Development of simultaneous quantitative analytical method for metabolites of hexosamine biosynthesis pathway in lung cancer cells using ultra-high-performance liquid chromatography-tandem mass spectrometry.

The hexosamine biosynthesis pathway (HBP) is a glucose metabolism pathway that produces uridine diphosphate N-acetyl glucosamine (UDP-GlcNAc). Substantial changes in HBP, including elevated HBP flux and UDP-GlcNAc levels, are associated with cancer pathogenesis. Particularly, cancer cells expressing oncogenic Kirsten rat sarcoma virus (KRAS) are highly dependent on HBP for growth and survival. To differentiate between HBP metabolites in KRAS wild-type (WT) and mutant (MT) lung cancer cells, a simultaneous quantitative method for analyzing seven HPB metabolites was developed using ultra-high-performance liquid chromatography-tandem mass spectrometry. A simple method without complicated preparation steps, such as derivatization or isotope labeling, was optimized for the simultaneous analysis of highly hydrophilic HBP metabolites, and the developed method was successfully verified. The intra- and inter-day coefficients of variation were less than 15% for all HBP metabolites, and the recovery was 89.67-114.5%. All results of the validation list were in accordance with ICM M10 guidelines. Through this method, HBP metabolites in lung cancer cells were accurately quantified, and it was confirmed that all HBP metabolites were upregulated in KRAS MT cells compared with KRAS WT lung cancer cells. We expect that this will be a useful tool for metabolic research on cancer and for the development of new drugs for cancer treatment.

Objective structured clinical examination as a competency assessment tool of students' readiness for advanced pharmacy practice experiences in South Korea: a pilot study.

BACKGROUND: The assessment of pharmacy students' readiness to begin the education of an advanced pharmacy practice experience (APPE) in clinical pharmacy settings continues to gain increasing attention. This study aimed to develop an objective structured clinical examination (OSCE) in the core domains acquired through an introductory pharmacy practice experience (IPPE), for evaluating its appropriateness as a tool of assessing clinical pharmacist competency for APPEs in Korean pharmacy students throughout a pilot study. METHODS: OSCE's core competency domains and case scenarios were developed through a literature review, ideation by researchers, and external experts' consensus by a Delphi method. A prospective single-arm pilot test was conducted to implement the OSCE for Korean pharmacy students who completed a 60-h course of in-class simulation IPPE. Their competencies were assessed by four assessors in each OSCE station with a pass-fail grading system accompanied by a scoring rubric. RESULTS: OSCE competency areas including patient counseling, provision of drug information, over-the-counter (OTC) counseling, and pharmaceutical care services were developed with four interactive and one non-interactive cases. Twenty pharmacy students participated in the OSCE pilot test, and their competencies were evaluated by 20 assessors. The performance rate was the lowest in the area of patient counseling for a respiratory inhaler (32.1%) and the highest (79.7%) in OTC counseling for constipation. The students had an average performance rate of 60.4% in their communication skills. Most participants agreed on the appropriateness, necessity, and effectiveness of the OSCE in evaluating pharmacy students' clinical performance and communication skills. CONCLUSIONS: The OSCE model can be used to assess pharmacy students' readiness for off-campus clinical pharmacy practice experience. Our pilot study suggests the necessity of conducting an OSCE domain-based adjustment of difficulty levels, and strengthening simulation-based IPPE education.

Novel innovative computer-based test (Inno-CBT) item types for national licensing examinations for health care professionals.

BACKGROUND: An effective test mechanism to evaluate clinical knowledge and skills of the entry-level healthcare professionals is important for providing clinical competency and improving patient care. This study aimed to develop novel, innovative computer-based test (Inno-CBT) item types for application in the national examination of Korean healthcare professionals. METHODS: This exploratory study was conducted from May 2021 to March 2022 by a team of faculty members from pharmacy schools in South Korea. A literature search using PubMed, Google Scholar, RISS, Web of Science, and KoreaMed was performed. Forum presentations, media articles, and previous reports by the Korea Health Personnel Licensing Examination Institute (KHPLEI) were included. Workshops were held, information and ideas were collected and conceptualized, and item types were designed, drafted, and refined. By repeating this process, the Inno-CBT item types were finalized. RESULTS: Forty-one Inno-CBT item types with 28 subtypes were developed. New digital technologies, such as a reactive responsive media interface, an animation insertion, multimedia embedding, and network surfing, were utilized in these novel types. It was anticipated that these Inno-CBT item types would effectively measure abilities in healthcare knowledge, problem-solving skills, and professional behaviors. Some potential barriers to implementing the Inno-CBT item types include item difficulty, operational unfamiliarity, complexity in scoring protocols, and network security. CONCLUSIONS: A variety of styles of novel Inno-CBT item types were developed to evaluate the multifaceted and in-depth professional abilities required for healthcare professionals. Prior to implementing these item types in the national examination, item validation and technical support should be conducted.

A Pharmacokinetic Study of Ephedrine and Pseudoephedrine after Oral Administration of Ojeok-San by Validated LC-MS/MS Method in Human Plasma.

A sensitive and reproducible liquid chromatography-tandem mass spectrometry (LC-MS/MS) system was developed and fully validated for the simultaneous determination of ephedrine and pseudoephedrine in human plasma after oral administration of the herbal prescription Ojeok-san (OJS); 2-phenylethylamine was used as the internal standard (IS). Both compounds presented a linear calibration curve (r2 ≥ 0.99) over a concentration range of 0.2-50 ng/mL. The developed method was fully validated in terms of selectivity, lower limit of quantitation, precision, accuracy, recovery, matrix effect, and stability, according to the regulatory guidelines from the U.S. Food and Drug Administration and the Korea Ministry of Food and Drug Safety. This validated method was successfully applied for the pharmacokinetic assessment of ephedrine and pseudoephedrine in 20 healthy Korean volunteers administered OJS.

Quantitation of plasma and biliary cefpiramide concentrations in human samples using high-performance liquid chromatography.

Cefpiramide is frequently used to treat biliary infections. However, no bioanalytical method has been validated to quantitate cefpiramide in human samples, particularly in bile. Therefore, this study was conducted to develop a simple, selective and validated high-performance liquid chromatographic method to determine cefpiramide in human plasma and bile. A protein precipitation procedure was used to extract cefpiramide and cefoperazone (internal standard, IS) from 200 µl of plasma and bile. Utilizing a Capcell Pak C18 column (4.6 × 250 mm), cefpiramide and IS were separated using the timed-gradient mobile phase consisting of 0.1 m sodium acetate (pH 5.2) and acetonitrile at a flow rate of 1 ml/min with photodiode array detector (wavelength set at 273 nm). The calibration curves showed linearity at concentrations ranging from 1 to 150 µg/ml in both plasma and bile (r2 > 0.999). The within- and between-run coefficients of variation (CVs) for plasma samples were 0.570-4.43 and 1.10-2.76%, respectively; for bile samples, the within- and between-day precision (CV) was 0.814-6.34 and 2.05-4.00%, respectively. Our newly developed bioanalytical method was successfully employed to quantify cefpiramide concentrations in both plasma and bile at multiple time points in patients with acute cholangitis.

Development and Validation of an LC-MS/MS Assay to Quantitate 2',4',6'-Trihydroxyacetophenone in Rat and Dog Plasma and its Application to a Pharmacokinetic Study.

In the present study, a simple, rapid, and reliable bioanalytical method was developed using liquid chromatography with tandem-mass spectrometry (LC-MS/MS) to quantify 2',4',6'-trihydroxyacetophenone (THAP) in rat and dog plasma with 2',4',6'-trihydroxybenzaldehyde as an internal standard (IS). The LC-MS/MS instrument was operated in the multiple reaction monitoring (MRM) mode to detect THAP at m/z transition 166.89 > 82.8 and IS at 152.89 > 82.8, respectively. A simple, one-step protein precipitation (PP) method was employed with acetonitrile for sample preparation. Utilizing a Gemini C18 column, THAP and IS were separated with an isocratic mobile phase consisting of 10 mM ammonium acetate and methanol (10:90, v/v) at a flow rate of 0.2 mL/min. Total chromatographic run time was 2.5 min per sample injection. The standard calibration curve for THAP was linear (r2 ≥ 0.9987) over the concentration range of 0.1 to 100 µg/mL with the lower limit of quantitation (LLOQ) of 0.1 µg/mL (S/N ratio > 10). According to the regulatory guidelines from the U.S. Food and Drug Administration (FDA) and the Korea Ministry of Food and Drug Safety (MFDS), our newly developed biomedical analytical method was fully and adequately validated in terms of selectivity, sensitivity, linearity, intra- and inter-day precision and accuracy, recovery, matrix effect, stability, and dilution integrity. Our validated assay was successfully utilized in a nonclinical pharmacokinetic study of THAP in rats and dogs.

Pharmacokinetics and bioequivalence of two fenofibrate choline formulations in healthy subjects under fed and fasted condition
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OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and bioequivalence of two formulations (the original capsule ("reference") and the new tablet ("test") formulations) of 135-mg choline fenofibrate under fed and fasted conditions. MATERIALS AND METHODS: This was an open-label, randomized, single-dose, crossover bioequivalence study in healthy Korean males. A total of 40 individuals were separately enrolled in the high-fat fed and the fasting study, respectively, and were randomized in a 1:1 ratio into two sequences. Serial blood samples were collected over 72 hours after drug administration. Plasma concentrations of fenofibric acid were determined by a validated LC-MS/MS method. Pharmacokinetic (PK) parameters were estimated using noncompartmental methods. RESULTS: Overall, 37 and 35 individuals completed the fed and the fasting study, respectively, as planned. The estimated Cmax, AUC0-∞, and AUC0-last were comparable between the test and the reference formulations in both fed and fasting studies (p > 0.05). The 90% confidence intervals for the geometric mean ratios of Cmax, AUC0-∞, and AUC0-last were 0.92 - 1.06, 0.95 - 1.01, and 0.95 - 1.01 in the fed study; and 0.94 - 1.12, 0.94 - 1.00, and 0.94 - 1.00 in the fasting study, respectively. For both formulations, tmax was significantly prolonged under fed condition compared to fasting condition (p < 0.0001); all other PK parameters were comparable between the fed and the fasting studies (p > 0.05). CONCLUSION: The reference and the test formulations of 135 mg choline fenofibrate show comparable pharmacokinetic profiles of fenofibric acid under both fed and fasted conditions and are considered bioequivalent.
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Population Pharmacokinetics and Pharmacodynamics of Doripenem in Obese, Hospitalized Patients.

BACKGROUND: Doripenem population pharmacokinetics and dosing recommendations are limited in obesity. OBJECTIVE: To evaluate the population pharmacokinetics and pharmacodynamics of doripenem in obese patients. METHODS: Hospitalized adults with a body mass index (BMI) ≥ 40 kg/m2 or total body weight (TBW) ≥45.5 kg over their ideal body weight received doripenem 500 mg every 8 hours, infused over 1 hour. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed for 5 intermittent and prolonged infusion dosing regimens to calculate probability of target attainment (PTA) at 40% and 100% fT>MIC (free drug concentrations above the minimum inhibitory concentration). RESULTS: A total of 20 patients were studied: 10 in an intensive care unit (ICU) and 10 in a non-ICU. A 2-compartment model with first-order elimination best described the serum concentration-time data. Doripenem clearance (CL) was significantly associated with creatinine CL (CRCL), volume of the central compartment with TBW and ICU residence, and volume of the peripheral compartment with TBW ( P < 0.05). Using 40% fT>MIC, PTA was >90% for all simulated dosing regimens at MICs ≤2 mg/L. Using 100% fT>MIC, prolonged infusions of 1 g every 6 hours and 2 g every 8 hours achieved >90% PTA at MICs ≤2 mg/L. CONCLUSIONS: CRCL, ICU residence, and TBW are significantly associated with doripenem pharmacokinetics. Currently approved dosing regimens provide adequate pharmacodynamic exposures at 40% fT>MIC for susceptible bacteria in obese patients. However, prolonged infusions of larger doses are needed if a higher pharmacodynamic target is desired.

Antimicrobials for the treatment of drug-resistant Acinetobacter baumannii pneumonia in critically ill patients: a systemic review and Bayesian network meta-analysis.

BACKGROUND: An optimal therapy for the treatment of pneumonia caused by drug-resistant Acinetobacter baumannii remains unclear. This study aims to compare various antimicrobial strategies and to determine the most effective therapy for pneumonia using a network meta-analysis. METHODS: Systematic search and quality assessment were performed to select eligible studies reporting one of the following outcomes: all-cause mortality, clinical cure, and microbiological eradication. The primary outcome was all-cause mortality. A network meta-analysis was conducted with a Bayesian approach. Antimicrobial treatments were ranked based on surface under the cumulative ranking curve (SUCRA) value along with estimated median outcome rate and corresponding 95% credible intervals (CrIs). Two treatments were considered significantly different if a posterior probability of superiority (P) was greater than 97.5%. RESULTS: Twenty-three studies evaluating 15 antimicrobial treatments were included. Intravenous colistin monotherapy (IV COL) was selected as a common comparator, serving as a bridge for developing the network. Five treatments ranked higher than IV COL (SUCRA, 57.1%; median all-cause mortality 0.45, 95% CrI 0.41-0.48) for reducing all-cause mortality: sulbactam monotherapy (SUL, 100.0%; 0.18, 0.04-0.42), high-dose SUL (HD SUL, 85.7%; 0.31, 0.07-0.71), fosfomycin plus IV COL (FOS + IV COL, 78.6%; 0.34, 0.19-0.54), inhaled COL plus IV COL (IH COL + IV COL, 71.4%; 0.39, 0.32-0.46), and high-dose tigecycline (HD TIG, 71.4%; 0.39, 0.16-0.67). Those five treatments also ranked higher than IV COL (SUCRA, 45.5%) for improving clinical cure (72.7%, 72.7%, 63.6%, 81.8%, and 90.9%, respectively). Among the five treatments, SUL (P = 98.1%) and IH COL + IV COL (P = 99.9%) were significantly superior to IV COL for patient survival and clinical cure, respectively. In terms of microbiological eradication, FOS + IV COL (P = 99.8%) and SUL (P = 98.9%) were significantly superior to IV COL. CONCLUSIONS: This Bayesian network meta-analysis demonstrated the comparative effectiveness of fifteen antimicrobial treatments for drug-resistant A. baumannii pneumonia in critically ill patients. For survival benefit, SUL appears to be the best treatment followed by HD SUL, FOS + IV COL, IH COL + IV COL, HD TIG, and IV COL therapy, in numerical order.

Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children.

The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m(2), respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.

6'-O-Caffeoyldihydrosyringin isolated from Aster glehni suppresses lipopolysaccharide-induced iNOS, COX-2, TNF-α, IL-1ß and IL-6 expression via NF-κB and AP-1 inactivation in RAW 264.7 macrophages.

Previously, we found that ethyl acetate extract fraction of Aster glehni exhibited anti-hyperuricemic effects in animal models and also five new caffeoylglucoside derivatives were isolated from this fraction. In this work, we evaluated the anti-inflammatory effects of these caffeoylglucoside derivatives and found that 6'-O-caffeoyldihydrosyringin (2, CDS) most potently inhibited the LPS-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7 macrophages. In addition, CDS was found to concentration-dependently reduce the production of NO, PGE2, and the pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) induced by LPS in macrophages. Consistent with these observations, CDS concentration-dependently inhibited LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxidase-2 (COX-2) expression at the protein level and also iNOS, COX-2, TNF-α, and IL-6, IL-1ß expression at the mRNA level. Furthermore, CDS suppressed the LPS-induced transcriptional activities of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) as well as the phosphorylation of p65 and c-Fos. Taken together, these results suggest that the anti-inflammatory effect of CDS is associated with the downregulation of iNOS, COX-2, TNF-α, IL-1ß, and IL-6 expression via the negative regulation of NF-κB and AP-1 activation in LPS-induced RAW 264.7 macrophages.

Comparative Physicochemical and Pharmacokinetic Properties of Quetiapine and Its Active Metabolite Norquetiapine.

Quetiapine (QTP) is an atypical antipsychotic drug commonly used to treat several psychiatric disorders and is metabolized into the active metabolite norquetiapine (NQTP). This study was designed to evaluate and compare the physicochemical properties, metabolic stability, brain distribution, and pharmacokinetics of QTP and NQTP. Compared to QTP, NQTP had a higher pKa, solubility, and rat liver microsomal stability, optimal log D and similar log P values. For pharmacokinetic evaluation, QTP and NQTP were administered orally and intravenously to rats at various doses. The plasma QTP and NQTP concentrations in rats were determined by a fully-validated liquid-chromatography tandem mass spectrometry (LC-MS/MS). Over the investigated dosing range, both QTP and NQTP showed linear pharmacokinetics. Following oral administration of the same dose, the area under the concentration-time curve (AUC0-∞) and maximum serum concentration (Cmax) were larger after NQTP administration compared to QTP administration. In addition, NQTP had a greater absolute oral bioavailability compared to QTP (15.6% vs. 0.63%, respectively). The brain-to-plasma concentration ratio was greater after NQTP administration compared to the QTP and NQTP ratios after QTP administration. NQTP administration results in increased systemic exposure and brain distribution compared to QTP administration. Future studies are needed to evaluate the pharmacologic and toxicologic effects of increased NQTP exposures.

Comparative pharmacokinetics and pharmacodynamics of doripenem and meropenem in obese patients.

BACKGROUND: Antimicrobial pharmacokinetic and pharmacodynamic data are limited in obesity. OBJECTIVE: To evaluate the steady-state pharmacokinetics and pharmacodynamics of doripenem and meropenem in obese patients hospitalized on a general ward. METHODS: Patients with a body mass index (BMI) ≥40 kg/m² or total body weight (TBW) ≥100 pounds over their ideal body weight randomly received doripenem 500 mg (1-hour infusion) or meropenem 1 g (0.5-hour infusion) every 8 hours. Differences in pharmacokinetic parameters were determined by unpaired t test. Monte Carlo simulations were performed for 500 mg and 1 g every 8 hours, infused over 1 and 4 hours for doripenem and 0.5 and 3 hours for meropenem. Probability of target attainment (PTA) was calculated using a pharmacodynamic target of 40% fT > MIC (free drug concentrations above the minimum inhibitory concentration [MIC]), and cumulative fraction of response (CFR) was calculated using MIC data for 8 Gram-negative pathogens. RESULTS: Twenty patients were studied. Volume of distribution at steady state, corrected for TBW, was significantly larger (0.18 ± 0.04 vs 0.13 ± 0.05 L/kg, P = .048) and systemic clearance was significantly faster for doripenem (11.7 ± 4.1 vs 8.1 ± 2.6 L/h, P = .03). PTA was >90% for all regimens at MICs ≤2 µg/mL. CFR was >90% for all regimens against 6 enteric Gram-negative pathogens and for 3 of 4 regimens for each drug against Pseudomonas aeruginosa. CONCLUSIONS: Doripenem and meropenem pharmacokinetics differ in obesity. However, currently approved dosing regimens provide adequate pharmacodynamic exposures for susceptible bacteria in obese patients.

Development and Validation of an Improved HPLC-MS/MS Method for Quantifying Total and Unbound Lenalidomide in Human Plasma.

BACKGROUND/OBJECTIVES: This study aimed to develop a fully validated HPLC-MS/MS method for quantifying total and unbound lenalidomide concentrations in human plasma. METHODS: Unbound concentrations were measured using plasma ultrafiltrate prepared with Amicon® Centrifugal Filters. Lenalidomide and lenalidomide-d5 (internal standard) were extracted from 50 µL of human plasma using liquid-liquid extraction. Chromatography was conducted with a Halo® C18 column using 0.1% formic acid and methanol (20:80, v/v) as the mobile phase. The mass spectrometer was operated in a positive ion mode with an electrospray ionization interface and multiple reaction monitoring modes. RESULTS: Calibration curves were linear over the range of 5 to 1000 ng/mL (r2 > 0.996) for both the total and unbound lenalidomide. For total lenalidomide concentrations, between-run precision (coefficients of variation) and accuracy were 1.70-7.65% and 94.45-101.10%, respectively. For unbound concentrations, inter-day precision and accuracy were 1.98-10.55% and 93.95-98.48%, respectively. CONCLUSIONS: We developed a highly reproducible, sensitive, and efficient bioanalytical method using a smaller volume of plasma sample (50 µL) with a relatively short run time (2.5 min). The proposed analytical method was successfully applied to measure total and unbound lenalidomide concentrations at various time points in multiple myeloma patients with renal impairment.

Trends in Antidiabetic Drug Use and Safety of Metformin in Diabetic Patients with Varying Degrees of Chronic Kidney Disease from 2010 to 2021 in Korea: Retrospective Cohort Study Using the Common Data Model.

BACKGROUND/OBJECTIVES: This study aimed to investigate trends in antidiabetic drug use and assess the risk of metformin-associated lactic acidosis (MALA) in patients with chronic kidney disease (CKD). METHODS: A retrospective observational analysis based on the common data model was conducted using electronic medical records from 2010 to 2021. The patients included were aged ≥18, diagnosed with CKD and type 2 diabetes, and had received antidiabetic medications for ≥30 days. MALA was defined as pH ≤ 7.35 and arterial lactate ≥4 mmol/L. RESULTS: A total of 8318 patients were included, with 6185 in CKD stages 1-2 and 2133 in stages 3a-5. Metformin monotherapy was the most prescribed regimen, except in stage 5 CKD. As CKD progressed, metformin use significantly declined; insulin and meglitinides were most frequently prescribed in end-stage renal disease. Over the study period, the use of SGLT2 inhibitors (13.3%) and DPP-4 inhibitors (24.5%) increased significantly, while sulfonylurea use decreased (p < 0.05). Metformin use remained stable in earlier CKD stages but significantly decreased in stage 3b or worse. The incidence rate (IR) of MALA was 1.22 per 1000 patient-years, with a significantly increased IR in stage 4 or worse CKD (p < 0.001). CONCLUSIONS: Metformin was the most prescribed antidiabetic drug in CKD patients in Korea with a low risk of MALA. Antidiabetic drug use patterns varied across CKD stages, with a notable decline in metformin use in advanced CKD and a rise in SGLT2 inhibitor prescriptions, underscoring the need for further optimized therapy.

A Validated Chiral LC-MS/MS Method for the Enantioselective Determination of (S)-(+)- and (R)-(-)-Ibuprofen in Dog Plasma: Its Application to a Pharmacokinetic Study.

The purpose of this study was to develop a method for simultaneously separating ibuprofen enantiomers using electrospray ionization (ESI) liquid chromatography with tandem mass spectrometry (LC-MS/MS). LC-MS/MS was operated with negative ionization and multiple reaction monitoring modes; transitions were monitored at m/z of 205.1 > 160.9 for ibuprofen enantiomers, 208.1 > 163.9 for (S)-(+)-ibuprofen-d3 [internal standard 1 (IS1)], and 253.1 > 208.9 for (S)-(+)-ketoprofen (IS2), respectively. In a one-step liquid-liquid extraction, 10 µL plasma was extracted with ethyl acetate:methyl tertiary-butyl ether of 7:3. Enantiomer chromatographic separation was carried out with an isocratic mobile phase consisting of 0.008% formic acid in water-methanol (v/v) at a flow rate of 0.4 mL/min on a CHIRALCEL® OJ-3R column (150 × 4.6 mm, 3 µm). This method was fully validated for each enantiomer and results were in compliance with the regulatory guidelines of the U.S. Food and Drug Administration and the Korea Ministry of Food and Drug Safety. The validated assay was executed for nonclinical pharmacokinetic studies after oral and intravenous administration of racemic ibuprofen and dexibuprofen in beagle dogs.

Population pharmacokinetics and pharmacodynamics of cefazolin using total and unbound serum concentrations in patients with high body weight.

The objective of this study was to evaluate the steady state pharmacokinetics and pharmacodynamics of cefazolin in patients with a high body weight. Cefazolin was administered by 0.5-h infusions to 11 patients with total body weight (TBW) ≥120 kg receiving 3 g q8h, and 12 patients with TBW <120 kg receiving 2 g q8h. Total and unbound serum concentration-time data obtained from serial blood samples were analysed simultaneously by population pharmacokinetic modelling using NONMEM. Probability of target attainment (PTA) was calculated for various dosing regimens through Monte Carlo simulations based on the cumulative percentage of the dosing interval that the unbound concentration exceeds the minimum inhibitory concentration (MIC) value for the pathogen at steady state (fTMIC) ≥40%, ≥60% and 100%. A two-compartment model with non-linear protein binding and allometric scaling of the central volume of distribution using TBW best characterized both total and unbound concentration-time data. Unbound clearance was significantly associated with creatinine clearance, and maximum protein binding constant was significantly associated with serum albumin concentration and body mass index (P <0.05). Based on unbound concentration-time profiles, all simulated regimens achieved PTA >90% at MIC values ≤2 mg/L using fTMIC ≥40%, at MIC values ≤1 mg/L using fTMIC ≥60%, and at MIC values ≤0.5 mg/L using fTMIC of 100%. At fTMIC ≥60%, 0.5-h infusion of cefazolin 1 g q8h achieved PTA <90% at MIC values ≥2 mg/L in patients with TBW≥120 kg; however, prolonged-infusion and higher-dose regimens improved PTA to >90%. Overall, cefazolin pharmacokinetics are altered considerably in obese patients. Higher-dose and/or prolonged-infusion cefazolin regimens should be considered in patients with TBW ≥120 kg, particularly those with less-susceptible Gram-negative infections.

Population pharmacokinetics and model-based dosing optimization of teicoplanin in elderly critically ill patients with pneumonia.

PURPOSE: To evaluate the population pharmacokinetics and pharmacodynamics of teicoplanin in elderly critically ill patients with pneumonia for optimal dosages. METHODS: Fifteen critically ill patients (9 men) ≥ 60 years received teicoplanin 6 mg/kg for three doses followed by standard maintenance doses (6 mg/kg q24h) with renal dosing adjustment. Serial plasma samples from all patients were analyzed simultaneously by population pharmacokinetic modeling using NONMEM. Probability of target attainment (PTA) was calculated through Monte Carlo simulations for various dosing regimens to achieve adequate systemic exposures. RESULTS: The median (interquartile range, IQR) age, body mass index, and creatinine clearance (CrCl) was 75 (64-78) years, 22.5 (20.8-25.4) kg/m2, and 64 (47-106) mL/min, respectively. The median (IQR) peak and trough concentration was 46.5 (42.7-51.0) and 8.7 (7.2-9.5) mg/L. The population pharmacokinetic model showed slower clearance (CL) and larger peripheral volume of distribution (V2) in patients with reduced CrCl: CL (L/h) = 0.629 × (CrCl/64)0.656, V2 (L) = 55.7 × (CrCl/64)-0.665. Model-based simulations showed PTAs ≥85% only for higher-dose regimens (12 mg/kg) up to an MIC of 0.5 mg/L. CONCLUSIONS: Standard teicoplanin dosages for pneumonia may provide inadequate systemic exposures in elderly critically ill patients. High-dose regimens should be considered as empiric therapy or for less susceptible pathogens.

Effects of Early Initiation of High-Dose Dexamethasone Therapy on Pro-Inflammatory Cytokines and Mortality in LPS-Challenged Mice.

This study aims to explore the effects of early dexamethasone therapy at low to high doses on the survival and inflammatory responses in lipopolysaccharide (LPS)-challenged mice. We performed two-series experiments to explore the impact of early dexamethasone therapy at different doses (0.5 mg/kg, 1.5 mg/kg, and 5 mg/kg; PO) on pro-inflammatory cytokine levels, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), as well as survival in LPS-treated mice (10 mg/kg, IP). Dexamethasone was administered daily from 24 h before and 5 days after LPS challenge. Dose-dependent improved survival was demonstrated with dexamethasone (p < 0.05). Body weight was significantly decreased within 24 h of LPS injection, with significantly greater weight loss in the dexamethasone groups (p < 0.05). Weight changes were significantly associated with the days after LPS administration (p < 0.01), but not with the dexamethasone dose (p > 0.05). Mice treated with high-dose dexamethasone (5 mg/kg) had a significantly lowered serum TNF-α (134.41 ± 15.83 vs. 408.83 ± 18.32) and IL-6 (22.08 ± 4.34 vs. 91.27 ± 8.56) compared with those without dexamethasone. This study provides essential insights that the suppression of early-phase hyperactivation of pro-inflammatory activities through the early initiation of high-dose dexamethasone therapy increases sepsis-related prognosis.

Characterization of Medication Errors in a Medical Intensive Care Unit of a University Teaching Hospital in South Korea.

OBJECTIVES: The objective of this study was to characterize the current status of medication errors (MEs) throughout the medication therapy process from prescribing to use and monitoring in a medical intensive care unit (MICU) in Korea. METHODS: Four trained research pharmacists collected data through retrospectively reviewing electronic medical records for adults hospitalized in the MICU in 2017. The occurrence of MEs was determined through interprofessional team discussion led by an academic faculty pharmacist and a medical intensivist based on the medication administration records (MARs). The type of MEs and the consequent ME-related outcome severity were categorized according to the Pharmaceutical Care Network Europe and the National Coordinating Council for Medication Error Reporting and Prevention, respectively. RESULTS: Overall, electronic medical records for 293 patients with 78,761 MARs were reviewed in this study. At least one type of ME occurred in 271 patients (92.5%) in association with 16,203 MARs (21%), primarily caused by inappropriate dose (35.5%), drug (27.8%), and treatment duration (25.1%). Clinically significant harmful events occurred in 24 patients (8%), including life-threatening (n = 5) and death (n = 2) cases. The 2 patients died of enoxaparin-induced fatal hemorrhage and neutropenia associated with ganciclovir and cefepime. Antibiotics were the most common culprit medications leading to clinically significant harmful events. CONCLUSIONS: In conclusion, MEs are prevalent in the MICU in Korea, most commonly prescribing errors. Although mostly benign, harmful events including deaths may occur due to MEs, mainly associated with antibiotics. Systematic strategies to minimize these potentially fatal MEs are urgently needed.