Pharmacokinetic Calculations Research Articles

P-809. Evaluating the Usage, Safety, and Accuracy of Vancomycin Dosing Practices at VA Eastern Colorado Health Care System (VA ECHCS)

Abstract Background Vancomycin is a glycopeptide antibiotic used as a mainstay of therapy for gram positive bacterial infections, including MRSA (methicillin-resistant staphylococcus aureus). Vancomycin requires pharmacokinetic calculations to determine dosing and close therapeutic drug monitoring to achieve goal trough between 15-20 mg/L (AUC/MIC goal between 400-600 mg ■h/L) and prevent nephrotoxicity. The purpose of this study is to assess our current vancomycin usage patterns, including empiric dosing accuracy & safety outcomes to help inform a decision whether a change to our current practice is indicated. Methods This retrospective, observational cohort study evaluated 117 vancomycin trough levels from 63 patients who received at least two doses of vancomycin between August 1, 2022 and July 31, 2023. Patients were excluded if they received hemodialysis or were dosed by random levels in the setting of severe renal dysfunction. Collected demographics included age, sex, weight, height, BMI, indication for vancomycin, dosing, trough levels, source of infection, MRSA nares, concomitant nephrotoxic medications, spinal cord injury diagnosis, serum creatinine, and cystatin C. Estimated AUC was calculated using VancoPK.com based on the reported trough using patient specific pharmacokinetic parameters. This study is exempt from IRB approval. Results A total of 58 trough levels from 49 patients were included. The majority of patients were male (87.7%) with an average age 61±13 years old. Out of the 58 trough levels evaluated, 20 (41%) were at goal. Of the levels not a goal 27 (71%) were subtherapeutic, and 11 (29%) were supratherapeutic. The estimated AUC was at goal for 35 (60%) of the 58 total troughs. Of the 27 patients who had a subtherapeutic trough 21 (77%) had an AUC at goal, and 14 of them increased the dose despite having a therapeutic AUC. Only 1 patient (2%) developed possible vancomycin associated AKI (acute kidney injury). Conclusion A higher number of patients were within therapeutic range when evaluating AUC compared to trough. The low incidence of vancomycin associated AKI was likely due to low frequency of supratherapeutic troughs in this study. Further analysis of these results will be used to identify opportunities for education and improvement of our current vancomycin dosing process. Disclosures All Authors: No reported disclosures

Enhancing Therapeutic Drug Monitoring in Indonesia: An Android-Based Pharmacokinetic Calculator for Amikacin

Pharmacokinetics employs complex mathematics to study, model, and predict how drugs are absorbed, distributed, metabolized, and excreted by the body. Amikacin, as a model drug with a narrow therapeutic window, requires Therapeutic Drug Monitoring (TDM) to ensure safety. This study developed an Android-based pharmacokinetic calculator, the "Indonesia Pharmacokinetic Calculator" (KFI), to assist clinical practitioners in quickly and accurately calculating pharmacokinetic parameters using patient weight and Amikacin doses as inputs. The application is designed to provide calculations of pharmacokinetic parameters, a pharmacokinetic simulation graph (plasma concentration-time curve), and predictions of individual patient amikacin plasma concentrations to assess therapeutic effectiveness and minimize toxicity risks. The rigorous testing process has demonstrated that KFI reliably produces expected output data, enhancing clinical pharmacy services in Indonesia through the integration of cutting-edge technology. This tool is expected to improve therapeutic outcomes, particularly for sepsis patients, by facilitating accurate and efficient pharmacokinetic calculations.

Docking Study on Caspase 3 Inhibitors As Potential Drugs For Traumatic Brain Cell Apoptosis

Background: Apoptosis of brain cells (neurons and glia) has a crucial role in humans' pathology of traumatic brain injury (TBI). So, a decrease in the apoptosis rate can potentially reduce the harmful effects and lead to better functional outcomes. Drug repurposing by computational methodologies like protein-ligand docking allows us to make drug discovery more efficient and less expensive. Objective: In the current study, we used the methodology to study the inhibitory effect of thousands of FDA/non-FDA approved, investigational compounds on caspase 3 as one of the most important members of the cell apoptosis pathway. Methods: Molecular docking and pharmacokinetic properties calculations were done. The molecular dynamics (MD) simulations of all complexes and free caspase 3 were carried out. We carried out docking experiments using in silico methods and docked a pool of medications to the active site of the human caspase-3 X-ray structure. The best compounds were selected and subjected to pharmacokinetic analysis, molecular simulation, and free energy calculations. Results: Finally, 6 components (Naldemedine, Celastrol, Nilotinib, Drospirenone, Lumacaftor, and R- 343) were selected as the best in terms of structural and pharmaceutical properties, low toxicity that can be administered orally for the preclinical and clinical future investigations.

975. Age and Body Mass Index Impact Optimal Vancomycin Model Selection for Bayesian Dosing: Results from a Large Multi-site Retrospective Study of Adult Patients

Abstract Background Vancomycin population pharmacokinetic (popPK) models embedded in Bayesian software are crucial to informing optimal initial dosing. Since pharmacokinetics (PK) vary based on patients’ age and body mass index (BMI), pharmacists are faced to select the best model amongst many for their patients. To aid in model selection, we used a large multi-site database to determine which models were the most accurate across age and BMI categories. Methods Data on adult patients receiving intravenous vancomycin therapy during January 1, 2022 - December 31, 2022, at healthcare organizations across the U.S. were queried from a Bayesian software database. Data collected included age, weight, height, serum creatinine, sex, vancomycin doses received, and vancomycin concentration levels. The a priori root mean square error (RMSE) for six well-performing and previously validated models was calculated for each patient to measure what the accuracy would have theoretically been if each were used. The average RMSE value per model was calculated and compared between age and BMI categories shown in Table 1. Each age-BMI combination’s most accurate model was reported. Results There were 79,600 patient treatment courses included across 84 health systems. The results for the most accurate model for each age-BMI combination are reported in Table 2. The lowest RMSE was 3.91 mg/L using the modified Goti model in patients > 80 years with BMI < 18.5 kg/m2. The highest RMSE was 7.86 mg/L using the Carreno model in patients < 35 years with BMI > 30 and < 35 kg/m2. A relationship was observed where older age categories lead to better model performance. Conclusion Age and BMI categories influenced which vancomycin popPK models performed best a priori within a Bayesian software when studied within a very robust dataset. These findings may help pharmacists choose which model to use for the most accurate PK calculations and thus inform optimal initial pop-PK vancomycin dosing. It also highlights that adults under 35 years, which tend to be underrepresented in model development populations, showed higher prediction error. Further research is needed on how to best implement these findings into practice. Disclosures Maria-Stephanie Hughes, PharmD, InsightRX: Stocks/Bonds Tiffany Lee, PharmD, InsightRX: Employment

Comparison of pharmacokinetic parameters calculation techniques in studies with animal-point design

In pharmacokinetics (PK) studies of medicinal products with small laboratory animals models, primarily rodents, the design of the animal-point experiment is often used, involves the selection of biological material after euthanasia of the animal. The question of experimental data processing and the PK parameters calculation method in a situation where all concentration values are obtained from different individuals is relevant.Purpose of the study. Comparison of pharmacokinetic parameters calculation methods in studies with the animal-point design.Materials and methods. For a number of previously conducted studies with male outbred rats test systems, a retrospective data analysis was performed and PK parameters were calculated in three different ways: from the average concentration values at each time point (method 1): from data obtained for animals with the same sequence numbers in subgroups corresponding to time points (method 2); using resempling based on modeling of individual PK profiles (method 3). Pharmacokinetic parameters (maximum concentration — Cmax, time to reach maximum concentration — Tmax, area under the curve "concentration-time" — AUC0-t, average time to stay in the body — MRT, half-life — T1/2) were calculated by non-compartment method of statistical moments using the validated PKSolver application for Microsoft Office Excel.Results. The comparison of the obtained results did not reveal any patterns and preferences for the use of a particular method of calculating PK parameters depending on the studied drugs, route and administration way. For all evaluated PK parameters (Cmax, Tmax, AUC0-t, MRT, T1/2), similar values and/or intervals were obtained, which indicated the correctness of all considered calculation methods.Conclusion. Based on advantages and disadvantages of the calculation methods comparison it is shown that it is optimal to use method 2, which is a special case of reception (method 3) with a minimum number of replications. It is important to emphasis the method of PK parameters calculation when describing the methodology of studies to improve their quality.

Oxycodone, Morphine, and Fentanyl in Patients With Chronic Pain: Proposal of Dose-Specific Concentration Ranges.

Interpreting opioid concentrations is challenging because of the lack of reference ranges. Therefore, the authors aimed to propose dose-specific concentration ranges in serum for oxycodone, morphine, and fentanyl in patients with chronic pain, based on concentration measurements from a large number of patients and supported by theoretical pharmacokinetic calculations and previously published concentrations. The opioid concentrations in patients undergoing therapeutic drug monitoring (TDM) for various indications (TDM group) and patients with cancer (cancer group) were investigated. Patients were divided based on the daily opioid doses, and the 10th and 90th percentiles of the concentrations in each dose interval were evaluated. In addition, the expected average serum concentrations were calculated for each dose interval based on published pharmacokinetic data, and a targeted literature search for previously reported dose-specific concentrations was performed. The opioid concentrations in 1054 patient samples were included: 1004 in the TDM group and 50 in the cancer group. In total, 607 oxycodone, 246 morphine, and 248 fentanyl samples were evaluated. The authors proposed dose-specific concentration ranges based mainly on 10th-90th percentiles of the concentrations measured in patient samples, whereas the calculated average concentrations and previously published concentrations were used to adjust the ranges. In general, results from calculations and concentrations retrieved from previous literature were within the 10th-90th percentiles of concentrations from patient samples. However, the lowest calculated average concentrations of fentanyl and morphine were below the 10th percentiles of patient samples in all dose groups. The proposed dose-specific ranges may be useful for interpreting steady-state opioid serum concentrations in clinical and forensic settings.

Review of Tobramycin Dosing in Pediatric Patients With Cystic Fibrosis.

An institution's tobramycin pharmacokinetics (PK) database was reviewed to evaluate the efficacy and safety of empiric tobramycin dosing and monitoring strategies used in pediatric patients with cystic fibrosis (CF). The relationship between patient age and tobramycin dosing needed to achieve the area under the curve (AUC) goal was investigated. Retrospective chart review was performed for patients who received tobramycin during a CF exacerbation from 2009 to 2019 who received PK monitoring by pediatric pharmacists. Tobramycin dosing needed to achieve an AUC of 100 mg·hr/L was calculated for each patient. Serum creatinine and concomitant nephrotoxin use were collected as surrogate nephrotoxicity endpoints to evaluate safety. Goal AUC (100 ± 15 mg·hr/L) was achieved based on initial or repeat PK calculations in 43.5% (95% CI, 37.7-49.3) of 85 unique patients across 326 encounters. Patients with calculated recommended doses of 9.5 to 11.9 mg/kg every 24 hours empirically achieved goal AUC in 77% (78/101) of encounters. The odds of achieving goal AUC were 56% higher for children aged 10 vs 5 years (OR = 1.56; 95% CI, 1.04-2.34; p = 0.033) and 32% higher for children aged 15 vs 10 years (OR = 1.32; 95% CI, 1.07-1.61; p = 0.008). Overall rates of acute kidney injury and concomitant nephrotoxin use were 10.8% (95% CI, 6.2-15.5) and 80.7% (95% CI, 74.3-87.1), respectively. Desired AUC was achieved by 43.5% of pediatric patients with CF using tobramycin 10 mg/kg every 24 hours. Older patient age was associated with higher initial AUC attainment and fewer dose modifications. Younger children may require higher weight-based dosing to meet AUC goals.

Efficient Antibacterial/Antifungal Activities: Synthesis, Molecular Docking, Molecular Dynamics, Pharmacokinetic, and Binding Free Energy of Galactopyranoside Derivatives.

The chemistry and biochemistry of carbohydrate esters are essential parts of biochemical and medicinal research. A group of methyl β-d-galactopyranoside (β-MGP, 1) derivatives was acylated with 3-bromobenzoyl chloride and 4-bromobenzoyl chloride in anhydrous N,N-dimethylformamide/triethylamine to obtain 6-O-substitution products, which were subsequently converted into 2,3,4-tri-O-acyl derivatives with different aliphatic and aromatic substituents. Spectroscopic and elemental data exploration of these derivatives confirmed their chemical structures. In vitro biological experiments against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) revealed ascending antifungal and antibacterial activities compared with their antiviral activities. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) experiments were performed for two derivatives, 3 and 9, based on their antibacterial activities. Most of these derivatives showed >780% inhibition of fungal mycelial growth. Density functional theory (DFT) was used to calculate the chemical descriptors and thermodynamic properties, whereas molecular docking was performed against antibacterial drug targets, including PDB: 4QDI, 5A5E, 7D27, 1ZJI, 3K8E, and 2MRW, and antifungal drug targets, such as PDB: 1EA1 and 1AI9, to identify potential drug candidates for microbial pathogens. A 100 ns molecular dynamics simulation study revealed stable conformation and binding patterns in a stimulating environment by their uniform RMSD, RMSF, SASA, H-bond, and RoG profiles. In silico pharmacokinetic and quantitative structure-activity relationship (QSAR) calculations (pIC50 values 3.67~8.15) suggested that all the designed β-MGP derivatives exhibited promising results due to their improved kinetic properties with low aquatic and non-aquatic toxicities. These biological, structure-activity relationship (SAR) [lauroyl-(CH3(CH2)10CO-) group was found to have potential], and in silico computational studies revealed that the newly synthesized MGP derivatives are potential antibacterial/antifungal candidates and can serve as therapeutic targets for human and plant pathogens.

Impact of Patient-Specific Aminoglycoside Monitoring for Treatment of Pediatric Cystic Fibrosis Pulmonary Exacerbations.

Aminoglycosides are frequently used for empiric and definitive treatment of cystic fibrosis (CF) pulmonary exacerbations. Various methods have been described for aminoglycoside therapeutic drug monitoring. The objective of this study is to evaluate the effect of patient-specific pharmacokinetic calculations for aminoglycosides used to treat CF pulmonary exacerbations. Ambidirectional cohort study of patients admitted to a children's hospital from June 1, 2018, through February 28, 2019, and June 1, 2019, through February 8, 2021. The primary outcome was the occurrence of dosing changes after analysis of initial serum concentrations in either group. Secondary outcomes included occurrence of nephrotoxicity, duration of antibiotics, and length of stay. Twenty-four patients (75%) in the intervention group versus zero in the control group required dosing adjustments after initial analysis of serum concentrations were completed (p < 0.001). There was not a statistically significant between-group difference for duration of antibiotics in days (median, 14 vs 13.5; Z, 1.07; p = 0.29) or length of stay (median, 11 vs 11; Z, -0.31; p = 0.76). There was also not a statistically significant between-group difference in forced expiratory volume in one second (FEV1) change from admission to discharge (11.4% vs 13.9%; t, 0.61; Degrees of Freedom, 39; p = 0.55). Two patients (6.25%) in the intervention group experienced nephrotoxicity compared with zero patients in the control group (risk difference, 6.25%; 95% CI, -2.14 to 14.64; number needed to harm, 16). Patient-specific pharmacokinetic monitoring led to significantly more dosing changes and was associated with similar patient outcomes as trough-only monitoring. Further studies are needed to identify methods to optimize aminoglycoside dosing and monitoring for these patients with the goal of reducing toxicities while maximizing efficacy.

Effects of excessive alcohol drinking on nicotine biotransformation in rats

Alcohol and nicotine (tobacco smoke) are often used together, and taking both addictive substances is associated with an increased risk of certain diseases. It is extremely important to understand the pharmacodynamic and pharmacokinetic mechanisms of the interaction between nicotine and ethanol, which are still not fully understood. The study aimed to evaluate the influence of chronic alcohol consumption on nicotine biotransformation in ethanol-preferring and non-preferring male and female rats. Rats were divided into four groups depending on their alcohol preferences and gender. Nicotine, nornicotine, nicotine N-oxide, cotinine, trans-3'-hydroxycotinine, and cotinine N-oxide in rats plasma were determined by LC–MS/MS after five days of exposure to tobacco smoke. A non-compartmental analysis of nicotine and its metabolites was used for pharmacokinetic parameters calculation. Our experimental results showed that the rate of nicotine elimination depends on gender, regardless of alcohol preferences (significantly slower in females than in males). Mean residence timeof nornicotine, cotinine, and trans-3'-hydroxycotinine were significantly higher in alcohol-preferring male rats than in alcohol preferring female rats. In non-alcohol preferring female rats compared to ethanol-preferring female rats, significantly more nicotine N-oxide (fivefold) and trans-3'-hydroxycotinine (twofold) reached the general circulation unchanged. Drinking ethanol influenced the elimination of nornicotine and cotinine in male rats. Ethanol consumption was identified as a modifier of nicotine pharmacokinetics and this was gender-dependent.

PB2325: APPLICATION AND COMPARISON OF TWO PHARMACOKINETIC DETECTION METHODS IN CHILDREN WITH HEMOPHILIA A—AN INSPECTION REPORT FROM SINGLE CENTER

Background: Personalized prophylaxies for moderate and severe hemophilia A and B are based on personal pharmacokenetics (PK), half-life(T1/2). While classical method for personal PK needs multiple blood collections, at least 5 points collections for children and 11points for adults, and expensive for testing and leads low compliance. Popular PK based on pupolar data can have a less blood collections but a rough data(range) is recommended for reference. One-chamber model may also have a less blood collection 2-3 collections for PK detection. Aims: Objective: To analyze and compare the half-life (T1/2) results of Factor VIII (FVIII) calculated by modified one-chamber model by “CAI’s” hemophilia pharmacokinetic calculation tool and WinNolin software (five-point sampling), non-av model, and to explore the reliability and clinical application value of “CAI’s” hemophilia pharmacokinetic calculation tool. Methods: A total of 30 patients with moderate and severe hemophilia A were treated with FVIII (50IU/Kg) after the 72-hour elution period. Peripheral blood samples were collected at five time points before and after FVIII injection (0h, 1h, 9h, 24h, 48h), and FVIII activity was detected by one-stage method. The T1/2 of FVIII was calculated by WinNolin software. Two of the three time points of FVIII activities (9h~24h, 9h~48h, 24h~48h) were used to calculate the FVIII T1/2 by “CAI’s” hemophilia A pharmacokinetic calculation tool, and the results were compared with those of WinNolin software, and the correlation analysis was conducted. Results: 1. 30 cases of T1/2 of FVIII calculated by WinNolin software was from 5.55 hs to 12.5 hs. 2. Compared with WinNolin software (five-point method, the results of T1/2 of FVIII caculated by “CAI’s” hemophilia A pharmacokinetic calculation tool, (the modified one-chamber model method) at 9h~24h, 9h~48h and 24h~48h showed that the detection periods with highist consistent T1/2 were 9h~48h, 24 out of 30, 80.0%, while 9h~24h 6 out of 30, 20.00%; 3. Correlation analysis shows that there is a good correlation between the T1/2 of the modified one-chamber model and the results of WinNolin’s calculation in all three time periods, but the correlation/consistency is the highest in the period of 9h~48h (see fig 1); 4. Analysis of the FVIII T1/2 results of 9h~24h, 9h~48h and 24h~48h we found that there were 8 out of 30 cases (26.67%) of T1/2 were basically stable at the same level, while 53.33% (16/30) of the children had significant changes at each time period. Image:Summary/Conclusion: 1. Compared with the T1/2 results by WinNolin’s method and modified ond-chambor modle (”CAI’s” tool), the most consistency of T1/2 of blood sampling was 9h~48h. However, for those T1/2 short than 7~8hs, the detection time should be adjusted (the later blood sample taking should be adjust to earlier); 2. Nearly 3/4 of the 30 cases, the T1/2 results fluctuated among three periods (9h~24h, 24h~48h, 9h~48h) in one case, suggesting a standardized test procedures such as specimen collection, sample transportation and detection ect needs to set up to ensure the stability and reliability of test results. 3. The classical pharmacokinetic test requires at least 5 points of blood sample collections, which is difficult to be popularized and applied in clinical practice. If a standardized and standardized testing process is established, the one-chamber model method is relatively simple and easy to be accepted and popularized by patients. Key words: hemophilia A, pharmacokinetics, children, one-chamber model, non-av-model

A review on advances in the development of electrochemical sensors for the detection of anesthetic drugs.

Surgeries are a crucial medical intervention that has saved countless lives from time immemorial. To reduce pain during surgeries patients are administered with anesthetic drugs, which cause loss of sensation and thus reduce the pain involved. However, anesthetists control the effects of the drug by depending on pharmacokinetic calculations, which may vary from patient to patient, thus leading to a reduction in the quality of anesthetic care and adverse effects. To avoid these adverse effects, it is highly necessary to implement a real time monitoring of plasma drug concentration, which will adjust the drug infusion and maintain the levels of drug within therapeutic levels. To implement such a system, it is highly essential to analyze current advances in electrochemical sensor systems for different types of anesthetic drugs like opioids, intravenous anesthetics, and neuromuscular blockers. This review focuses on the present strategy of electrochemical sensors implemented for the detection of anesthetic drugs and it helps towards developing a real time drug dispensing system with respect to the plasma concentration of the drug. This analysis will contribute towards establishing highly effective real time drug dispensing systems like the total intravenous anesthesia technique and patient-controlled analgesia. Such systems will lead to better usage of anesthetic drugs and improve the quality of anesthetic care thus making surgeries safer and more painless.

Synthesis, X-ray crystallographic analysis, DFT studies and biological evaluation of triazolopyrimidines and 2-anilinopyrimidines

Inspired by the reported antiviral activity of pyrimidines and triazolopyrimidines, two series of 2-anilinopyrimidines (5a-e) and 1-aryl-[1,2,4]triazolo[4,3-a]pyrimidines (14a-k) were designed and synthesized as potential antiviral agents. X-ray crystallographic study of compounds (14d) and (14k) confirmed the structure of the desired isomer and revealed the coplanarity of the fused [1,2,4]triazolo[4,3-a]pyrimidine rings with the aryl side group. DFT studies revealed insights into the mechanism of the micro-reversible cyclisation step using DFT [B3LYP-D3(BJ)/6–31++G(d,p)]. The pharmacokinetic properties and calculation of drug likeness scores (DLS) of (5a-e) and (14a-k) suggested good traditional drug-like properties and led to the synthesis of derivatives (14a-k) which were evaluated for their anti-viral activity with the most potent derivatives subjected to cytotoxicity screening. Compounds (14a), (14c), (14e), (14f) and (14k) showed moderate to strong antiviral activity with EC50 values 38 - 186 μM. Compound (14e) (DLS = 0.29) showed the best anti-CHIKV activity (EC50 = 38 μM) and lowest cytotoxicity (CC50 > 300 μg/ml) against breast cancer cell lines, MCF-7 and MD-AMB-231 and normal cell line EA.hy926. Simplification of [1,2,4]triazolo[4,3-a]pyrimidine ring, led to series (5a-e) (DLS = 0.03 - 0.77). Derivatives (5a-d) showed fair anti-CHIKV activity (EC50 > 200 μM), while (5e) emerged as the most active antiviral agent, however the most cytotoxic.

Predicting New Anti-Norovirus Inhibitor With the Help of Machine Learning Algorithms and Molecular Dynamics Simulation-Based Model.

Hepatitis C virus (HCV) inhibitors are essential in the treatment of human norovirus (HuNoV). This study aimed to map out HCV NS5B RNA-dependent RNA polymerase inhibitors that could potentially be responsible for the inhibitory activity of HuNoV RdRp. It is necessary to develop robust machine learning and in silico methods to predict HuNoV RdRp compounds. In this study, Naïve Bayesian and random forest models were built to categorize norovirus RdRp inhibitors from the non-inhibitors using their molecular descriptors and PubChem fingerprints. The best model observed had accuracy, specificity, and sensitivity values of 98.40%, 97.62%, and 97.62%, respectively. Meanwhile, an external test set was used to validate model performance before applicability to the screened HCV compounds database. As a result, 775 compounds were predicted as NoV RdRp inhibitors. The pharmacokinetics calculations were used to filter out the inhibitors that lack drug-likeness properties. Molecular docking and molecular dynamics simulation investigated the inhibitors’ binding modes and residues critical for the HuNoV RdRp receptor. The most active compound, CHEMBL167790, closely binds to the binding pocket of the RdRp enzyme and depicted stable binding with RMSD 0.8–3.2 Å, and the RMSF profile peak was between 1.0–4.0 Å, and the conformational fluctuations were at 450–460 residues. Moreover, the dynamic residue cross-correlation plot also showed the pairwise correlation between the binding residues 300–510 of the HuNoV RdRp receptor and CHEMBL167790. The principal component analysis depicted the enhanced movement of protein atoms. Moreover, additional residues such as Glu510 and Asn505 interacted with CHEMBL167790 via water bridge and established H-bond interactions after the simulation. http://zinc15.docking.org/substances/ZINC000013589565.

The pharmacokinetics of transdermal flunixin in lactating dairy goats

Flunixin is a nonsteroidal anti-inflammatory drug approved for use in cattle to manage pyrexia associated with bovine respiratory disease, mastitis, and endotoxemia. In the United States, no nonsteroidal anti-inflammatory drugs are approved for use in goats, but analgesics are needed for management of painful conditions to improve animal welfare. The objective of this study was to evaluate the pharmacokinetics of transdermal flunixin in dairy goats to determine a milk withdrawal interval (WDI) to avoid violative residue contamination in the food supply. Six adult lactating dairy goats received 3.3 mg/kg of transdermal flunixin before milk, interstitial fluid (ISF), and blood samples were collected at various time points for 360 h. The samples were analyzed using tandem mass spectrometry to detect flunixin as well as the flunixin marker metabolite, 5-hydroxyflunixin followed by a pharmacokinetic WDI calculation using the US Food and Drug Administration tolerance limit method to propose safe residue levels in goat milk. The mean flunixin apparent plasma half-life was 21.63 h. The apparent milk half-life for 5-hydroxyflunixin was 17.52 h. Our findings provide a milk WDI of 60 h using the US Food and Drug Administration tolerance of 0.002 µg/mL (established for bovine milk) and a more conservative WDI of 96 h using a limit of quantification of 0.001 µg/mL following the extralabel use of transdermal flunixin in dairy goats.

Feasibility, Tolerability, and Patient-Reported Outcomes with Pharmacokinetic (PK)-Directed Dosing of Evomela® (propylene glycol free melphalan) for Multiple Myeloma and AL Amyloidosis Patients Undergoing Autologous Hematopoietic Stem Cell Transplant (AHCT)

Background: For multiple myeloma (MM) and AL amyloidosis (AL) patients undergoing autologous hematopoietic stem cell transplant (AHCT), high-dose melphalan is given at a fixed dose based on body surface area with five-fold inter-patient variability in exposure, as measured by area under the curve (AUC). Patients with higher than the median AUC (12.85mg/L*h) have prolonged survival, but increased toxicity (Shaw et al., BBMT 2012). Pharmacokinetically (PK)-directed dosing has the potential to achieve an optimal concentration in each patient. We prospectively evaluated the feasibility of PK-directed dosing of propylene glycol free melphalan (Evomela®, PGF-MEL), a more stable and possibly less toxic intravenous formulation of melphalan, to personalize therapy for maximum efficacy and tolerability.Methods: MM and AL patients age 18-75 received a 10mg/m2 test dose of PGF-MEL within 14 days of AHCT. Serum samples were drawn at 5, 15, 30, 40, 75, and 150 min after PGF-MEL administration. Liquid chromatography tandem mass spectrometry was used to measure MEL concentrations. AUC PK modeling with Phoenix WinNonlin v6.4 was used to determine a target dose to achieve an AUC of 13.5mg/L*h (+/-1), which was given on day -2 prior to AHCT. PK samples were collected after the target dose at the same time points as after the test dose. AHCT with 3-10 x10^6 CD34+ cells/kg was conducted per institutional guidelines. Patient-reported symptom burden was collected prospectively using the MD Anderson Symptom Inventory - MM (MDASI-MM) on day +1, 6, 11, 30, 60, and 90. Toxicities were collected by chart review through day +100 after AHCT and compared using either a T-test or Fisher's exact test between patients above and below AUC 14.5 mg/L*h.Results: Ten patients (7 MM, 3 AL) with 50% male, median age 67yr (range 53-74), and median body surface area 1.95 (range 1.56-2.35) had a median of 4.5 days (range 1-24) between the test and target doses of PGF-MEL. Target doses were calculated for 90% of patients and 70% received the calculated dose. The reasons for not administering the calculated dose were inability to calculate a test dose AUC (N=1), toxicity after the test dose (N=1), and target dose outside study safety parameters (N=1). Median test and target dose AUCs were 0.655 (range 0.447-0.869) and 15.65mg/L*h (range 10.1-17.2, Figure 1), respectively. No patients receiving the calculated target dose had an AUC within the goal range. MDASI-MM AUCs were calculated for fatigue, pain, sleep, appetite, drowsiness, and the average of these 5 symptoms. Overall, higher scores were seen in patients with MEL AUCs above 14.5mg/L*h compared with below (Figure 2). More patients with higher AUCs had fevers (83 vs 50%), ≥500ml of diarrhea per day (83 vs 75%), grade ≥3 mucositis (50 vs 25%), and need for patient-controlled analgesia (33 vs 25%), but these were not statistically significantly different between the groups (Table 1). Neutrophil engraftment occurred at a median of 10 (range 9-11) days post AHCT in both groups; patients with AUCs above 14.5mg/L*h required more pRBC and platelet transfusions. With a median follow-up of 217 days (range 179-250) in surviving patients, no patients progressed, and one AL patient died of failure to thrive at 134 days post AHCT.Conclusion: Collection of PK levels and calculation of a target dose was feasible. However, using a 10mg/m2 test dose we did not achieve the target AUC in our patients. This could be due to the small test dose which may have been insufficient to saturate the two-compartment model, rendering the PK analysis inaccurate. Patients with higher AUCs required more transfusions, had more toxicities, and had prolonged patient-reported symptom burden. Due to the small number of patients, these differences were not statistically significant, but suggest there may be an ideal concentration to minimize toxicity and maximize efficacy. Disease response and outcome data continue to be collected. Further study is needed to determine the optimum test dose and schedule, and modifications to the schema are ongoing. [Display omitted] DisclosuresKoehne:Atara: Consultancy, Patents & Royalties. Landau:Janssen: Honoraria; Takeda: Research Funding; Spectrum Pharmaceuticals: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board; Pfizer: Honoraria; Karyopharm: Consultancy; Amgen: Research Funding.

RETRACTED ARTICLE: Discovery of (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20): the first potent and specific anti-COVID-19 drug.

Specific inhibition of the viral RNA-dependent RNA polymerase (RdRp) of the newly-emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising strategy for developing highly potent medicines for coronavirus disease 2019 (COVID-19). However, almost all of the reported viral RdRp inhibitors (either repurposed drugs or new antiviral agents) lack selectivity against the SARS-CoV-2 RdRp. Herein, I discovered a new favipiravir derivative, (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20), as the first potent SARS-CoV-2 inhibitor with very high selectivity (209- and 45-fold more potent than favipiravir and remdesivir, respectively). Based on the significant reduction in the in vitro SARS-CoV-2 replication/copies, strong computational cyanorona-20 ligand-RdRp protein interactions, and anti-RdRp activity of the parent favipiravir drug, SARS-CoV-2 inhibition is thought to be mediated through the coronaviral-2 RdRp inhibition. This promising selective anti-COVID-19 compound is also, to the best of our knowledge, the first bioactive derivative of favipiravir, the known antiinfluenza and antiviral drug. This new nucleoside analog was designed, synthesized, characterized, computationally studied (through pharmacokinetic calculations along with computational molecular modeling and prediction), and biologically evaluated for its anti-COVID-19 activities (through a validated in vitro anti-COVID-19 assay). The results of the biological assay showed that cyanorona-20 surprisingly exhibited very significant anti-COVID-19 activity (anti-SARS-CoV-2 EC50 = 0.45 μM), and, in addition, it could be also a very promising lead compound for the design of new anti-COVID-19 agents. Cyanorona-20 is a new favipiravir derivative with promise for the treatment of SARS-CoV-2 infection.Graphic abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s11696-021-01640-9.

Pharmacokinetics Evaluation of Acamprosate Tablets in Healthy Human Volunteers

Pharmacokinetic data of acamprosate tablets was not accessible on large number of human. Rationale to examine the pharmacokinetic properties of acamprosate calcium in healthy male subject, on single or multiple dosage administration, to evaluate the bioequivalence of two formulations of acamprosate calcium tablets in fast or fed environment. This work engross the study of pharmacokinetic property of Acamprosate calcium tablets in single dosing under fasting condition.&#x0D; Methods: Bioequivalence study of delayed release acamprosate tablets 333 mg for a randomized, single dose, open label, two treatment, two periods, two sequences and crossover design in 12 healthy, adult human subjects under fasting condition was conducted. The wash out period within the each treatment and each stage was 1 week. The quantification of acamprosate was done by LCMS/MS method. Accessibility was evaluated by monitoring adverse events, physical examinations and ECG and laboratory tests.&#x0D; Results: The entire study was conducted by using 12 male subjects to fulfill all stages in the study. The pharmacokinetic calculations for test and reference formulations are as follows: single dosing, Tmax 8.54 ± 5.24 and 10.71 ± 5.41 h, Cmax 146.06 ± 99.73 and 115.01 ±86.26 ng · mL−1, AUC0-t 1391.95 ± 731.24 and 1557.03 ± 960.98 ng·mL−1·h, AUC0–∞ 1987.40 ± 962.84 and 2720.21 ± 1931.79 ng·mL−1·h, respectively. In all three stages, 90% CIs for the test/reference ratio of AUC0–t and AUC0–∞ was to be found within 80% –125% of acamprosate calcium.&#x0D; Conclusions: As per regulatory guidelines, pharmacokinetics parameters for acamprosate calcium were found to be within the acceptance criteria.

1326. Vancomycin Area Under the Concentration-Time Curve (AUC) Estimation Using a Bayesian Approach Versus First-Order Pharmacokinetic Equations: A Pilot Study

BackgroundCurrent guidelines endorse area under the concentration-time curve (AUC)-based monitoring over trough-only monitoring for systemic vancomycin. Vancomycin AUC can be estimated using either Bayesian modeling software or first-order pharmacokinetic (PK) calculations. The objective of this pilot study was to evaluate and compare the efficiency and feasibility of these two approaches for calculating the estimated vancomycin AUC.MethodsA single-center crossover study was conducted in four medical/surgical units at Brigham and Women’s Hospital over a 3-month time period. All adult patients who received vancomycin were included. Patients were excluded if they were receiving vancomycin for surgical prophylaxis, were on hemodialysis, if vancomycin was being dosed by level, or if vancomycin levels were never drawn. The primary endpoint was the amount of time study team members spent calculating the estimated AUC and determining regimen adjustments with Bayesian modeling compared to first-order PK calculations. Secondary endpoints included the number of vancomycin levels drawn and the percent of those drawn that were usable for AUC calculations.ResultsOne hundred twenty-four patients received vancomycin during the study, of whom 47 met inclusion criteria. The most likely reasons for exclusion were receiving vancomycin for surgical prophylaxis (n=40) or never having vancomycin levels drawn (n=32). The median time taken to assess levels in the Bayesian arm was 9.3 minutes [interquartile range (IQR) 7.8-12.4] versus 6.8 minutes (IQR 4.8-8.0) in the 2-level PK arm (p=0.004). However, if Bayesian software is integrated into the electronic health record (EHR), the median time to assess levels was 3.8 minutes (IQR 2.3-6.8, p=0.019). In the Bayesian arm, 30 of 34 vancomycin levels (88.2%) were usable for AUC calculations, compared to 28 of 58 (48.3%) in the 2-level PK arm.ConclusionWith EHR integration, the use of Bayesian software to calculate the AUC was more efficient than first-order PK calculations. Additionally, vancomycin levels were more likely to be usable in the Bayesian arm, thereby avoiding delays in estimating the vancomycin AUC.Disclosures All Authors: No reported disclosures

Pharmacokinetic properties of tramadol and M1 metabolite in Northeast Brazilian donkeys (Equus asinus).

There is currently little information available on the pharmacokinetics and pharmacodynamics of the analgesic opioid tramadol when used in the veterinary medicine of domestic species. In this study, we aimed to determine the pharmacokinetics of tramadol and its active metabolite M1 following intravenous administration of 2 (T2) and 4 (T4) mg/kg to Northeast Brazilian donkeys. Tramadol and M1 plasma levels were quantified using a validated liquid chromatography-tandem mass spectrometry method. We found that plasma levels of tramadol and M1 were higher than those reported as clinically meaningful in humans for at least 3hr. However, the pharmacokinetic parameter calculation corrected by dose analysis identified no proportional increase with dose for the AUC of tramadol (T2: 2,663±1,827 vs. T4: 2,964±1,038ng*h/ml) and M1 (T2: 378±237 vs. T4: 345±142ng*h/ml). This finding appears to be attributable to a significant increase in clearance and a reduction in the terminal half-life of tramadol. The frequency of adverse effects observed at the higher dose indicates that 2mg/kg administered intravenously would be suitable for donkeys. Clinical studies are required to determine the implications of these observations regarding the pharmacodynamic response to tramadol in Northeast Brazilian donkeys.