Metabolomics unveil key pathways underlying the synergistic activities of aztreonam and avibactam against multidrug-resistant Escherichia coli.

PURPOSE: Aztreonam/avibactam is effective against serious infections caused by Gram-negative bacteria including Enterobacterales harboring metallo-ß-lactamases. While the utility of this combination has been established in vitro and in clinical trials, the purpose of this study is to enhance our understanding of the underlying mechanism responsible for their activities through metabolomic profiling of a multidrug-resistant Escherichia coli clinical isolate. METHODS: Metabolomic analyses of time-dependent changes in endogenous bacterial metabolites in a clinical isolate of a multidrug-resistant E. coli treated with aztreonam and avibactam were performed. E. coli metabolomes were compared at 15 min, 1 h and 24 h following treatments with either avibactam (4 mg/L), aztreonam (4 mg/L), or aztreonam (4 mg/L) + avibactam (4 mg/L). RESULTS: Drug treatment affected 326 metabolites with magnitude changes of at least 2-fold, most of which are involved primarily in peptidoglycan biosynthesis, nucleotide metabolism, and lipid metabolism. The feedstocks for peptidoglycan synthesis were depleted by aztreonam/avibactam combination; a significant downstream increase in nucleotide metabolites and a release of lipids were observed at the three timepoints. CONCLUSION: The findings indicate that the aztreonam/avibactam combination accelerates structural damage to the bacterial membrane structure and their actions were immediate and sustained compared to aztreonam or avibactam alone. By inhibiting the production of crucial cell wall precursors, the combination may have inflicted damages on bacterial DNA.

Utility and impact of quantitative pharmacology on dose selection and clinical development of immuno-oncology therapy.

Immuno-oncology (IO) therapies have changed the cancer treatment landscape. Immune checkpoint inhibitors (ICIs) have improved overall survival in 20-40% of patients with malignancies that were previously refractory. Due to the uniqueness in biology, modalities and patient responses, drug development strategies for IO differed from that traditionally used for cytotoxic and target therapies in oncology, and quantitative pharmacology utilizing modeling approach can be applied in all phases of the development process. In this review, we used case studies to showcase how various modeling methodologies were applied from translational science and dose selection through to label change, using examples that included anti-programmed-death-1 (anti-PD-1), anti-programmed-death ligand-1 (anti-PD-L1), anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), and anti-glucocorticoid-induced tumor necrosis factor receptor-related protein (anti-GITR) antibodies. How these approaches were utilized to support phase I-III dose selection, the design of phase III trials, and regulatory decisions on label change are discussed to illustrate development strategies. Model-based quantitative approaches have positively impacted IO drug development, and a better understanding of the biology and exposure-response relationship may benefit the development and optimization of new IO therapies.

Simultaneous Determination of Levo-tetrahydropalmatine and Naltrexone in Rat Plasma by LC-MS/MS and its Application in a Pharmacokinetic Study.

BACKGROUND: Levo-tetrahydropalmatine and low-dose naltrexone are used in association with reducing cocaine-related cravings, but there are no analytical methods for the quantitative simultaneous analysis of this drug combination. OBJECTIVE: A highly selective and sensitive LC-MS/MS assay was developed and validated to simultaneously quantify l-THP and naltrexone. The analytical method for l-THP offers improved sensitivity compared to previously published methods. METHODS: The product ion transitions of l-THP and naltrexone were 357.0→193.0 and 342.2→324.1, respectively. Chromatographic separations were performed using a BEH-C18 column by an isocratic elution mode with acetonitrile and 0.1% formic acid in water containing 3 mM ammonium acetate. L-THP and naltrexone were extracted from rat plasma using a liquidliquid extraction method. RESULTS: For l-THP and naltrexone, the assay displayed good linear response over a concentration range of 0.5-1000 ng/mL and 0.25-500 ng/mL, respectively. The intra-day accuracy of the method for l-THP and naltrexone was 93.8-101% with a precision (%CV) of 2.43-8.15% and 93.4-108% with a precision of 3.47-8.22%. The inter-day accuracy for l-THP and naltrexone was 91.2-102% with a CV of 2.46-8.06% and 91.5-97.8% with a CV of 3.29-8.92%, respectively. CONCLUSION: The assay has been used for pharmacokinetic studies of l-THP and naltrexone in the rat.

Comparative metabolomics reveal key pathways associated with the synergistic activities of aztreonam and clavulanate combination against multidrug-resistant Escherichia coli.

IMPORTANCE: Multidrug-resistant Escherichia coli is a major threat to the health care system and is associated with poor outcomes in infected patients. The combined use of antibiotics has become an important treatment method for multidrug-resistant bacteria. However, the mechanism for their synergism has yet to be explored.

Metabolomics revealed mechanism for the synergistic effect of sulbactam, polymyxin-B and amikacin combination against Acinetobacter baumannii.

Introduction: The emergence of multidrug-resistant (MDR) Acinetobacter baumannii prompts clinicians to consider treating these infections with polymyxin combination. Methods: Metabolomic analysis was applied to investigate the synergistic effects of polymyxin-B, amikacin and sulbactam combination therapy against MDR A. baumannii harboring OXA-23 and other drug resistant genes. The drug concentrations tested were based on their clinical breakpoints: polymyxin-B (2 mg/L), amikacin (16 mg/L), polymyxin-B/amikacin (2/16 mg/L), and polymyxin-B/amikacin/sulbactam (2/16/4 mg/L). Results: The triple antibiotic combination significantly disrupted levels of metabolites involved in cell outer membrane structure including fatty acids, glycerophospholipids, nucleotides, amino acids and peptides as early as 15 min after administration. Amikacin and polymyxin-B alone perturbed a large number of metabolites at 15 min and 1 h, respectively, but the changes in metabolites were short-lived lasting for less than 4 h. In contrast, the combination treatment disrupted a large amount of metabolites beyond 4 h. Compared to the double-combination, the addition of sulbactam to polymyxin-B/amikacin combination produce a greater disorder in A. baumannii metabolome that further confer susceptibility of bacteria to the antibiotics. Conclusion: The metabolomic analysis identified mechanisms responsible for the synergistic activities of polymyxin-B/amikacin/sulbactam against MDR A. baumannii.

Physiologically-based pharmacokinetic modeling to inform dosing regimens and routes of administration of rifampicin and colistin combination against Acinetobacter baumannii.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) is resistant to major antibiotics such as penicillin, cephalosporin, fluoroquinolone and aminoglycoside, and has become a significant nosocomial pathogen. The efficacy of rifampicin and colistin combination against CRAB could be dependent on the administration routes and drug concentrations at the site of infection. OBJECTIVE: The objective is to predict drug disposition in biological tissues. Treatment efficacy is extrapolated by assessing respective pharmacodynamic (PD) indices, as well as parameters associated with the emergence of resistance. METHODS: Physiologically-based pharmacokinetic models of rifampicin and colistin were utilized to predict tissue exposures. Dosing regimens and administration routes for combination therapy were evaluated in terms of in vitro antimicrobial susceptibility of A. baumannii associated with targeted PD indices and resistance parameters. RESULTS: Simulated exposures in blood, heart, lung, skin and brain were consistent with reported penetration rates. The results demonstrated that a combination of colistin and rifampicin using conventional intravenous (i.v.) doses could achieve effective exposures in the blood and skin. However, for lung infections, colistin by inhalation would be required due to low lung penetration from intravenous route. Inhaled colistin alone provided good PD coverage but this practice could encourage the emergence of additional resistance which may be overcome by a combination regimen that includes inhaled rifampicin. CONCLUSION: This in silico extrapolation provides valuable information on dosing regimens and routes of administration against CRAB infections in specific tissues. The PBPK modeling approach could be a non-invasive way to inform therapeutic benefits of combination antimicrobial therapy.

Physiologically based pharmacokinetic modelling to inform combination dosing regimens of ceftaroline and daptomycin in special populations.

AIMS: The combination of daptomycin and ceftaroline used as salvage therapy is associated with higher survival and decreased clinical failure in complicated methicillin-resistant Staphylococcus aureus (MRSA) infections that are resistant to standard MRSA treatment. This study aimed to evaluate dosing regimens for coadministration of daptomycin and ceftaroline in special populations including paediatrics, renally impaired (RI), obese and geriatrics that generate sufficient coverage against daptomycin-resistant MRSA. METHODS: Physiologically based pharmacokinetic models were developed from pharmacokinetic studies of healthy adults, geriatric, paediatric, obese and RI patients. The predicted profiles were used to evaluate joint probability of target attainment (PTA), as well as tissue-to-plasma ratios. RESULTS: The adult dosing regimens of 6 mg/kg every (q)24h or q48h daptomycin and 300-600 mg q12h ceftaroline fosamil by RI categories achieved ≥90% joint PTA when the minimum inhibitory concentrations in the combination are at or below 1 and 4 µg/mL against MRSA. In paediatrics, wherein there is no recommended daptomycin dosing regimen for S. aureus bacteraemia, ≥90% joint PTA is achieved when the minimum inhibitory concentrations in the combination are up to 0.5 and 2 µg/mL for standard paediatric dosing regimens of 7 mg/kg q24h daptomycin and 12 mg/kg q8h ceftaroline fosamil. Model predicted tissue-to-plasma ratios of 0.3 and 0.7 in the skin and lung, respectively, for ceftaroline and 0.8 in the skin for daptomycin. CONCLUSION: Our work illustrates how physiologically based pharmacokinetic modelling can inform appropriate dosing of adult and paediatric patients and thereby enable prediction of target attainment in the patients during multitherapies.

Pharmacokinetic/Pharmacodynamic Evaluation of Aztreonam/Amoxicillin/Clavulanate Combination against New Delhi Metallo-ß-Lactamase and Serine-ß-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-ß-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 ß-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 ß-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.

Population Pharmacokinetics and Pharmacodynamics of Crizanlizumab in Healthy Subjects and Patients with Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: Crizanlizumab is a humanized monoclonal antibody against P-selectin for the prevention of vaso-occlusive crises in sickle cell disease (SCD). The objective of this study was to investigate crizanlizumab population pharmacokinetics (PK) and pharmacodynamics (PD), as well as influential covariates. METHODS: A population PK model for crizanlizumab was developed from healthy volunteer and SCD patient data, using a two-compartment intravenous infusion model utilizing a target-mediated drug disposition (TMDD) approach. The relationship between crizanlizumab concentration and ex vivo P-selectin inhibition was fitted to a non-linear sigmoidal Emax model. Covariate selection was performed in a stepwise manner. RESULTS: Crizanlizumab exhibits nonlinear pharmacokinetics in the wide dose range of 0.2-8 mg/kg body weight. The population pharmacokinetic base model incorporated body weight as covariate in the form of allometric scaling wherein the exponents were fixed to 0.8. SCD patients had higher baseline soluble P-selectin concentration, resulting in a higher estimated initial target concentration. The typical individual in the model is a 70 kg SCD patient with normal renal function and a baseline albumin of 43 g/L; CL was 0.012 L/h while Vss was 5.2 L. For the population PD model, none of the identified additional factors beyond PD assay and covariates, such as body weight at baseline nor patient type differences, led to relevant differences in P-selectin % inhibition. CONCLUSIONS: Renal and hepatic impairments, concomitant hydroxyurea usage, and presence of anti-drug antibody are not expected to impact the exposure of crizanlizumab. The model allows for extrapolating the PK of crizanlizumab to pediatric population and evaluation of alternative regimens and route of administration. TRIAL REGISTRATION NUMBER [DATE OF REGISTRATION]: SUSTAIN (CSEG101A2201 Phase 2), ClinicalTrials.gov identifier: NCT01895361 [10 July 2013]; CSEG101A2202 (Phase 2), ClinicalTrials.gov identifier: NCT03264989 [29 August 2017].

The combination effect of meropenem/sulbactam/polymyxin-B on the pharmacodynamic parameters for mutant selection windows against carbapenem-resistant Acinetobacter baumannii.

The objective of this study was to evaluate whether combinations of sulbactam, meropenem, and polymyxin-B could reduce or close the gap of mutant selection window (MSW) of individual antibiotics against Acinetobacter baumannii harboring OXA-23. MICs of three antimicrobials used alone and in combination (meropenem/polymyxin-B or meropenem/polymyxin-B/sulbactam) were obtained in 11 clinical isolates and mutant prevention concentrations were determined in 4 of the 11 isolates. All isolates were resistant to meropenem or polymyxin-B. Combining meropenem and polymyxin-B with or without sulbactam resulted in synergistic bactericidal activities. Pharmacokinetic (PK) simulations of drug concentrations in the blood and epithelial lining fluid coupled with pharmacodynamic (PD) evaluations revealed that the fractions of time over the 24-h in terms of free drug concentration within the MSW (fTMSW) and above the MPC (fT>MPC) were optimized by combination therapy. The resultant clinical regimens of meropenem, polymyxin-B, and sulbactam evaluated in the PK-PD analysis were 2 g q8h, 2.5 mg/kg loading dose followed by 1.5 mg/kg q12h, and 3 g q8h, respectively, in patients with normal renal function. Subsequent corresponding equivalent exposure regimens would depend on the extent of renal failure. The overall results indicate that combination antibiotics consisting of sulbactam/meropenem/polymyxin-B can confer potential efficacy against A. baumannii harboring OXA-23, and reduce the opportunity for bacteria to develop further resistance. This study provides a framework for pharmacodynamic evaluation of drug-resistant mutant suppression in an antimicrobial co-administration setting. The results thereby lay the groundwork for additional studies and future clinical confirmation is warranted.

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.

Metabolomic profiling of polymyxin-B in combination with meropenem and sulbactam against multi-drug resistant Acinetobacter baumannii.

Empirical therapies using polymyxins combined with other antibiotics are recommended in the treatment of Acinetobacter baumannii infections. In the present study, the synergistic activities of polymyxin-B, meropenem, and sulbactam as combination therapy were investigated using metabolomic analysis. The metabolome of A. baumannii was investigated after treatment with polymyxin-B alone (2 mg/l), meropenem (2 mg/l) alone, combination of polymyxin-B/meropenem at their clinical breakpoints, and triple-antibiotic combination of polymyxin-B/meropenem and 4 mg/l sulbactam. The triple-antibiotic combination significantly changed the metabolite levels involved in cell outer membrane and cell wall biosynthesis, including fatty acid, glycerophospholipid, lipopolysaccharide, peptidoglycan, and nucleotide within 15 min of administration. In contrast, significant changes in metabolome were observed after 1 h in sample treated with either meropenem or polymyxin-B alone. After 1 h of administration, the double and triple combination therapies significantly disrupted nucleotide and amino acid biosynthesis pathways as well as the central carbon metabolism, including pentose phosphate and glycolysis/gluconeogenesis pathways, and tricarboxylic acid cycle. The addition of sulbactam to polymyxin-B and meropenem combination appeared to be an early disruptor of A. baumannii metabolome, which paves the way for further antibiotic penetration into bacteria cells. Combination antibiotics consisting of sulbactam/meropenem/polymyxin-B can effectively confer susceptibility to A. baumannii harboring OXA-23 and other drug resistant genes. Metabolomic profiling reveals underlying mechanisms of synergistic effects of polymyxin-B combined with meropenem and sulbactam against multi-drug resistant A. baumannii.

Prediction of Tissue Exposures of Meropenem, Colistin, and Sulbactam in Pediatrics Using Physiologically Based Pharmacokinetic Modeling.

BACKGROUND: The combination of polymyxins, meropenem, and sulbactam demonstrated efficacy against multi-drug-resistant bacillus Acinetobacter baumannii. These three antibiotics are commonly used against major blood, skin, lung, and heart muscle infections. OBJECTIVE: The objective of this study was to predict drug disposition and extrapolate the efficacy in these tissues using a physiologically based pharmacokinetic modeling approach that linked drug exposures to their target pharmacodynamic indices associated with antimicrobial activities against A. baumannii. METHODS: An adult physiologically based pharmacokinetic model was developed for meropenem, colistin, and sulbactam and scaled to pediatrics accounting for both renal and non-renal clearances. The model reliability was evaluated by comparing simulated plasma and tissue drug exposures to observed data. Target pharmacodynamic indices were used to evaluate whether pediatric and adult dosing regimens provided sufficient coverage. RESULTS: The modeled plasma drug exposures in adults and pediatric patients were consistent with reported literature data. The mean fold errors for meropenem, colistin, and sulbactam were in the range of 0.710-1.37, 0.981-1.47, and 0.647-1.39, respectively. Simulated exposures in the blood, skin, lung, and heart were consistent with reported penetration rates. In a virtual pediatric population aged from 2 to < 18 years, the interpretive breakpoints were achieved in 85-90% of subjects for their targeted pharmacodynamic indices after administration of pediatric dosing regimens consisting of 30 mg/kg of meropenem, and 40 mg/kg of sulbactam three times daily as a 3-h or continuous infusion and 5 mg/kg/day of colistin base activity. CONCLUSIONS: The physiologically based pharmacokinetic modeling supports pediatric dosing regimens of meropenem/colistin/sulbactam in a co-administration setting against infections in the blood, lung, skin, and heart tissues due to A. baumannii.

Exposure-Efficacy Analysis of Asciminib in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase.

Asciminib (Scemblix) is a first-in-class BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP) and has potent activity against the T315I mutation. This study aimed to characterize the effect of asciminib exposure on disease progression and to elucidate factors influencing efficacy. Our analysis included 303 patients with chronic myeloid leukemia in chronic phase recruited in a phase I study with dose ranging from 10 to 200 mg twice a day (b.i.d.) or 40 to 200 mg once a day (q.d.) (NCT02081378) and in the phase III ASCEMBL (Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs) study receiving asciminib 40 mg b.i.d. (NCT03106779). A total of 67 patients harbored the T315I mutation. A longitudinal pharmacokinetic/pharmacodynamic model was developed to characterize the exposure-efficacy relationship, in which the efficacy was assessed through BCR::ABL1 transcript levels over time. Specifically, a three-compartment model representing quiescent leukemic stem cells, proliferating bone marrow cells, and resistant cells was developed. Drug killing of the proliferating cells by asciminib was characterized by a power model. A subgroup analysis was performed on the patients with the T315I mutation using a maximum drug effect model to characterize the drug effect. The model demonstrated the appropriateness of a total daily dose of asciminib 80 mg in patients without the T315I mutation and 200 mg b.i.d. in patients with the T315I mutation with further validation in light of safety data. This model captured key characteristics of patients' response to asciminib and helped inform dosing rationale for resistant and difficult-to-treat populations.

Model-informed drug development for immuno-oncology agonistic anti-GITR antibody GWN323: Dose selection based on MABEL and biologically active dose.

GWN323, an agonistic human anti-GITR (glucocorticoid-induced TNFR-related protein) IgG1 antibody, was studied clinically as an immuno-oncology therapeutic agent. A model-based minimum anticipated biological effect level (MABEL) approach integrating in vitro and in vivo data informed dose selection for the first-in-human (FIH) study. Data evaluated included pharmacokinetics (PK) of DTA-1.mIgG2a (mouse surrogate GITR antibody for GWN323), target-engagement pharmacodynamic (PD) marker soluble GITR (sGITR), tumor shrinkage in Colon26 syngeneic mice administered with DTA-1.mIgG2a, cytokine release of GWN323 in human peripheral blood mononuclear cells, and GITR binding affinity. A PK model was developed to describe DTA-1.mIgG2a PK, and its relationship with sGITR was also modeled. Human GWN323 PK was predicted by allometric scaling of mouse PK. Based on the totality of PK/PD modeling and in vitro and in vivo pharmacology and toxicology data, MABEL was estimated to be 3-10 mg once every 3 weeks (Q3W), which informed the starting dose selection of the FIH study. Based on tumor kinetic PK/PD modeling of tumor inhibition by DTA-1.mIgG2a in Colon26 mice and the predicted human PK of GWN323, the biologically active dose of GWN323 was predicted to be 350 mg Q3W, which informed the dose escalation of the FIH study. GWN323 PK from the FIH study was described by a population PK model; the relationship with ex vivo interleukin-2 release, a target-engagement marker, was also modeled. The clinical PK/PD modeling data supported the biological active dose projected from the translational PK/PD modeling in a "learn and confirm" paradigm of model-informed drug development of GWN323.

Florfenicol/Chlortetracycline Effect on Pharmacodynamic Indices for Mutant Selection of Riemerella anatipestifer in Ducks.

Riemerella anatipestifer can cause septicemia and death in ducks and geese, leading to significant economic losses to animal farms. The emergence of resistance of R. anatipestifer to commonly used antibiotics increases the difficulty of treating R. anatipestifer infection. The aim of this study was to evaluate the utility of antibiotic combination to restrict mutant selection of multidrug-resistant (MDR) R. anatipestifer isolates. Pharmacokinetics of florfenicol and chlortetracycline in Pekin ducks were evaluated using both noncompartmental analysis and population pharmacokinetic models. The areas under the curve of florfenicol and chlortetracycline after single 20 and 10 mg/kg oral administration were 49.3 and 6.84 mg*h/L, respectively. Chlortetracycline exhibited high apparent clearance and low systemic exposure. Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) values of the two antibiotics were determined in 10 and 2 MDR R. anatipestifer isolates, respectively, to derive fTMSW (the fraction of time over 24 hours wherein the free drug concentration was within the mutant selection window [MSW]) and fT>MPC (the fraction of time that the free drug concentration was above the MPC). Both fTMSW and fT>MPC were estimated from simulated concentration-time profiles relative to MIC and MPC. Florfenicol and chlortetracycline combination have additive activities against R. anatipestifer in majority of isolates and could significantly decrease monotherapy MPC of florfenicol and chlortetracycline, as well as optimize both fTMSW and fT>MPC parameters, provided that the bioavailability of chlortetracycline is improved. The application of pharmacokinetic/pharmacodynamic analyses to MPC concepts to restrict selection of mutant bacterial strains can help improve short- and long-term outcomes of antibiotic treatment in animal farms.

Population Pharmacokinetics of Asciminib in Tyrosine Kinase Inhibitor-Treated Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic and Acute Phases.

BACKGROUND: Asciminib, a first-in-class, highly potent and specific ABL/BCR-ABL1 inhibitor, has shown superior efficacy compared to bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, treated with two or more tyrosine kinase inhibitors. This study aimed to describe pharmacokinetic (PK) properties of asciminib and to identify clinically relevant covariates impacting its exposure. METHODS: A population PK (PopPK) model was developed using a two-compartment model with delayed first-order absorption and elimination. The analysis included PK data from two clinical studies (Phases 1 and 3) involving 353 patients, with total daily dose of asciminib in the range of 20-400 mg. RESULTS: The nominal total daily dose was incorporated as a structural covariate on clearance (CL), and body weight (BW) was included as a structural covariate via allometric scaling on CL and central volume. Renal function and formulation were included as statistically significant covariates on CL and absorption (ka), respectively. The simulation results revealed a modest but clinically non-significant effect of baseline BW and renal function on ka. Correlations between covariates, such as baseline demographics and disease characteristics, heavy smoking status, hepatic function, and T315I mutation status, were not statistically significant with respect to CL, and they were not incorporated in the final model. Additionally, the final model-based simulations demonstrated comparable exposure and CL for asciminib 40 mg twice daily and 80 mg once daily (an alternative regimen not studied in the Phase 3 trial), as well as similar PK properties in patients with and without the T315I mutation. CONCLUSIONS: The final PopPK model adequately characterized the PK properties of asciminib and assessed the impact of key covariates on its exposure. The model corroborates the use of the approved asciminib dose of 80 mg total daily dose as 40 mg twice daily, and supports the use of 80 mg once daily as an alternative dose regimen to facilitate patient's compliance. TRIAL REGISTRATION NUMBER [DATE OF REGISTRATION]: First-in-human (CABL001X2101, Phase 1), ClinicalTrials.gov identifier: NCT02081378 [28 February 2014]; ASCEMBL (CABL001A2301, Phase 3), ClinicalTrials.gov identifier: NCT03106779 [10 April 2017].

Aztreonam/avibactam effect on pharmacodynamic indices for mutant selection of Escherichia coli and Klebsiella pneumoniae harbouring serine- and New Delhi metallo-ß-lactamases.

OBJECTIVES: Ceftazidime/avibactam is not active against MBL-producing bacteria. Combining ceftazidime/avibactam or avibactam with aztreonam can counter the resistance of MBL-producing Enterobacterales. The aim of this study was to evaluate whether the addition of avibactam could reduce or close the mutant selection window (MSW) of aztreonam in Escherichia coli and Klebsiella pneumoniae harbouring MBLs; MSW is a pharmacodynamic (PD) parameter for the selection of emergent resistant mutants. METHODS: In vitro susceptibility of 19 clinical isolates to ceftazidime/avibactam, aztreonam alone, and in co-administration (aztreonam/ceftazidime/avibactam and aztreonam/avibactam) was determined, as well as the mutant prevention concentration (MPC). The fraction of time within 24 h that the free drug concentration was within the MSW (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) in both plasma and epithelial lining fluid (ELF) were determined from simulations of 10 000 profiles. The joint PTA was used to derive a joint cumulative fraction of response (CFR). RESULTS: All isolates were resistant to ceftazidime/avibactam or aztreonam. Combining aztreonam and avibactam or ceftazidime/avibactam resulted in synergistic bactericidal activities against all isolates. Synergism was primarily due to the aztreonam/avibactam combination. For aztreonam/avibactam dosing regimens evaluated in clinical trials, fT>MPC values were >90% and >80%, whereas fTMSW measures were <10% and <20% in plasma and ELF, respectively. The CFR was 100% for aztreonam/avibactam against the collection of clinical isolates. CONCLUSIONS: Effective antimicrobial combination optimized the PD parameters measuring selection for emergent mutants by increasing fT>MPC and reducing fTMSW.