Clinical Dosing Regimen Research Articles

Inhibitory effect of quercetin-3-O-α-rhamnoside, p-coumaric acid, phloridzin and 4-O-β-glucopyranosyl-cis-coumaric acid on rats liver microsomes cytochrome P450 enzyme activities.

P-coumaric acid, phloridzin, quercetin-3-O-α-rhamnoside and 4-O-β-glucopyranosyl-cis-coumaric acid isolated in Malus micromalus Makino fruit were investigated the inhibitory activity of cytochrome CYP450 enzyme by the probe test method of rat liver microsomes in vitro, and determined the role in drug metabolism and/or toxicology. Enzymatic kinetics method was used to determine the inhibition type of these components and corresponding inhibition constants. The results demonstrated that all the 4 compounds had no significance to inhibit the activities of CYP2E1 and CYP2C11. P-coumaric acid, phloridzin and quercetin-3-O-α-rhamnoside had a weak inhibitory effect on CYP3A4, which belonged to the competitive inhibitory type with inhibitory constants of 10.56, 30.79 and 40.29μmolL-1, respectively. 4-O-β-glucopyranosyl-cis-coumaric acid had a moderate inhibitory effect on CYP3A4, which belonged to the anti-competitive inhibition type and the inhibition constant was 5.56μmolL-1. The CYP1A2 could be weakly inhibited by p-coumaric acid in the competitive type, and the inhibition constant is 25.20μmolL-1 4-O-β-glucopyranosyl-cis-coumaric acid exhibited anti-competitive inhibition of CYP1A2 with an inhibition constant of 19.91μmolL-1, and the inhibition effect was weak. The results will be useful to optimize the clinical dosage regimen and avoid drug-drug interactions when it is utilized comminating with other medicines in the clinic.

A PK/PD model for the evaluation of clinical rifaximin dosage for the treatment of dairy cow mastitis induced by Escherichia coli

Escherichia coli (E. coli) is an opportunistic pathogen that can cause clinical mastitis in dairy cows worldwide. Mastitis produces severe symptoms in dairy cows, such as udder inflammation, the production of harmful substances, reduced milk production, and altered milk quality. Intramammary injections of rifaximin have a beneficial effect on dairy cow mastitis, especially for mastitis caused by E. coli. However, we do not know whether the currently accepted clinical administration scheme is reasonable. Therefore, the purpose of this experiment was to evaluate the clinical dosing regimen for curing mastitis induced by E. coli. In this study, the pharmacokinetics of four single dose groups (50, 100, 200, and 400 µg/gland) were studied in CD-1 lactating mice, and the main pharmacokinetic parameters were obtained by non-compartment and two-compartment model of Phoenix 8.1 software. A total of 5,000 colony-forming units (CFU) of E. coli ATCC25922 were injected into the mammary glands of mice under anatomic microscope guidance. After 12 h of growth in vivo, the mouse mastitis model was successfully developed. In pharmacodynamics experiment, 12 different dosing regimens (doses ranged from 25 to 800 µg/gland and two dosing intervals of 12 and 24 h) were used to study the therapeutic potential of rifaximin for mastitis. The PK/PD model was established by integrating pharmacokinetics and pharmacodynamics using the inhibitory sigmoid Emax model. The optimal antibacterial effect was 2log10CFU/gland reduction of bacterial colony counts in vivo, when the magnitude of AUC24/MIC exceeded 57.80 h. A total of 57.80 h of AUC24/MIC was defined as a target value in the Monte Carlo simulation. The clinically recommended dosage regimen of 100 mg/gland every 12 h in a day achieved a 91.08% cure rate for the treatment of bovine mastitis caused by E. coli infection.

Pharmacokinetic/Pharmacodynamic Evaluation of Aztreonam/Amoxicillin/Clavulanate Combination against New Delhi Metallo-β-Lactamase and Serine-β-Lactamase Co-Producing Escherichia coli and Klebsiella pneumoniae.

This study aimed to examine specific niches and usage for the aztreonam/amoxicillin/clavulanate combination and to use population pharmacokinetic simulations of clinical dosing regimens to predict the impact of this combination on restricting mutant selection. The in vitro susceptibility of 19 New-Delhi metallo-β-lactamase (NDM)-producing clinical isolates to amoxicillin/clavulanate and aztreonam alone and in co-administration was determined based on the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC). The fractions of a 24-h duration that the free drug concentration was within the mutant selection window (fTMSW) and above the MPC (fT>MPC) in both plasma and epithelial lining fluid were determined from simulations of 10,000 subject profiles based on regimens by renal function categories. This combination reduced the MIC of aztreonam and amoxicillin/clavulanate to values below their clinical breakpoint in 7/9 K. pneumoniae and 8/9 E. coli, depending on the β-lactamase genes detected in the isolate. In the majority of the tested isolates, the combination resulted in fT>MPC > 90% and fTMSW < 10% for both aztreonam and amoxicillin/clavulanate. Clinical dosing regimens of aztreonam and amoxicillin/clavulanate were sufficient to provide mutant restriction coverage for MPC and MIC ≤ 4 mg/L. This combination has limited coverage against NDM- and extended-spectrum β-lactamase co-producing E. coli and K. pneumoniae and is not effective against isolates carrying plasmid-mediated AmpC and KPC-2. This study offers a potential scope and limitations as to where the aztreonam/amoxicillin/clavulanate combination may succeed or fail.

Dosing and efficacy of extracorporeal shockwave therapy for diabetic foot ulcer healing: a systematic review protocol

Background: Effective interventions to improve diabetic foot ulcer (DFU) healing are urgently required. Extracorporeal shockwave therapy (ESWT) has the potential to transform DFU care, but is limited by uncertainties around clinical effectiveness and optimal dosing regimen. This protocol outlines the methodology of a systematic review that will address these unknowns. Methods: Databases and the grey literature will be searched for randomised controlled trials (RCTs) comparing ESWT plus standard ulcer care to standard ulcer care ± sham ESWT in patients with a DFU. The primary outcome of the review is time to ulcer healing. Two independent reviewers will screen search results against pre-determined eligibility criteria and extract data onto a pre-piloted spreadsheet. A meta-analysis is planned to compare time to healing for ESWT versus standard care and different doses of ESWT. The Risk of Bias 2 and GRADE tool will be used to assess the quality of the evidence. Outputs, dissemination, impact: The review will provide an estimate of the effect of ESWT on DFU healing and the impact of the ESWT dose on DFU healing. The systematic review will be submitted for publication in a peer-reviewed journal. A plain English summary will be produced. Outputs from the review will guide patient care and research.

Progress of triazole antifungal agent posaconazole in individualized therapy.

Posaconazole is the second-generation triazole antifungal agent with widespread clinical application. Posaconazole exposure is influenced by various factors such as drug interactions, disease state and diet, resulting in a high interindividual variability in many patients and failure to ensure therapeutic efficacy. Therefore, it is necessary to conduct individualized therapy on posaconazole to ensure the efficacy and safety of treatment. Articles were identified through PubMed using the keywords such as "posaconazole," "therapeutic drug monitoring" and "Population pharmacokinetics" from 1 January 2001 to 30 April 2022. In this paper, we review the individualized treatment studies of posaconazole from the three aspects of therapeutic drug monitoring, population pharmacokinetic study and Monte Carlo simulation to provide reference for in-depth individualized posaconazole dosing studies. This review suggests that therapeutic drug monitoring should be performed in patients taking posaconazole to adjust the dosage and assess the efficacy and cost-effectiveness of posaconazole under different clinical conditions and different dosing regimens through Monte Carlo simulations. In the future, a more detailed delineation and comprehensive examination of posaconazole PPK for specific populations requires further study.

Deciphering longitudinal optical-density measurements to guide clinical dosing regimen design: A model-based approach

BackgroundModel-based analysis of longitudinal optical density measurements from a bacterial suspension exposed to antibiotics has been proposed as a potentially efficient and effective method for extracting useful information to improve the individualized design of treatments for bacterial infections. To that end, the authors developed in previous work a mathematical modeling framework that can use such measurements for design of effective dosing regimens. ObjectivesHere we further explore ways to extract information from longitudinal optical density measurements to predict bactericidal efficacy of clinically relevant antibiotic exposures. MethodsLongitudinal optical density measurements were collected in an automated instrument where Acinetobacter baumannii, ATCC BAA747, was exposed to ceftazidime concentrations of 1, 4, 16, 64, and 256 mg/L and to ceftazidime/amikacin concentrations of 1/0.5, 4/2, 16/8, 64/32, and 256/128 (mg/L)/(mg/L) over 20 h. Calibrated conversion of measurements produced total (both live and dead) bacterial cell concentration data (CFU/mL equivalent) over time. Model-based data analysis predicted the bactericidal efficacy of ceftazidime and of ceftazidime/amikacin (at ratio 2:1) for periodic injection every 8 h and subsequent exponential decline with half-life of 2.5 h. Predictions were experimentally tested in an in vitro hollow-fiber infection model, using peak concentrations of 60 and 150 mg/L for injected ceftazidime and of 40/20 (mg/L)/(mg/L) for injected ceftazidime/amikacin. ResultsModel-based analysis predicted low (<62%) confidence in clinically relevant suppression of the bacterial population by periodic injections of ceftazidime alone, even at high peak concentrations. Conversely, analysis predicted high (>95%) confidence in bacterial suppression by periodic injections of ceftazidime/amikacin combinations at a wide range of peak concentrations ratioed at 2:1. Both predictions were experimentally confirmed in an in vitro hollow fiber infection model, where ceftazidime was periodically injected at peak concentrations 60 and 150 mg/L (with predicted suppression confidence 38% and 59%, respectively) and a combination of ceftazidime/amikacin was periodically injected at peak concentrations 40/20 (mg/L)/(mg/L) (with predicted suppression confidence 98%). ConclusionsThe paper highlights the potential of clinicians using the proposed mathematical framework to determine the utility of different antibiotics to suppress a patient-specific isolate. Additional studies will be needed to consolidate and expand the utility of the proposed method.

Effects of amikacin, polymyxin-B, and sulbactam combination on the pharmacodynamic indices of mutant selection against multi-drug resistant Acinetobacter baumannii.

Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant Acinetobacter baumannii at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit in vitro synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of A. baumannii harboring OXA-23, respectively, in order to derive the fraction of time over the 24-h wherein the free drug concentration was within the mutant selection window (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) from simulated pharmacokinetic profiles. The combination of these three antibiotics can confer susceptibility in multi-drug resistant A. baumannii and reduce the opportunity for bacteria to develop further resistance. Clinical intravenous dosing regimens of amikacin, polymyxin-B, and sulbactam were predicted to optimize fTMSW and fT>MPC from drug exposures in the blood. Mean fT>MPC were ≥ 60% and ≥ 80% for amikacin and polymyxin-B, whereas mean fTMSW was reduced to <30% and <15%, respectively, in the triple antibiotic combination. Due to the low free drug concentration of amikacin and polymyxin-B simulated in the epithelial lining fluid, the two predicted pharmacodynamic parameters in the lung after intravenous administration were not optimal even in the combination therapy setting.

Pharmacodynamics of colistin resistance in carbapenemase-producing Klebsiella pneumoniae: the double-edged sword of heteroresistance and adaptive resistance.

Introduction. The presence of heteroresistant subpopulations and the development of resistance during drug exposure (adaptive resistance) limits colistin's efficacy against carbapenemase-producing Klebsiella pneumoniae (CP-Kp) isolates.Hypothesis/Gap statement. The pharmacokinetic/pharmacodynamic (PK/PD) characteristics of both types of colistin resistance against CP-Kp are unknown.Aim. We therefore studied the PK/PD characteristics of colistin resistance in an in vitro PK/PD model simulating clinical colistin exposures.Methods. Two K. pneumoniae clinical isolates, one non-CP-Kp and one CP-Kp, with colistin MICs of 0.5-1 mg l-1 at a final inoculum of 107 c.f.u. ml-1 were used in an in vitro PK/PD dialysis/diffusion closed model simulating 4.5 MU q12h and 3 MU q8h clinical dosing regimens. Heteroresistant (HRS, bacteria with stable high-level resistance present before drug exposure) and adaptive resistant (ARS, bacteria with reversible low-level resistance emerging after drug exposure) subpopulations were measured and optimal PK/PD targets for reducing both ARS and HRS were determined. Cumulative fractional response (CFR) was calculated with Monte Carlo simulation for 9 MU q24h, 4.5 MU q12h and 3 MU q8h clinical dosing regimens.Results. A 2-5 log10c.f.u. ml-1 decrease of the total bacterial population was observed within the first 2 h of exposure, followed by regrowth at 12 h. Colistin exposure was positively and negatively correlated with HRS and ARS 24-0 h c.f.u. ml-1 changes, respectively. An optimal PK/PD (~0.5log10 increase) target of 35 fAUC/MIC (the ratio of the area under the unbound concentration-time curve to the MIC) was found for reducing both HRS and ARS of high-level resistance (MIC >16 mg l-1). The 4.5 MU q12h regimen had slightly higher CFR (74 %) compared to the other dosing regimens.Conclusions. High colistin exposures reduced high-level adaptive resistance at the expense of selection of heteroresistant subpopulations.

Serum pharmacochemistry and pharmacokinetics of major components after oral administration of Luhong recipe in rats using ultra-performance liquid chromatography-tandem mass spectrometry.

Luhong recipe (LHR) is has been used as an empirical prescription for treating chronic heart failure for long, with safety, reliability, and significant efficacy. However, its pharmacokinetics has not yet been studied. This study aims to establish aultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous analysis of epimedin A, epimedin B, epimedin C, icariin, psoralen, and isopsoralen in rat plasma and apply it to the pharmacokinetic study of LHR after oral administration. These six analytes were ionized using positive electrospray ionization (ESI+ ). The MS/MS transitions used for monitoring are successively converted to m/z 839.3 → 369.1, m/z 809.2 → 369.1, m/z 823.3 → 369.1, m/z 677.2 → 205.2, m/z 187.1 → 115.2, and m/z 230 → 120.9. Linearity, precision, accuracy, stability, matrix effect, and recovery of the established method were within the acceptable range. The method was suitable for the determination of six analytes after oral administration of LHR. The pharmacokinetic results showed that the time to reach the peak concentration (Tmax ) was from 0.17 to 13.5h, the peak concentration (Cmax ) was 109.23-980 ng/mL, the area under the concentration-time curve (AUC[0 - t] ) was 65.48-8846.08 ng·h/mL, and the apparent distribution volume (Vd) was 24,772-896,132 mL/kg. These results provided a meaningful basis for formulating the clinical dose regimen of LHR.

Environmental pharmacology-Dosing the environment: IUPHAR review 36.

Pesticide action is predominantly measured as a toxicological outcome, with pharmacological impact of sublethal doses on bystander species left largely undocumented. Likewise, chronic exposure, which often results in responses different from acute administration, has also been understudied. In this article, we propose the application of standard pharmacological principles, already used to establish safe clinical dosing regimens in humans, to the 'dosing of the environment'. These principles include relating the steady state dose of an agent to its beneficial effects (e.g. pest control), while minimising harmful impacts (e.g. off-target bioactivity in beneficial insects). We propose the term 'environmental therapeutic window', analogous to that used in mammalian pharmacology, to guide risk assessment. To make pharmacological terms practically useful to environmental protection, quantitative data on pesticide action need to be made available in a freely accessible database, which should include toxicological and pharmacological impacts on both target and off-target species.

Circadian Clock Genes Act as Diagnostic and Prognostic Biomarkers of Glioma: Clinic Implications for Chronotherapy.

Gliomas are the most common primary intracranial tumors and closely related to circadian clock. Due to the high mortality and morbidity of gliomas, exploring novel diagnostic and early prognostic markers is necessary. Circadian clock genes (CCGs) play important roles in regulating the daily oscillation of biological processes and the development of tumor. Therefore, we explored the influences that the oscillations of circadian clock genes (CCGs) on diagnosis and prognosis of gliomas using bioinformatics. In this work, we systematically analyzed the rhythmic expression of CCGs in brain and found that some CCGs had strong rhythmic expression; the expression levels were significantly different between day and night. Four CCGs (ARNTL, NPAS2, CRY2, and DBP) with rhythmic expression were not only identified as differentially expressed genes but also had significant independent prognostic ability in the overall survival of glioma patients and were highly correlated with glioma prognosis in COX analysis. Besides, we found that CCG-based predictive model demonstrated higher predictive accuracy than that of the traditional grade-based model; this new prediction model can greatly improve the accuracy of glioma prognosis. Importantly, based on the four CCGs' circadian oscillations, we revealed that patients sampled at night had higher predictive ability. This may help detect glioma as early as possible, leading to early cancer intervention. In addition, we explored the mechanism of CCGs affecting the prognosis of glioma. CCGs regulated the cell cycle, DNA damage, Wnt, mTOR, and MAPK signaling pathways. In addition, it also affects prognosis through gene coexpression and immune infiltration. Importantly, ARNTL can rhythmically modulated the cellular sensitivity to clinic drugs, temozolomide. The optimal point of temozolomide administration should be when ARNTL expression is highest, that is, the effect is better at night. In summary, our study provided a basis for optimizing clinical dosing regimens and chronotherapy for glioma. The four key CCGs can serve as potential diagnostic and prognostic biomarkers for glioma patients, and ARNTL also has obvious advantages in the direction of glioma chronotherapy.

In vitro Antibacterial Activity and Resistance Prevention of Antimicrobial Combinations for Dihydropteroate Synthase-Carrying Stenotrophomonas maltophilia.

BackgroundStenotrophomonas maltophilia (S. maltophilia) is a multidrug-resistant gram-negative bacillus that is known to be an opportunistic pathogen, particularly in a hospital environment. The infection has a high morbidity and mortality. Sulfamethoxazole-trimethoprim (SXT) is the first-line agent recommended for its treatment. The global spread of dihydropteroate synthase (sul) genes has resulted in an increased resistance rate. However, the appropriate therapy for infections caused by sul-carrying S. maltophilia has not yet been established.ObjectiveOur study aimed to identify the optimal antibiotic combinations that could both show high antibacterial activity against sul-carrying S. maltophilia and the ability to prevent the emergence of resistance at clinical dosage regimens.MethodsTime-killing experiments and mutant prevention concentration (MPC) experiments were conducted to evaluate the antibacterial effect and ability to prevent resistance to minocycline, tigecycline, moxifloxacin, and ticarcillin/clavulanic acid (T/K), both alone and in combination, at clinically relevant antimicrobial concentrations.ResultsMinocycline, tigecycline, and T/K all exhibited bacteriostatic activity to sul-carrying S. maltophilia. The combination of minocycline plus T/K and tigecycline plus T/K neither enhanced the bactericidal ability nor prevented drug-resistant mutations. Moxifloxacin, at 2 mg/L, showed good bactericidal activity to most S. maltophilia, but bacterial regrowth at 24 h was observed in two strains. When combined with T/K, moxifloxacin showed good bactericidal activity in all moxifloxacin-sensitive strains. The concentrations of moxifloxacin alone were lower than most MPCs of the tested sul-carrying strains. When combined with T/K, the mean steady-state concentrations (MSC) of moxifloxacin could prevent 70% of resistance, and the peak concentration (Cmax) prevented 95% of resistance.ConclusionThe combination of moxifloxacin and T/K can achieve a good in vitro bactericidal effect and prevent the emergence of resistance at clinical dosage regimens, and may be an optimal therapeutic strategy for S. maltophilia infections, especially for vulnerable immunocompromised and critically ill patients.

Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC50 Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model

BackgroundVery little knowledge exists on the impact of Alzheimer’s disease on the CNS target site pharmacokinetics (PK).AimTo predict the CNS PK of cognitively healthy young and elderly and of Alzheimer’s patients using the physiologically based LeiCNS-PK3.0 model.MethodsLeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brainECF) and intracellular (brainICF) fluids and cerebrospinal fluid of the subarachnoid space (CSFSAS) of donepezil, galantamine, memantine, rivastigmine, and semagacestat in young, elderly, and Alzheimer’s patients. The physiological parameters of LeiCNS-PK3.0 were adapted for aging and Alzheimer’s based on an extensive literature search. The CNS PK profiles at plateau for clinical dose regimens were related to in vitro IC50 values of acetylcholinesterase, butyrylcholinesterase, N-methyl-D-aspartate, or gamma-secretase.ResultsThe PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. BrainECF, brainICF and CSFSAS PK profile relationships were different between the drugs. Aging and Alzheimer’s had little to no impact on CNS PK. Rivastigmine acetylcholinesterase IC50 values were not reached. Semagacestat brain PK plateau levels were below the IC50 of gamma-secretase for half of the interdose interval, unlike CSFSAS PK profiles that were consistently above IC50.ConclusionThis study provides insights into the relations between CNS compartments PK profiles, including target sites. CSFSAS PK appears to be an unreliable predictor of brain PK. Also, despite extensive changes in blood-brain barrier and brain properties in Alzheimer’s, this study shows that the impact of aging and Alzheimer’s pathology on CNS distribution of the five drugs is insignificant.

Population Pharmacokinetics of Nifurtimox in Adult and Pediatric Patients With Chagas Disease

Nifurtimox (LAMPIT) has been used for decades for the treatment of Chagas disease, a chronic and potentially life-threatening disease caused by the parasite Trypanosoma cruzi. The pharmacokinetic (PK) information on nifurtimox in humans derived from controlled clinical studies is very limited. The objective was to investigate and compare the population PK of nifurtimox in adult and pediatric patients with Chagas disease to confirm the clinical dosing regimen in children, which was based on allometric approaches using the concept that a dose-equivalent exposure would reach equivalent antiparasitic efficacy as in adults. The resulting adult model adequately described the PK in adults. Significant predictors of the availability in PK were food intake, tablet formulation (fast- vs slow-dissolution tablet), study, and body weight. As the resulting adult model could not adequately predict the sparse sampled pediatric patient data, these data were analyzed separately to derive exposure estimates for comparison with adult exposure. In the population PK model for pediatric patients, significant covariates were body weight and age. As compared to adults, children aged >2 years were estimated to have 50.6% higher apparent clearance. No hints of dose nonlinearity were observed in a dose range of 30 to 240 mg single dose in adults and 15 to 300 mg 3 times daily (8-20 mg/kg) in children. Altogether, this study retroactively showed that the current mg/kg dosing regimen in children reached similar exposure as in adults receiving an 8 mg/kg total daily dose.

One percent of the clinical dose used for antenatal steroid therapy is sufficient to induce lung maturation when administered directly to the preterm ovine fetus.

Antenatal steroids (ANSs) are routinely administered to women judged to be at imminent risk of preterm delivery. Their principal benefit is precocious functional maturation of the preterm fetal lung. Current dosing regimens expose the mother and fetus to high steroid levels that may be unnecessary, increasing the potential risks of disruption to the maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis and glucose regulation, alterations in placental function, and reduced fetal growth. Using a sheep model of pregnancy, we tested the hypothesis that direct fetal administration of an ultra-low dose course of betamethasone phosphate (∼0.33 mg) would be sufficient to elicit functional maturation of the fetal lung. A jugular catheter was installed in singleton ovine fetuses at 122-day gestation under general anesthesia. Animals were randomized to receive either: 1) fetal intravenous betamethasone phosphate to target fetal plasma betamethasone mean levels of 2 ng/mL for 26 h (fetal treatment group; n = 16); 2) fetal intravenous saline for 26 h and two maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + betamethasone acetate, simulating a standard clinical treatment (maternal treatment group; n = 12); or 3) fetal intravenous saline only for 26 h (negative control group; n = 10). Fetuses were delivered 48 h after surgery, ventilated for 30 min to allow the collection of lung function and physiological data, and euthanized. Quantitative PCR and Western blots were used to assess markers of lung maturation. The average total betamethasone phosphate dose for the fetal treatment group was 1% (0.3 mg) of the maternal treatment group (31-mg betamethasone phosphate + betamethasone acetate). At 30 min of ventilation, arterial [Formula: see text], pH, heart rate, and ventilation efficacy index (VEI) were significantly (P < 0.05) and equivalently improved in both the fetal treatment group and maternal treatment group, relative to the negative control group. Similarly, SP-A, SP-C, and AQ-5 mRNA expression was significantly higher in both the fetal treatment group and maternal treatment group, relative to negative control. Maternal steroid administration was not required to generate preterm fetal lung maturation in sheep. Using a low dose and targeting steroid treatments directly to the fetus has the potential to significantly reduce maternal exposures, while simultaneously reducing the potential risk of adverse outcomes associated with current clinical dosing regimens.

The clinical population pharmacokinetics, metabolomics and therapeutic analysis of alkaloids from Alstonia scholaris leaves in acute bronchitis patients

BackgroundCapsule of alkaloids from leaf of Alstonia scholaris (CALAS) is a new investigational botanical drug (No. 2011L01436) for respiratory disease. Clinical population pharmacokinetics (PK), metabolomics and therapeutic data are essential to guide dosing in patients. Previous research has demonstrated the potential therapeutic effect of CALAS on acute bronchitis. Further clinical trial data are needed to verify its clinical efficacy, pharmacokinetics behavior, and influence of dosage and other factors. PurposeTo verify the clinical efficacy and explore the potential biomarkers related to CALAS treatment for acute bronchitis. Materials and Methods: Oral CALAS was assessed in a randomized, double-blind, placebo-controlled trial. Fifty-five eligible patients were randomly assigned to four cohorts to receive 20, 40 or 80 mg, of CALAS three times daily for seven days, or placebo. Each CALAS cohort included 15 subjects, and the placebo group included 10 subjects. A population PK model of CALAS was developed using plasma with four major alkaloid components. Metabolomics analysis was performed to identify biomarkers correlated with the therapeutic effect of CALAS, and efficacy and safety were assessed based on clinical symptoms and adverse events. ResultsThe symptoms of acute bronchitis were alleviated by CALAS treatment without serious adverse events or clinically significant changes in vital signs, electrocardiography or upper abdominal Doppler ultrasonography. Moreover, one compartment model with first-order absorption showed that an increase in aspartate transaminase will reduce the clearance (CL) of scholaricine, and picrinine CL was inversely proportional to body mass index, while 19-epischolaricine and vallesamine CL increased with aging. The serum samples from acute bronchitis patients at different time points were analyzed using UPLC-QTOF in combination with the orthogonal projection to latent structures-discriminant analysis, which indicated higher levels of lysophosphatidylcholines, lysophosphatidylethanolamines and amino acids with CALAS treatment than with placebo. ConclusionThis is the first study to evaluate the clinical efficacy and explored the potential biomarkers related to CALAS therapeutic mechanism of acute bronchitis by means of clinical trial combined the metabolomics study. This exploratory study provides a basis for further research on clinical efficacy and optimal dosing regimens based on pharmacokinetics behavior. Additional acute bronchitis patients and CALAS PK samples collected in future studies may be used to improve model performance and maximize its clinical value.

Značaj farmakokinetike u doziranju lekova kod pedijatrijskih pacijenata

Optimizing the dosing of medicines for pediatric patients in routine clinical practice and determining the dose for clinical trials is still a challenging task. Children differ from adults in their response to drugs due to inherent differences in pharmacokinetics and/or pharmacodynamics, and responses may also vary among pediatric patients of different ages. However, the greatest disparities compared to adult pharmacokinetic profiles are observed in children below 2 years of age. The maturation of the liver and the kidneys, as well as the variation in body composition, are considered to be the main sources of pharmacokinetic variability. Hence, besides specific pharmacodynamic features, understanding age-related changes in drug absorption, distribution, and elimination is fundamental for optimizing drug efficacy and avoiding toxicity. This paper summarizes the pharmacokinetic changes throughout the childhood, along with the effect of developmental changes on drug dosage calculation. In clinical practice, age and body weight-based dosing regimens are usually used. In spite of dosing recommendations based on age and/or body weight, variabilities in pharmacokinetics and pharmacodynamic response remain, implying a need to monitor patients and optimize the dosing regimen according to physiological characteristics, disease characteristics and therapy.

The Monte Carlo Simulation of Three Antimicrobials for Empiric Treatment of Adult Bloodstream Infections With Carbapenem-Resistant Enterobacterales in China.

Introduction: The aim of this study was to predict and evaluate three antimicrobials for treatment of adult bloodstream infections (BSI) with carbapenem-resistant Enterobacterales (CRE) in China, so as to optimize the clinical dosing regimen further.Methods: Antimicrobial susceptibility data of blood isolates were obtained from the Blood Bacterial Resistance Investigation Collaborative Systems in China. Monte Carlo simulation was conducted to estimate the probability target attainment (PTA) and cumulative fraction of response (CFR) of tigecycline, polymyxin B, and ceftazidime/avibactam against CRE.Results: For the results of PTAs, tigecycline following administration of 50 mg every 12 h, 75 mg every 12 h, and 100 mg every 12 h achieved > 90% PTAs when minimum inhibitory concentration (MIC) was 0.25, 0.5, and 0.5 μg/mL, respectively; polymyxin B following administration of all tested regimens achieved > 90% PTAs when MIC was 1 μg/mL with CRE; ceftazidime/avibactam following administration of 1.25 g every 8 h, 2.5 g every 8 h achieved > 90% PTAs when MIC was 4 μg/mL, 8 μg/mL with CRE, respectively. As for CFR values of three antimicrobials, ceftazidime/avibactam achieved the lowest CFR values. The highest CFR value of ceftazidime/avibactam was 77.42%. For tigecycline and ceftazidime/avibactam, with simulated regimens daily dosing increase, the CFR values were both increased; the highest CFR of tigecycline values was 91.88%. For polymyxin B, the most aggressive dosage of 1.5 mg/kg every 12 h could provide the highest CFR values (82.69%) against CRE.Conclusion: This study suggested that measurement of MICs and individualized therapy should be considered together to achieve the optimal drug exposure. In particular, pharmacokinetic and pharmacodynamic modeling based on local antimicrobial resistance data can provide valuable guidance for clinicians for the administration of empirical antibiotic treatments for BSIs.

Should Isotretinoin be Stopped Prior to Surgery?

Should Isotretinoin be Stopped Prior to Surgery?

Translational PK/PD and model‐informed development of JNJ‐67842125, a Fab reversal agent for JNJ‐64179375, a long‐acting thrombin inhibitor

Antigen-binding fragment (Fab ) reversal agents (RAs) were developed to reverse, in situations of bleeding emergency, the anticoagulant activity of JNJ-64179375 (JNJ-9375), a monoclonal antibody that specifically binds exosite-1 on thrombin and functions as a long-acting anticoagulant. The pharmacokinetic and pharmacodynamic (PK/PD) activities of three RAs with varying in vitro binding affinities to JNJ-9375 were characterized in cynomolgus monkeys. The time course of JNJ-9375 anticoagulant activity and reversal effects of each RA were evaluated. A mechanism-based PK/PD model, which integrated free serum concentrations of RA, total and free serum concentrations of JNJ-9375, and thrombin time (TT), was developed to quantitatively relate JNJ-9375 neutralization to reversal of JNJ-9375-induced TT prolongation. Model-based allometric scale-up of the lead RA and the PK/PD relationship of JNJ-9375 in healthy volunteers were utilized to predict clinical dosing regimens. Lowering of free JNJ-9375 by the RAs corresponded well with reversal of TT prolongation. Total JNJ-9375 displayed typical mAb clearance at 2.75 mL/day/kg whereas RAs cleared faster between 1400-2400 mL/day/kg. The model-estimated in vivo KD values for JNJ-9375 RAs were 9 nM (ICHB-256), 0.4 nM (ICHB-281), and 13.7 pM (ICHB-164), in rank-ordered agreement of their KD values determined in vitro. The three RAs exhibited different neutralization characteristics in vivo, governed primarily by their binding kinetics to JNJ-9375. The model predicted a priori free JNJ-9375 kinetics after dosing ICHB-164 (JNJ-67842125) and JNJ-9375 under a different regimen. The results enabled selection of JNJ-67842125 as the RA for JNJ-9375.