Interspecies interactions alter the antibiotic sensitivity of Pseudomonas aeruginosa.

Polymicrobial infections are infections that are caused by multiple pathogens and are common in patients with cystic fibrosis (CF). Although polymicrobial infections are associated with poor treatment responses in CF, the effects of the ecological interactions between co-infecting pathogens on antibiotic sensitivity and treatment outcome are poorly characterized. To this end, we systematically quantified the impact of these effects on the antibiotic sensitivity of Pseudomonas aeruginosa for nine antibiotics in medium conditioned by 13 secondary cystic fibrosis-associated bacterial and fungal pathogens through time-kill assays. We fitted pharmacodynamic models to these kill curves for each antibiotic-species combination and found that interspecies interactions changing the antibiotic sensitivity of P. aeruginosa are abundant. Interactions that lower antibiotic sensitivity are more common than those that increase it, with generally more substantial reductions than increases in sensitivity. For a selection of co-infecting species, we performed pharmacokinetic-pharmacodynamic modeling of P. aeruginosa treatment. We predicted that interspecies interactions can either improve or reduce treatment response to the extent that treatment is rendered ineffective from a previously effective antibiotic dosing schedule and vice versa. In summary, we show that quantifying the ecological interaction effects as pharmacodynamic parameters is necessary to determine the abundance and the extent to which these interactions affect antibiotic sensitivity in polymicrobial infections.IMPORTANCEIn cystic fibrosis (CF) patients, chronic respiratory tract infections are often polymicrobial, involving multiple pathogens simultaneously. Polymicrobial infections are difficult to treat as they often respond unexpectedly to antibiotic treatment, which might possibly be explained because co-infecting pathogens can influence each other's antibiotic sensitivity, but it is unknown to what extent such effects occur. To investigate this, we systematically quantified the impact of co-infecting species on antibiotic sensitivity, focusing on P. aeruginosa, a common CF pathogen. We studied for a large set co-infecting species and antibiotics whether changes in antibiotic response occur. Based on these experiments, we used mathematical modeling to simulate P. aeruginosa's response to colistin and tobramycin treatment in the presence of multiple pathogens. This study offers comprehensive data on altered antibiotic sensitivity of P. aeruginosa in polymicrobial infections, serves as a foundation for optimizing treatment of such infections, and consolidates the importance of considering co-infecting pathogens.

Exposure-Efficacy Analysis and Dopamine D2 Receptor Occupancy in Adults with Schizophrenia after Treatment with the Monthly Intramuscular Injectable Risperidone ISM.

Dopamine D2 receptor occupancy (D2RO) significantly influences the clinical effectiveness and safety of many antipsychotic drugs. Maintaining a D2RO range of 65%-80% provides the best antipsychotic effects while minimizing adverse reactions. Data from a Phase III trial were used to establish an exposure-response relationship for monthly intramuscular Risperidone ISM (75 and 100 mg) or placebo administered to adults with schizophrenia. Pharmacodynamic analysis was based on an Emax model for Positive and Negative Syndrome Scale (PANSS) developed in NONMEM. Plasma concentrations of the active moiety were derived using a previously developed population pharmacokinetic model, which was used for D2RO simulations in conjunction with a published Emax model. The optimal D2RO range (65%-80%) was reached for the median within hours following the first injection of both Risperidone ISM doses. At steady state, median D2RO for both doses remained above 65% throughout the 28-day dosing period and demonstrated lower variability than oral risperidone. PANSS response did not differ significantly between dose groups, most likely because active moiety concentrations had already reached the plateau of the concentration-response relationship. The pharmacokinetic/pharmacodynamic analysis showed a profound placebo effect (-11.7%), and an additional maximal drug effect (-6.6%) resulting in a total PANSS improvement over time of -18.3%. Pharmacokinetic/pharmacodynamic modeling quantified a PANSS improvement over time after Risperidone ISM administration. The response was not significantly different in either dose group, likely because D2RO was already above the proposed efficacy threshold (65%) within 1 h after the first Risperidone ISM injection and remained above this level following repeated administrations.

Establishing a Relationship between In Vitro Potency in Cell-Based Assays and Clinical Efficacious Concentrations for Approved GLP-1 Receptor Agonists.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) play an important role in the treatment of type 2 diabetes (T2D) and obesity. The relationship between efficacy and dosing regimen has been studied extensively for this class of molecules. However, a comprehensive analysis of the translation of in vitro data to in vivo efficacious exposure is still lacking. Methods: We collected clinical pharmacokinetics for five approved GLP-1RAs to enable the simulation of exposure profiles and compared published clinical efficacy endpoints (HbA1c and body weight) with in-house in vitro potency values generated in different cell-based assays. Additionally, we investigated the correlation with target coverage, expressed as a ratio between the steady state drug exposure and unbound potency, body weight, or HbA1c reduction in patients with T2D. Results: We found that the best correlation with in vivo efficacy was seen for in vitro potency data generated in cellular assays performed in the absence of any serum albumin or using ovalbumin. Residual variability was larger using in vitro potency data generated in endogenous cell lines or in the presence of human serum albumin. For the human receptor assay with no albumin, exposures above 100-fold in vitro EC50 resulted in >1.5% point HbA1c reduction, while a 5% BW reduction was related to approximately 3× higher exposures. A similar relationship was seen in the ovalbumin assay. Conclusions: Overall, the relationship established for in vitro potency and in vivo efficacy will help to increase confidence in human dose prediction and trial design for new GLP-1RAs in the discovery and early clinical phases.

Preclinical Assessment of the PI3Kα Selective Inhibitor Inavolisib and Prediction of Its Pharmacokinetics and Efficacious Dose in Human.

1. Small molecule inhibitors of the PI3K pathway have been extensively investigated as potential anticancer agents. Among the effectors in this pathway, PI3Kα is the kinase most frequently associated with the development of tumors, through mutations and amplifications of the PIK3CA gene encoding the p110α catalytic subunit.2. Inavolisib (GDC-0077) is a potent and PI3Kα-selective inhibitor that also specifically triggers the degradation of the mutant p110α protein.3. We characterized inavolisib ADME properties in preclinical in vitro and in vivo studies, assessed its efficacy in the PIK3CA mutant KPL-4 breast cancer xenograft model, and predicted its pharmacokinetics and efficacious dose in humans.4. Inavolisib had a moderate permeability (1.9•10-6 cm/s) in MDCK cells and was a P-gp and Bcrp1 substrate. It appeared metabolically stable in hepatocytes incubations from human and preclinical species. The systemic clearance was low in mouse, monkey and dog and high in rat. Oral bioavailability ranged from 57.5% to 100%. Inavolisib was efficacious in the KPL-4 sub-cutaneous xenograft model.5. The PK/PD model parameters estimated from the efficacy study, combined with PBPK model-predicted human PK profiles, projected that a dose of 3 mg could lead to clinical response. Inavolisib is currently being tested in phase 3 trials.

In vivo pharmacodynamic evaluation of the novel nystatin derivative BSG005 in the invasive candidiasis and invasive pulmonary aspergillosis mouse models.

Nystatin, a polyene, is one of the oldest antifungal drugs with wide in vitro potency. BSG005 is a novel, chemically modified, nystatin-like molecule in development for systemic therapy. We evaluated the pharmacokinetic/pharmacodynamic (PK/PD) relationships and target exposures using in vivo invasive pulmonary aspergillosis (IPA) and invasive candidiasis (IC) infection models for BSG005 against common fungal pathogens including Aspergillus fumigatus, Candida albicans, Candida auris, and Candida glabrata. For each species group, three to four strains were selected. Minimum inhibitory concentration (MIC) testing was done by Clinical Laboratory Standards Institute (CLSI) methods. Single-dose kinetics for BSG005 were performed at four dose levels. The immunosuppressed mouse IPA model was used for A. fumigatus studies. For all Candida studies, we utilized the neutropenic disseminated candidiasis model. We used quantitative PCR to enumerate Aspergillus in the lung and colony forming units (CFU) counts for Candida in the kidney. Treatment results were evaluated based on both area under the concentration-time curve (AUC)/MIC and maximum plasma concentration (Cmax)/MIC exposures. The BSG005 MIC was 1 mg/L against all strains. Escalating doses of BSG005 resulted in increased effect and, in general, the dose-response curves within each species were concordant. The median 96-h AUC/MIC associated with net stasis was lowest at 6.08 for C. glabrata. Increasing exposures were needed for same outcome for C. auris at 18.7, C. albicans at 29.3, and A. fumigatus at 102.4. Cmax/MIC targets for the four groups were 0.22, 0.48, 0.60, and 1.41. BSG005 demonstrated potent activity against a variety of fungal pathogens in the neutropenic mouse models. Cmax/MIC PK/PD targets were numerically lower than other polyene studies using the same infection models.

Synergistic effect of fosfomycin and colistin against KPC-producing Klebsiella pneumoniae: pharmacokinetics-pharmacodynamics combined with transcriptomic approach.

OBJECTIVES: The aim of this study was to identify the synergistic effect and mechanisms of fosfomycin (FM) combined with colistin (COL) against KPC-producing Klebsiella pneumoniae (KPC-Kp). METHODS: The bactericidal effects, induced drug resistance and cytotoxicity of FM combined with COL were evaluated by time-kill assays and mutation rate test. Time-kill assays and transcriptomics analysis were used to further clarify the mechanism of FM combined with COL. The bacteria were taken from different points in time-kill assays, reactive oxygen species (ROS), nitric oxide and redox related enzymes were detected. The mechanism of synergistic bactericidal action was analyzed by transcriptome. RESULTS: The bactericidal effect of FM combined with COL was better than that of monotherapy. The mutation frequency of FM alone at low dose (8 mg/L) was higher than that at high dose (64 mg/L). COL induced resistant isolates resulted in FM and COL resistance, while FM alone or combined with COL only resulted in FM resistance. The survival rate of Thp-1 cells in FM combined with COL against K. pneumoniae was higher than that of monotherapy. The intracellular nitric oxide, activities of total superoxide dismutase and catalase were increased along with the increase of FM concentration against KPC-Kp. FM combined with COL induced ROS accumulation and antioxidant capacity increase. Transcriptome analysis showed FM combined with COL could regulate the levels of soxRS and oxidative phosphorylation, in order to clear ROS and repair damage. In addition, FM combined with COL could result in synergetic bactericidal efficacy by inhibiting ribosomal transcription. CONCLUSIONS: FM combined with COL mediated synergistic bactericidal effect by regulating ROS accumulation and inhibiting ribosomal protein transcription, resulting in lower resistance and cytotoxicity.

Review of dose justifications for antibody-drug conjugate approvals from clinical pharmacology perspective: A focus on exposure-response analyses.

Antibody-drug conjugates (ADCs) are revolutionizing cancer treatment by specific targeting of the cancer cells thereby improving the therapeutic window of the drugs. Nevertheless, they are not free from unwanted toxicities mainly resulting from non-specific targeting and release of the payload. Therefore, the dosing regimen must be optimized through integrated analysis of the risk-benefit profile, to maximize the therapeutic potential. Exposure-response (E-R) analysis is one of the most widely used tools for risk-benefit assessment and it plays a pivotal role in dose optimization of ADCs. However, compared to conventional E-R analysis, ADCs pose unique challenges since they feature properties of both small molecules and antibodies. In this article, we review the E-R analyses that have formed the key basis of dose justification for each of the 12 ADCs approved in the USA. We discuss the multiple analytes and exposure metrics that can be utilized for such analysis and their relevance for safety and efficacy of the treatment. For the endpoints used for the E-R analysis, we were able to uncover commonalities across different ADCs for both safety and efficacy. Additionally, we discuss dose optimization strategies for ADCs which are now a critical component in clinical development of oncology drugs.

PK-PD relationship of poorly absorbable active ingredients from traditional Chinese medicines explaining by metabolic enzyme of gut microbiota: A case study of Dehydrocorydaline.

Many active ingredients in traditional Chinese medicines generally have the characteristic of poor oral absorption but definite efficacy. It is necessary to establish a comprehensive technical system to explain the "PK-PD relationship" of them. Dehydrocorydaline (DHC), the quality control component in the Chinese patent drug "Kedaling Tablets", has poor oral absorption but clear efficacy for coronary heart disease. Using DHC as a model drug, the changes in absorption and pharmacological effects of DHC in rats before and after inhibiting nitroreductase (NR) from gut microbiota were studied. The results showed that after inhibiting of NR activity, the plasma concentration of DHC in rats was decreased, the serum level of total cholesterol, triglyceride and low-density lipoprotein cholesterol were significantly increased. The levels of tumor necrosis factor-α, interleukin-1ß, hypersensitive C-reactive protein, intercellular cell adhesion molecule-1 and Monocyte chemoattractant protein-1 were significantly increased, and pathological sections also showed that the efficacy of DHC decreased after inhibiting the activity of NR. We further investigated the drug metabolism of DHC under NR and found that DHC was metabolized into a hydrogenated metabolite, which may have stronger membrane permeability. In summary, NR may mediate the absorption degree and efficacy of DHC in vivo by metabolizing DHC into absorbable metabolite.

The Impact of Fosfomycin on Gram Negative Infections: A Comprehensive Review.

Multidrug-resistant or extended drug resistance has created havoc when it comes to patient treatment, as options are limited because of the spread of pathogens that are extensively or multidrug-resistant (MDR or XDR) and the absence of novel antibiotics that are effective against these pathogens. Physicians have therefore started using more established antibiotics such as polymyxins, tetracyclines, and aminoglycosides. Fosfomycin has just come to light as a result of the emergence of resistance to these medications since it continues to be effective against MDR and XDR bacteria that are both gram-positive and gram-negative. Fosfomycin, a bactericidal analogue of phosphoenolpyruvate that was formerly utilised as an oral medication for uncomplicated urinary tract infections, has recently attracted the interest of clinicians around the world. It may generally be a suitable therapy option for patients with highly resistant pathogenic infections, according to the advanced resistance shown by gram-negative bacteria. This review article aims to comprehensively evaluate the impact of fosfomycin on gram negative infections, highlighting its mechanism of action, pharmacokinetics, clinical efficacy, and resistance patterns.

Clinical pharmacokinetics of antimicrobials in critical care: a narrative review.

INTRODUCTION: The management of critically ill septic patients presents considerable challenges due to multifaceted physiological alterations. Rapid changes such as fluid shifts, hyperdynamic states, and altered renal clearance often require special attention for better clinical outcomes. Vital organ dysfunction, with or without MODS, often necessitates supportive management like RRT, ventilatory support, and ECMO. These interventions can significantly affect the PK/PD of administered antimicrobials, complicating effective treatment. AREA COVERED: Patient-specific parameters such as age, weight, and comorbid illnesses (e.g. cystic fibrosis, burns, and immunocompromised states) are critical determinants of antimicrobial pharmacokinetics. Understanding PK/PD determinants is crucial for developing optimized dosing regimens that enhance therapeutic efficacy and minimize toxicity in critically ill patients. EXPERT OPINION: Incorporating pharmacometrics approaches in dose optimization can significantly improve patient outcomes. This review focuses on the nuances of PK/PD for optimized antimicrobial dosing in critically ill septic patients, emphasizing the importance of individualized treatment plans to address the complex and dynamic needs of this patient population. The adoption of these advanced pharmacokinetic and pharmacodynamic principles into clinical practice is essential for advancing patient care and optimizing therapeutic outcomes in critically ill patients.

Unraveling Ritlecitinib: an in-depth analysis of JAK3 inhibitor for the treatment of alopecia areata.

INTRODUCTION: Alopecia Areata (AA), characterized by non-scarring hair loss due to the dysregulation of the JAK/STAT pathway, has long lacked effective treatment. In 2023, Ritlecitinib, a novel Janus kinase (JAK) 3 and tyrosine kinase family inhibitor, received its first approval from the US FDA to treat AA, followed by approvals in Japan, Europe, China, and the UK. This development aims to address the challenges faced by millions of individuals affected by this condition globally. AREAS COVERED: This review offers an overview of Ritlecitinib's pharmacological properties, biological targets, and development strategies. It examines its mechanism of action, pharmacokinetics, pharmacodynamics, and clinical trial insights. Additionally, it covers the drug's chemical synthesis, contraindications, drug interactions, and potential adverse effects, with special attention to its use in adolescents, pregnant women, and the elderly. EXPERT OPINION: Ritlecitinib represents a significant advancement in treating AA, offering a targeted approach with promising efficacy and a favorable safety profile. While long-term safety data and real-world effectiveness studies are needed, its oral administration and efficacy in both adults and adolescents position it as a potentially transformative therapy. Ongoing research should focus on optimizing treatment strategies, identifying predictive biomarkers, and assessing cost-effectiveness to fully realize Ritlecitinib's potential in improving outcomes.

Quantifying trade-offs between therapeutic efficacy and resistance dissemination for enrofloxacin dose regimens in cattle.

The use of antimicrobial drugs in food-producing animals contributes to the selection pressure on pathogenic and commensal bacteria to become resistant. This study aims to evaluate the existence of trade-offs between treatment effectiveness, cost, and the dynamics of resistance in gut commensal bacteria. We developed a within-host ordinary differential equation model to track the dynamics of antimicrobial drug concentrations and bacterial populations in the site of infection (lung) and the gut. The model was parameterized to represent enrofloxacin treatment for bovine respiratory disease (BRD) caused by Pastereulla multocida in cattle. Three approved enrofloxacin dosing regimens were compared for their effects on resistance on P. multocida and commensal E. coli: 12.5 mg/kg and 7.5 mg/kg as a single dose, and 5 mg/kg as three doses. Additionally, we explored non-FDA-approved regimes. Our results indicated that both 12.5 mg/kg and 7.5 mg/kg as a single dose scenario increased the most the treatment costs and prevalence of P. multocida resistance in the lungs, while 5 mg/kg as three doses increased resistance in commensal E. coli bacteria in the gut the most out of the approved scenarios. A proposed non-FDA-approved scenario (7.5 mg/kg, two doses 24 h apart) showed low economic costs, minimal P. multocida, and moderate effects on resistant E. coli. Overall, the scenarios that decrease P. multocida, including resistant P. multocida did not coincide with those that decrease resistant E. coli the most, suggesting a trade-off between both outcomes. The sensitivity analysis suggests that bacterial populations were the most sensitive to drug conversion factors into plasma ( ß ), elimination of the drug from the colon ( ϑ ), fifty percent sensitive bacteria (P. multocida) killing effect ( L s50 ), fifty percent of bacteria (E. coli) above ECOFF killing effect ( C r50 ), and net drug transfer rate in the lung ( γ ) parameters.

Dosing Evaluation of Ceftazidime-Avibactam in Intensive Care Unit Patients Based on Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling and Simulation.

P. aeruginosa is the most common microorganism involved in many ICU-acquired infections. A correct dosage regimen is pivotal to avoiding resistance development, worse outcomes and higher mortality rates. The aim of this study was to perform a pharmacokinetic-pharmacodynamic (PK/PD) evaluation of recommended dosing regimens of ceftazidime-avibactam (CAZ-AVI) in ICU patients with different degrees of renal function for a specific strain of Pseudomonas aeruginosa. A semi-mechanistic PK/PD model has been developed. It allows for the simulation of CAZ-AVI steady-state plasma level curves and the evolution of bacterial growth curves. The percentage of bacterial load reduction and the value of the recommended PK/PD indices have been taken into account to define the success or failure of the regimens. Probabilistic analysis was performed using Monte Carlo simulations of two populations: control and ICU. In both populations, dosing regimens endorsed for patients with CLcr higher than 10 mL/min reach the PK/PD indices recommended, T > MIC > 90% and Cmin/MIC > 1.3. While dosage regimens endorsed for patients with CLcr of 10 mL/min or lower fail (T > MIC < 60% and Cmin/MIC < 0.35). However, proposed dosing regimens based on shortening dosing intervals for these patients would be successful, increasing bacterial load reduction by almost 50% and reaching the proposed PK/PD indices. Therefore, CAZ-AVI dosing strategies based on model-informed precision dosing (MIPD) could directly influence the efficacy of results in ICU patients with renal insufficiency.

Synergistic efficacy of ceftazidime/avibactam and aztreonam against carbapenemase-producing Pseudomonas aeruginosa: insights from the hollow-fiber infection model.

BACKGROUND: Combination therapy is an attractive therapeutic option for extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. Existing data support the combination of aztreonam and ceftazidime/avibactam (CZA) against class serine-ß-lactamase (SBL)- and metallo-ß-lactamase (MBL) - producing Enterobacterales. However, data about that combination against SBL- and MBL-producing P. aeruginosa are scarce. The objective of the study was to assess the in vitro activity of CZA and aztreonam alone and in combination against SBL- and MBL-producing XDR P. aeruginosa isolates. METHODS: The combination was analyzed by means of the hollow-fiber infection model in three selected carbapenemase-producing P. aeruginosa isolates that were representative of the three most common XDRP. aeruginosa high-risk clones (ST175, ST111, ST235) responsible for global nosocomial infection outbreaks. RESULTS: The three isolates were nonsusceptible to CZA and nonsusceptible to aztreonam. In the dynamic hollow-fiber infection model, the combination of CZA plus aztreonam exerts a bactericidal effect on the isolates, regardless of their resistance mechanism and demonstrates synergistic interactions against three isolates, achieving a bacterial reduction of 5.07 log10 CFU/ml, 5.2 log10 CFU/ml and 4 log10 CFU/ml, respectively. CONCLUSION: The combination of CZA and aztreonam significantly enhanced the in vitro efficacy against XDR P. aeruginosa isolates compared to each monotherapy. This improvement suggests that the combination could serve as a feasible treatment alternative for infections caused by carbapenemase-producing XDR P. aeruginosa, especially in scenarios where no other treatment options are available.

Co-Administration of Amiodarone Increases Bleeding by Affecting Rivaroxaban Pharmacokinetics in Patients with Atrial Fibrillation.

This study aimed to investigate the impact of the drug-drug interaction between rivaroxaban and amiodarone on the clinical outcomes in patients with non-valvular atrial fibrillation (NVAF), focusing on pharmacokinetic and pharmacodynamic (PK/PD) aspects. A prospective study enrolling 174 patients with NVAF who were treated with rivaroxaban was conducted. The patients were divided into two groups based on postoperative antiarrhythmic and anticoagulation strategies: the rivaroxaban group (Control group) and the rivaroxaban plus amiodarone group (Riv/Amio group). The trough plasma concentrations (Ctrough) of rivaroxaban, activated partial thromboplastin time (APTT), prothrombin time (PT), and the clinical outcomes between the two groups were compared. Patients receiving 20 mg of rivaroxaban in the Riv/Amio group had a higher concentration of rivaroxaban Ctrough than those in the Control group (p = 0.009). Furthermore, in patients with moderate to severe renal impairment, rivaroxaban Ctrough was significantly increased in the Riv/Amio group. There was no significant difference in PT and APTT between the two groups. Regarding the clinical outcomes, the combination of rivaroxaban and amiodarone medication was associated with a higher incidence of bleeding events (p = 0.041; HR = 2.83, 95% CI 1.05-7.66) and clinically relevant non-major bleeding (p = 0.021; HR = 3.65, 95% CI 1.21-10.94). Finally, independent risk factors for bleeding in NAVF patients treated with rivaroxaban were identified as its combination with amiodarone (p = 0.044; OR = 2.871, 95% CI 1.028-8.023). The combination of rivaroxaban and amiodarone led to changes in rivaroxaban pharmacokinetics and an elevated risk of bleeding events. Therefore, physicians prescribing rivaroxaban medications should assess the potential bleeding risk associated with the concurrent use of amiodarone, particularly in patients with renal impairment.

Strategies for successful dose optimization in oncology drug development: a practical guide.

Dose optimization is a critical challenge in drug development. Historically, dose determination in oncology has followed a divergent path from other non-oncology therapeutic areas due to the unique characteristics and requirements in Oncology. However, with the emergence of new drug modalities and mechanisms of drugs in oncology, such as immune therapies, radiopharmaceuticals, targeted therapies, cytostatic agents, and others, the dose-response relationship for efficacy and toxicity could be vastly varied compared to the cytotoxic chemotherapies. The doses below the MTD may demonstrate similar efficacy to the MTD with an improved tolerability profile, resembling what is commonly observed in non-oncology treatments. Hence, alternate strategies for dose optimization are required for new modalities in oncology drug development. This paper delves into the historical evolution of dose finding methods from non-oncology to oncology, highlighting examples and summarizing the underlying drivers of change. Subsequently, a practical framework and guidance are provided to illustrate how dose optimization can be incorporated into various stages of the development program. We provide the following general recommendations: 1) The objective for phase I is to identify a dose range rather than a single MTD dose for subsequent development to better characterize the safety and tolerability profile within the dose range. 2) At least two doses separable by PK are recommended for dose optimization in phase II. 3) Ideally, dose optimization should be performed before launching the confirmatory study. Nevertheless, innovative designs such as seamless II/III design can be implemented for dose selection and may accelerate the drug development program.

DN-ODE: Data-driven neural-ODE modeling for breast cancer tumor dynamics and progression-free survivals.

Pharmacokinetic/Pharmacodynamic (PK/PD) modeling is crucial in the development of new drugs. However, traditional population-based PK/PD models encounter challenges when modeling for individual patients. We aim to explore the potential of constructing a pharmacodynamic model for individual breast cancer pharmacodynamics leveraging only limited data from early clinical trial phases. While previous studies on Neural Ordinary Differential Equations (ODEs) suggest promising results in clinical trial practices, they primarily focused on theoretical applications or independent PK/PD modeling. PD modeling from complex and irregular clinical trial data, especially when interacting with PK parameters, is still unclear. To achieve that, we introduce a Data-driven Neural Ordinary Differential Equation (DN-ODE) modeling for breast cancer tumor dynamics and progression-free survival data. To validate this approach, experiments are conducted with early-phase clinical trial data from the Amcenestrant (an oral treatment for breast cancer) dataset (AMEERA 1-2), aiming to predict pharmacodynamics in the later phase (AMEERA 3). DN-ODE model achieves RMSE scores of 8.78 and 0.21 in tumor size and progression-free survival, respectively, with R2 scores over 0.9 for each task. Compared to PK/PD methodologies, DN-ODE is able to predict robust individual tumor dynamics with only limited cycle data. We also introduce Principal Component Analysis visualizations for encoder results, demonstrating the DN-ODE's capability to discern individual distributions and diverse tumor growth patterns. Therefore, DN-ODE facilitates comprehensive drug efficacy assessments, pinpoints potential responders, and aids in trial design.

Design of a pharmacokinetic/pharmacodynamic model for administration of low dose peripheral norepinephrine during general anaesthesia.

AIMS: Intraoperative hypotension is a risk factor for kidney, heart and cognitive postoperative complications. Literature suggests that the use of low-dose peripheral norepinephrine (NOR) reduces organ dysfunction, yet its administration remains unstandardized. In this work we develop a pharmacokinetic (PK)/pharmacodynamic (PD) model of NOR and its effect on mean arterial pressure (MAP). METHODS: From June 2018 to December 2021, we included patients scheduled for elective neurosurgery and requiring vasopressors for intraoperative hypotension management at Lariboisière Hospital, Paris. Low doses of NOR were administered peripherally, and successive arterial blood samples were collected to track its plasmatic concentration. We used a compartmental modelling approach for NOR PK. We developed and compared 2 models for NOR PD on MAP. Model comparison was done using Bayes information criteria. The resulting PK/PD model parameters were fitted over the entire population and linked to age, weight, height and sex. RESULTS: We included 29 patients (age 52 [46-64] years, 69% female). NOR median time to peak effect on MAP was 74 [53-94] s. After bolus administration, MAP increased by 24% (15-31%). A 2-comparment model with depot best captured NOR PK. NOR PD effect on MAP was well represented by both Emax and Windkessel models, with better results for the former. We found that age, height and weight as well as history of smoking and hypertension were correlated with model parameters. CONCLUSION: We have developed a PK/PD model to accurately track norepinephrine plasma concentration and its effect on MAP over time, which could serve for target-controlled infusion.

Recombinant Adeno-Associated Virus Vectors for Gene Therapy of the Central Nervous System: Delivery Routes and Clinical Aspects.

The Central Nervous System (CNS) is vulnerable to a range of diseases, including neurodegenerative and oncological conditions, which present significant treatment challenges. The blood-brain barrier (BBB) restricts molecule penetration, complicating the achievement of therapeutic concentrations in the CNS following systemic administration. Gene therapy using recombinant adeno-associated virus (rAAV) vectors emerges as a promising strategy for treating CNS diseases, demonstrated by the registration of six gene therapy products in the past six years and 87 ongoing clinical trials. This review explores the implementation of rAAV vectors in CNS disease treatment, emphasizing AAV biology and vector engineering. Various administration methods-such as intravenous, intrathecal, and intraparenchymal routes-and experimental approaches like intranasal and intramuscular administration are evaluated, discussing their advantages and limitations in different CNS contexts. Additionally, the review underscores the importance of optimizing therapeutic efficacy through the pharmacokinetics (PK) and pharmacodynamics (PD) of rAAV vectors. A comprehensive analysis of clinical trials reveals successes and challenges, including barriers to commercialization. This review provides insights into therapeutic strategies using rAAV vectors in neurological diseases and identifies areas requiring further research, particularly in optimizing rAAV PK/PD.