Individualized, dynamic, and full-course vancomycin dosing prediction: a study on the customized dose model.

Purpose: The single-point trough-based therapeutic drug monitoring (TDM) and Bayesian forecasting approaches are still limited in individualized and dynamic vancomycin delivery. Until recently, there has not yet been enough focus on the direct integration of pharmacokinetic/pharmacodynamic (PK/PD) and TDM to construct a customized dose model (CDM) for vancomycin to achieve individualized, dynamic, and full-course dose prediction from empirical to follow-up treatment. This study sought to establish CDM for vancomycin, test its performance and superiority in clinical efficacy prediction, formulate a CDM-driven full-course dosage prediction strategy to overcome the above challenge, and predict the empirical vancomycin dosages for six Staphylococci populations and four strains in patients with various creatinine clearance rates (CLcr). Methods: The PK/PD and concentration models derived from our earlier research were used to establish CDM. The receiver operating characteristic (ROC) curve, with the area under ROC curve (AUCR) as the primary endpoint, for 21 retrospective cases was applied to test the performance and superiority of CDM in clinical efficacy prediction by comparison to the current frequently-used dose model (FDM). A model with an AUCR of at least 0.8 was considered acceptable. Based on the availability of TDM, the strategy of CDM-driven individualized, dynamic, and full-course dose prediction for vancomycin therapy was formulated. Based on the CDM, Monte Carlo simulation was used to predict the empirical vancomycin dosages for the target populations and bacteria. Results: Four CDMs and the strategy of CDM-driven individualized, dynamic, and full-course dose prediction for vancomycin therapy from empirical to follow-up treatment were constructed. Compared with FDM, CDM showed a greater AUCR value (0.807 vs. 0.688) in clinical efficacy prediction. The empirical vancomycin dosages for six Staphylococci populations and four strains in patients with various CLcr were predicted. Conclusion: CDM is a competitive individualized dose model. It compensates for the drawbacks of the existing TDM technology and Bayesian forecasting and offers a straightforward and useful supplemental approach for individualized and dynamic vancomycin delivery. Through mathematical modeling of the vancomycin dosage, this study achieved the goal of predicting doses individually, dynamically, and throughout, thus promoting "mathematical knowledge transfer and application" and also providing reference for quantitative and personalized research on similar drugs.

Pharmacokinetic-pharmacodynamic modelling and simulation of methotrexate dosing in patients with rheumatoid arthritis.

AIMS: To develop a non-linear mixed-effects population pharmacokinetic and pharmacodynamic (PK-PD) model describing the change in the concentration of methotrexate polyglutamates in erythrocytes (ery-MTX-PGn with "n" number of glutamate, representing PK component) and how this relates to modified 28-joint Disease Activity Score incorporating erythrocyte sedimentation rate (DAS-28-3) for rheumatoid arthritis (RA), representing PD component. METHODS: An existing PK model was fitted to data from a study consisting of 117 RA patients. The estimation of population PK-PD parameters was performed using stochastic approximation expectation maximisation algorithm in Monolix 2021R2. The model was used to perform Monte Carlo simulations of a loading dose regimen (50mg subcutaneous methotrexate as loading doses, then 20mg weekly oral methotrexate) compared to a standard dosing regimen (10mg weekly oral methotrexate for 2 weeks, then 20mg weekly oral methotrexate). RESULTS: Every 40 nmol/L increase in ery-MTX-PG3-5 total concentration correlated with 1-unit reduction in DAS-28-3. Significant covariate effects on the therapeutic response of methotrexate included the use of prednisolone in the first 4 weeks (positive use correlated with 25% reduction in DAS-28-3 when other variables were constant) and patient age (every 10-year increase in age correlated with 3.4% increase in DAS-28-3 when other variables were constant). 4 methotrexate loading doses led to a higher percentage of patients achieving a good/moderate response compared to the standard regimen (Week 4: 87.6% vs. 39.8%; Week 10: 64.7% vs. 57.0%). CONCLUSIONS: A loading dose regimen was more likely to achieve higher ery-MTX-PG concentration and better therapeutic response after 4 weeks of methotrexate treatment.

Application of Monte Carlo simulation to optimise the dosage regimen of meropenem in patients with augmented renal clearance for Pseudomonas aeruginosa infection.

Objective: To optimise the dosing regimen of meropenem for treating Pseudomonas aeruginosa (PA) infections in critically ill patients with augmented renal clearance (ARC) using pharmacokinetic/pharmacodynamic (PK/PD) principles and Monte Carlo simulation (MCS). Methods: This research involves an MCS based on PK data from patients with ARC and a minimum inhibitory concentration (MIC) distribution of PA. This study simplifies the methods section, focusing on the critical aspects of simulation and target values for effective treatment. Results: The study highlights key findings and emphasises that tailored dosing based on bacterial MIC values is essential for patients with ARC. It also notes that empirical treatment in patients with ARC should consider the MIC distribution, with 2 g every (q) 6 h administered to achieve the PK/PD target, while 3 g q 6 h is effective in inhibiting resistance. Conclusion: Tailored dosing based on bacterial MIC values is crucial for patients with ARC. Prolonged infusion time alone does not enhance efficacy. Empirical treatment in patients with ARC should consider MIC distribution; a dosage of 2 g q 6 h achieves the PK/PD target, while 3 g q 6 h (≥12 g daily) inhibits resistance.

The usefulness of determining plasma and tissue concentrations of phosphorodiamidate morpholino oligonucleotides to estimate their efficacy in Duchenne muscular dystrophy patients.

Currently four kinds of phosphorodiamidate morpholino oligomers (PMOs) such as viltolarsen have been approved for the treatment of Duchenne muscular dystrophy (DMD); however, it is unclear whether human efficacy can be estimated using plasma concentrations. This study summarizes the tissue distribution of viltolarsen in mice and cynomolgus monkeys and evaluates the relationship between exposure and efficacy based on exon skipping. In the tissue distribution studies, all muscles in DMD model mice showed higher concentrations of viltolarsen than those in wild-type mice and cynomolgus monkeys, and the concentrations in skeletal muscle were correlated with the exon-skipping efficiency in mice and cynomolgus monkeys. In addition, a highly sensitive bioanalytical method using liquid chromatography with tandem mass spectrometry shows promise for determining plasma concentrations up to a later time point, and the tissue (muscle)/plasma concentration ratio (Kp) in DMD model mice was shown to be useful for predicting changes in pharmacodynamic (PD) markers in humans. Our results suggest that pharmacokinetic (PK)/PD analysis can be conducted by using the human PK profile or Kp values and skipping efficiency in DMD model mice. This information will be useful for the efficient and effective development of PMOs as therapeutic agents. Significance Statement We compare that plasma and tissue concentrations with the efficiency of exon skipping for viltolarsen as an example phosphorodiamidate morpholino oligomers in skeletal and cardiac muscle of mice and cynomolgus monkeys for pharmacokinetics/pharmacodynamics (PK/PD) analysis. Our results suggest that PK/PD analysis can be conducted by using the human PK profile or Kp values and skipping efficiency in DMD model mice.

Adequacy of the Dosing and Infusion Time of Ceftazidime/Avibactam for the Treatment of Gram-Negative Bacterial Infections: A PK/PD Simulation Study.

Introduction: Recent studies suggested the potential benefits of extended infusion times to optimize the treatment efficacy of ceftazidime/avibactam, which indicated that the current pharmacokinetic/pharmacodynamic (PK/PD) target may not be sufficient, especially for severe infections. The purpose of this study is to assess the adequacy of dosing strategies and infusion durations of ceftazidime/avibactam when applying higher PK/PD targets. Methods: This study utilized published PK parameters to conduct Monte Carlo simulations. Different dosages including the recommended regimen based on renal function were simulated and evaluated by the probability of target attainment (PTA) and cumulative fraction of response (CFR). Different PK/PD targets were set for ceftazidime and avibactam. MIC distributions from various sources were used to calculate the CFR. Results: Multiple PK/PD targets have been set in this study, All recommended dosage could easily achieve the target of 50%fT ≥ MIC (ceftazidime) and 50%fT ≥ CT=1.0 mg/L (avibactam). However, for severe infection patients with normal renal function and augmented renal clearance at the recommended dosage (2000 mg/500 mg, every 8 hours), the infusion duration needs to be extended to 3 hours and 4 hours to achieve the targets of 100%fT ≥ MIC and 100%fT ≥ CT=1.0 mg/L. Only continuous infusion at higher dosages achieved 100%fT ≥ 4×MIC and 100%fT ≥ CT=4.0 mg/L targets to all currently recommended regimens. According to the varying MIC distributions, higher concentrations are needed for Pseudomonas aeruginosa, with the attainment rates vary across different regions. Conclusion: The current recommended dosing regimen of ceftazidime/avibactam is insufficient for severe infection patients, and continuous infusion is suggested.

Exploring the multiple effects of nifedipine and captopril administration in spontaneously hypertensive rats through pharmacokinetic-pharmacodynamic analyses.

This study assessed the pharmacokinetics (PKs) and pharmacodynamics (PDs) of two antihypertensive drugs, nifedipine and captopril, by exploring their main (blood pressure [BP]) and secondary effects (heart rate [HR] and QT interval [QT]) in spontaneously hypertensive rats. This study aimed to assess the relationship between PKs and PDs. Using these PD parameters, BP, HR, and QT during coadministration were estimated. The coadministration of nifedipine and captopril resulted in an increase in nifedipine's total body clearance (CLtot) and a reduction in its mean residence time (MRT) with an increase in the terminal elimination half-life (t1/2) and volume of distribution at steady state (Vdss) of captopril. However, no significant PK interactions were observed. During monotherapy, BP reduced rapidly following nifedipine infusion. Subsequently, despite the increase in nifedipine plasma concentration, BP recovered, likely because of homeostasis. Similar results were observed with coadministration. Subsequently, BP demonstrated a sustained reduction that was greater than or equal to the additive effect estimated from each PK. Captopril exhibited a minimal effect on HR, except for a transient increase observed immediately after starting infusion, consistent with observations during coadministration. Subsequently, the HR reduction was nearly equal to that calculated from the nifedipine PK. QT prolongation was more rapid with captopril than with nifedipine. Although QT prolongation during the initial 60 min of coadministration was approximately the sum of both effects, the recovery period to baseline QT was faster than that in the simulation.

Estimation of latamoxef (moxalactam) dosage regimens against ß-lactamase-producing Enterobacterales in dogs: a pharmacokinetic and pharmacodynamic analysis using Monte Carlo simulation.

One of the most significant research areas in veterinary medicine is the search for carbapenem substitutes for the treatment of extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales (ESBL-E). This study applied a pharmacokinetic/pharmacodynamic (PK/PD) strategy in validating optimal latamoxef (LMX) therapeutic regimens against canine ESBL-E infections. Five dogs were administered a bolus dose of 40 mg/kg LMX intravenously to measure serum drug concentrations and determine PK indices using the noncompartmental model. The highest minimum inhibitory concentration (MIC) with a probability of target attainment ≥90% was used to compute the PK/PD cutoff values for bacteriostatic (time for which the unbound drug concentration was above the MIC [fTAM] ≥40%) and bactericidal (fTAM ≥70%) effects when administered at 20, 30, 50, and 60 mg/kg, in addition to 40 mg/kg. The cumulative fraction of response (CFR) was determined using the MIC distribution of wild-type ESBL-E in companion animals. The PK/PD cutoff values can be increased by reducing the dosing interval rather than increasing the dose per time. Based on the calculated CFRs for ESBL-producing Escherichia coli and Klebsiella pneumoniae, all LMX regimens in this study and those administered at 30-60 mg/kg every 8 and 6 hr were found to be optimal (CFR ≥90%) for exerting bacteriostatic and bactericidal effects, respectively. However, the regimens of 50 and 60 mg/kg every 6 hr may merely exert bacteriostatic effects on ESBL-producing Enterobacter cloacae. Further clinical trials are required to confirm the clinical efficacy of LMX.

Concentration-resistance relationship and PK/PD evaluation of danofloxacin against emergence of resistant Pasteurella multocida in an in vitro dynamic model.

AIMS: This study aimed to assess the pharmacokinetic/pharmacodynamic (PK/PD) targets of danofloxacin to minimize the risk of selecting resistant Pasteurella multocida mutants and to identify the mechanisms underlying their resistance in an in vitro dynamic model, attaining the optimum dosing regimen of danofloxacin to improve its clinical efficacy based on the mutant selection window (MSW) hypothesis. METHODS AND RESULTS: Danofloxacin at seven dosing regimens and 5 days of treatment were simulated to quantify the bactericidal kinetics and enrichment of resistant mutants upon continuous antibiotic exposure. The magnitudes of PK/PD targets associated with different efficacies were determined in the model. The 24 h area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratios (AUC24h/MIC) of danofloxacin associated with bacteriostatic, bactericidal and eradication effects against P. multocida were 34, 52, and 64 h. This translates to average danofloxacin concentrations (Cav) over 24 h being 1.42, 2.17, and 2.67 times the MIC, respectively. An AUC/MIC-dependent antibacterial efficacy and AUC/mutant prevention concentration (MPC)-dependent enrichment of P. multocida mutants in which maximum losses in danofloxacin susceptibility occurred at a simulated AUC24h/MIC ratio of 72 h (i.e. Cav of three times the MIC). The overexpression of efflux pumps (acrAB-tolC) and their regulatory genes (marA, soxS, and ramA) was associated with reduced susceptibility in danofloxacin-exposed P. multocida. The AUC24h/MPC ratio of 19 h (i.e. Cav of 0.8 times the MPC) was determined to be the minimum mutant prevention target value for the selection of resistant P. multocida mutants. CONCLUSIONS: The emergence of P. multocida resistance to danofloxacin exhibited a concentration-dependent pattern and was consistent with the MSW hypothesis. The current clinical dosing regimen of danofloxacin (2.5 mg kg-1) may have a risk of treatment failure due to inducible fluoroquinolone resistance.

Belantamab mafodotin concentration-QTc relationships in patients with relapsed or refractory multiple myeloma from the DREAMM-1 and -2 studies.

AIMS: To evaluate relationships between plasma concentrations of belantamab mafodotin, total monoclonal antibody, and its payload and changes in electrocardiogram (ECG) parameters in patients with relapsed or refractory multiple myeloma from the DREAMM-1 and DREAMM-2 studies. METHODS: Hysteresis plots and linear regression analyses of pharmacokinetic (PK) analyte (belantamab mafodotin, total monoclonal antibody, and cytotoxic cysteine-maleimidocaproyl monomethyl auristatin F payload) concentrations vs. time-matched ECG parameters (absolute/change from baseline in QT interval corrected for RR interval [QTc/ΔQTc] and QT interval corrected for heart rate by Fridericia's formula [QTcF/ΔQTcF]) were performed. Concentrations of PK analyte required for a 10-ms increase in QTc in DREAMM-2 were calculated via simulation, as was the probability of ΔQTc/ΔQTcF exceeding 10 ms for the expected Cmax of PK analyte concentrations associated with the doses (2.5 and 3.4 mg/kg) administered in DREAMM-2. RESULTS: Time-matched PK and ECG data from 290 patients (DREAMM-1, n = 73; DREAMM-2, n = 217) were analysed. Hysteresis plots did not clearly indicate any concentration-related prolongation in QTc or QTcF; regression analyses indicated a very small rate of increase in ΔQTc and ΔQTcF with increasing concentrations of PK analytes. Calculated concentrations of PK analyte required for a 10-ms prolongation in QTc were higher than the maximum analyte concentrations observed following treatment with belantamab mafodotin in DREAMM-2; the probability that each dose would prolong ΔQTc and ΔQTcF by >10 ms was 0 and <0.25%, respectively. CONCLUSION: This study of belantamab mafodotin and its payload did not provide evidence of QT prolongation in patients with relapsed or refractory multiple myeloma at clinically relevant doses.

Pharmacokinetic-Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity.

This study aimed to investigate the effect of in vivo pH-responsive doxorubicin (DOX) release and the targetability of pilot molecules in folic acid (FA)-modified micelles using a pharmacokinetic-pharmacodynamic (PK-PD) model. The time profiles of intratumoral DOX concentrations in Walker256 tumor-bearing rats were monitored using a microdialysis probe, followed by compartmental analysis, to evaluate intratumoral tissue pharmacokinetics. Maximal DOX was released from micelles 350 min after the administration of pH-responsive DOX-releasing micelles. However, FA modification of the micelles shortened the time to peak drug concentration to 150 min. Additionally, FA modification resulted in a 27-fold increase in the tumor inflow rate constant. Walker256 tumor-bearing rats were subsequently treated with DOX, pH-responsive DOX-releasing micelles, and pH-responsive DOX-releasing FA-modified micelles to monitor the tumor growth-time profiles. An intratumoral threshold concentration of DOX (55-64 ng/g tumor) was introduced into the drug efficacy compartment to construct a PD model, followed by PK-PD analysis of the tumor growth-time profiles. Similar results of threshold concentration and drug potency of DOX were obtained across all three formulations. Cell proliferation was delayed as the drug delivery ability of DOX was improved. The PK model, which was developed using the microdialysis method, revealed the intratumoral pH-responsive DOX distribution profiles. This facilitated the estimation of intratumoral PK parameters. The PD model with threshold concentrations contributed to the estimation of PD parameters in the three formulations, with consistent mechanisms observed. We believe that our PK-PD model can objectively assess the contributions of pH-responsive release ability and pilot molecule targetability to pharmacological effects.

Assessing microplastics-antibiotics coexistence induced ciprofloxacin-resistant Pseudomonas aeruginosa at a water region scale.

Microplastics (MPs) waste is widespread globally in water systems. The opportunistic human pathogen Pseudomonas aeruginosa can cause serious acute and chronic infections that are notoriously difficult to treat. Ciprofloxacin (CIP) is broadly applied as an anti-P. aeruginosa drug. A growing evidence reveals that antibiotic-resistance genes-carrying Pseudomonas aeruginosa were detected on MPs forming plastisphere due to their adsorbability along with high occurrence of CIP in water environments. The MPs-niched CIP-resistant P. aeruginosa has been likely to emerge as an unignorable public health issue. Here, we offered a novel approach to assess the development of CIP-resistant P. aeruginosa under MPs-antibiotic coexistence at a water region scale. By combing the adsorption isotherm models used to estimate CIP condensation around MPs and a pharmacokinetic/pharmacodynamic-based microbial population dynamic model, we predicted the P. aeruginosa development on CIP-adsorbed MPs in waters. Our assessment revealed a high antibiotic resistance in the P. aeruginosa populations (∼50 %) with a wider range of waterborne total cell counts (∼10-2-104 cfu mL-1) among water regions in that the resistance proportion was primarily determined by CIP pollution level and relative abundance of various polymer type of MPs. We implicate that water region-specific MPs were highly likely to provide media for P. aeruginosa propagation. Our results highlight the importance of antibiotic-resistant pathogen colonization-emerging environmental medium interactions when addressing global threat from MPs pollution, in the context of MPs-antibiotics co-contamination assessment and for the continued provision of water system management.

Ex vivo pharmacokinetic/pharmacodynamic of hexahydrocolupulone against Clostridium perfringens in broiler chickens.

The economic impact of necrotizing enteritis (NE) resulting from Clostridium perfringens infection has been significant within the broiler industry. This study primarily investigated the antibacterial efficacy of hexahydrocolupulone against C. perfringens, and its pharmacokinetics within the ileal contents of broiler chickens. Additionally, a dosing regimen was developed based on the pharmacokinetic/pharmacodynamic (PK/PD) model specific to broiler chickens. Results of the study indicated that the minimum inhibitory concentration (MIC) of hexahydrocolupulone against C. perfringens ranged from 2 mg/L to 16 mg/L in MH broth. However, in ileal content, the MIC ranged from 8 mg/L to 64 mg/L. The mutation prevention concentration (MPC) in the culture medium was found to be 128 mg/L. After oral administration of hexahydrocolupulone at a single dosage of 10-40 mg/kg bodyweight, the peak concentration (Cmax), maximum concentration time (Tmax), and area under the concentration-time curve (AUC) in ileal content of broiler chickens were 291.42-3519.50 µg/g, 1-1.5 h, and 478.99-3121.41 µg h/g, respectively. By integrating the in vivo PK and ex vivo PD data, the AUC0-24h/MIC values required for achieving bacteriostatic, bactericidal, and bacterial eradication effects were determined to be 36.79, 52.67, and 62.71 h, respectively. A dosage regimen of 32.9 mg/kg at 24 h intervals for a duration of 3 days would yield therapeutic efficacy in broiler chickens against C. perfringens, provided that the MIC below 4 mg/L.

Pharmacokinetic and pharmacodynamic evaluation of nitrofurantoin against Escherichia coli in a murine urinary tract infection model.

The antimicrobial agent nitrofurantoin is becoming increasingly important for treatment of urinary tract infections (UTIs) due to widespread occurrence of multidrug-resistant Escherichia coli. Despite many years of use, little data on nitrofurantoin pharmacokinetics (PK) or -dynamics (PD) exist. The objective of this study was to (i) evaluate the pharmacokinetics of nitrofurantoin in a mouse model and (ii) use that data to design an in vivo dose fractionation study in an experimental model of UTI with E. coli for determination of the most predictive PK/PD index. Nitrofurantoin concentrations in urine were approximately 100-fold larger than concentrations in plasma after oral administration of 5, 10, and 20 mg/kg nitrofurantoin. The area under the curve over the minimum inhibitory concentration (AUC/MIC) was weakly correlated to bacterial reduction in urine (r2 = 0.24), while no such correlation was found for the time that nitrofurantoin stayed above the MIC (T > MIC). Increasing size of single-dose treatment was significantly correlated to eradication of bacteria in the urine, while this was not apparent when the same doses were divided in 2 or 3 doses 8 or 12 h apart. In conclusion, the results indicate that nitrofurantoin activity against E. coli in urine is driven by AUC/MIC.

Cassia angustifolia and tacrolimus interaction in a liver transplant patient, a case report.

Cassia angustifolia is a species of plant from the Senna family that has traditionally been used as a laxative in different herbal products and commercial medicines. Even though there are few documented drug-plant interactions, the use of C. angustifolia with different drugs may have additive effects, such as with other laxatives or potassium-depleting diuretics. Its use also increases peristalsis which, may reduce drug absorption. The combination with digoxin has been associated with an increased risk of digoxin toxicity, probably due to an increase in plasma digoxin concentrations and hypokalaemia. We present a case with supratherapeutic trough concentration of tacrolimus, an immunosuppressive agent, and a herbal product in a liver transplant patient after concomitant intake of tacrolimus and a herbal product based on C. angustifolia, suggesting a possible drug-lant interaction through by P-glycoprotein. We observed an increase in the patient's blood concentration 2.8-fold and the area under the curve at steady state 2.1-fold. This interaction could be of clinical relevance, given the dose-dependent side effects of tacrolimus, such as nephrotoxicity, neurotoxicity, hypertension, hyperglycaemia, or electrolyte alterations.

Evaluating omadacycline dosing regimens against drug-resistant pathogens including Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae in adults: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

The objective of this study was to evaluate the efficacy of various dosing regimens of omadacycline against main drug-resistant pathogens in the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Monte Carlo simulations were conducted using pharmacokinetic parameters and pharmacodynamic data to calculate cumulative fractions of response (CFRs) in terms of drug area under the concentration curve/minimum inhibition concentration targets.CFR ≥ 90% was considered optimal for a dosage regimen. CFR of any approved oral/intravenous regimen with loading-dose was ≥ 90% against methicillin-resistant Staphylococcus aureus (MRSA) for ABSSSI and penicillin-resistant Streptococcus pneumonia, tetracycline-resistant Streptococcus pneumonia, MRSA and ß-lactamase positive Haemophilus influenzae for CABP. In conclusion, approved oral/intravenous loading and maintenance doses of omadacycline showed enough efficacy in the treatment of ABSSI and CABP caused by the main drug-resistant pathogens.

Revisiting the Checkerboard to Inform Development of ß-Lactam/ß-Lactamase Inhibitor Combinations.

A two-dimensional "checkerboard" array employing systematic titration (e.g., serial two-fold dilutions) is a well-established in vitro method for exploring the antibacterial effects of novel drug combinations. Minimum inhibitory concentrations (MICs) on the checkerboard are isoeffective points at which the antibiotic potency is the same. Representations of checkerboard MIC curves for a ß-lactam and ß-lactamase inhibitor combination are used in hypothetical "thought experiments" and reveal the ways in which current practices can be improved. Because different types of response (i.e., independence vs. additivity vs. one effective agent; interaction vs. noninteraction) produce different MIC curves, data from different strains/isolates should not be pooled indiscriminately, as the composition of a pooled dataset will influence any derived pharmacokinetic/pharmacodynamic (PK/PD) index. Because the ß-lactamase inhibitor threshold concentration (CT) parameter is a function of the ß-lactam partner dosing regimen, it is not possible to derive a universal PK/PD index target based on CT. Alternative susceptibility testing methods represent different planes through the checkerboard; a fixed ratio method is less prone to bias for all ß-lactam and ß-lactamase inhibitor combinations. Susceptibility test MICs will often not reflect the sensitivity of the strain/isolate to the ß-lactamase inhibitor, so the use of these MICs to normalize PK/PD indices is inappropriate.

Integrated pharmacokinetic-pharmacodynamic modeling and metabolomic research on polyphenol-rich fraction of Thymus quinquecostatus Celak. Alleviating cerebral ischemia-reperfusion injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Thymus quinquecostatus Celak., a member of thymus genus in Lamiaceae family, has been used as a folk medicine for relieving exterior syndrome and alleviating pain in China. The polyphenol-rich fraction (PRF) derived from Thymus quinquecostatus Celak. had been validated that it can protect cerebral ischemia-reperfusion injury (CIRI) by activating Keap1/Nrf2/HO-1 signaling pathway. AIM OF THIS STUDY: To explore effective components and their pharmacokinetic and pharmacodynamic characteristics as well as possible mechanisms of PRF in treating CIRI. MATERIALS AND METHODS: Normal treated group (NTG) and tMCAO model treated group (MTG) rats were administrated PRF intragastrically. The prototype components and metabolites of PRF in plasma and brain were analyzed by the UPLC-Q-Exactive Orbitrap MSn method. Subsequently, the pharmacokinetics properties of indicative components were performed based on HPLC-QQQ-MS/MS. SOD and LDH activities were determined to study the pharmacodynamic (PD) properties of PRF. The PK-PD relationship of PRF was constructed. In addition, the effect of PRF on endogenous metabolites in plasma and brain was investigated using metabolomic method. RESULTS: Salvianic acid A, caffeic acid, rosmarinic acid, scutellarin, and apigenin-7-O-glucuronide were selected as indicative components based on metabolic analysis. The non-compartmental parameters were calculated for indicative components in plasma and brain of NTG and MTG rats. Furthermore, single-component and multi-component PK-PD modeling involved Emax, Imax PD models for effect indexes were fitted as well as ANN models were established, which indicated that these components can work together to regulate SOD and LDH activities in plasma and SOD activity in brain tissue to improve CIRI. Additionally, PRF may ameliorate CIRI by regulating the disorder of endogenous metabolites in lipid metabolism, amino acid metabolism, and purine metabolism pathways in vivo, among which lipid metabolism and purine metabolism are closely related to oxidative stress. CONCLUSION: The PK-PD properties of effect substances and mechanisms of PRF anti-CIRI were further elaborated. The findings provide a convincing foundation for the application of T. quinquecostatus Celak. in the maintenance of human health disorders.

Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis.

PURPOSE: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. METHODS: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design). RESULTS: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality. CONCLUSIONS: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes.

Stereoselective Analysis of the Antiseizure Activity of Fenfluramine and Norfenfluramine in Mice: Is l-Norfenfluramine a Better Follow-Up Compound to Racemic-Fenfluramine?

The aim of this study was to investigate the comparative antiseizure activity of the l-enantiomers of d,l-fenfluramine and d,l-norfenfluramine and to evaluate the relationship between their concentration in plasma and brain and anticonvulsant activity. d,l-Fenfluramine, d,l-norfenfluramine and their individual enantiomers were evaluated in the mouse maximal electroshock seizure (MES) test. d,l-Fenfluramine, d,l-norfenfluramine and their individual l-enantiomers were also assessed in the DBA/2 mouse audiogenic seizure model. All compounds were administered intraperitoneally. Brain and plasma concentrations of the test compounds in DBA/2 mice were quantified and correlated with anticonvulsant activity. In the MES test, fenfluramine, norfenfluramine and their enantiomers showed comparable anticonvulsant activity, with ED50 values between 5.1 and 14.8 mg/kg. In the audiogenic seizure model, l-norfenfluramine was 9 times more potent than d,l-fenfluramine and 15 times more potent than l-fenfluramine based on ED50 (1.2 vs. 10.2 and 17.7 mg/kg, respectively). Brain concentrations of all compounds were about 20-fold higher than in plasma. Based on brain EC50 values, l-norfenfluramine was 7 times more potent than d,l-fenfluramine and 13 times more potent than l-fenfluramine (1940 vs. 13,200 and 25,400 ng/g, respectively). EC50 values for metabolically formed d,l-norfenfluramine and l-norfenfluramine were similar to brain EC50 values of the same compounds administered as such, suggesting that, in the audiogenic seizure model, the metabolites were responsible for the antiseizure activity of the parent compounds. Because of the evidence linking d-norfenfluramine to d,l-fenfluramine to cardiovascular and metabolic adverse effects, their l-enantiomers could potentially be safer follow-up compounds to d,l-fenfluramine. We found that, in the models tested, the activity of l-fenfluramine and l-norfenfluramine was comparable to that of the corresponding racemates. Based on the results in DBA/2 mice and other considerations, l-norfenfluramine appears to be a particularly attractive candidate for further evaluation as a novel, enantiomerically pure antiseizure medication.