazolam (3.7%). Our results showed that midazolam, furosemide, phenobarbital, omeprazole, prednisone and captopril were the most prescribed drugs for which there are no pediatric formulations commercially available. Conclusion: This article reports the frequency of drug consumption at a pediatric hospital and discusses it in view of the lack of adequate formulations for pediatric patients in our country. [ABSTRACT FROM AUTHOR]