Search Results (22)

Background: Cardiac arrest is a time-critical medical emergency during which prompt and effective drug delivery plays a key role in patient outcomes. Current resuscitation guidelines recommend intravenous (IV) access as the first-line route, with intraosseous (IO) access recommended as an alternative when IV access is delayed or not feasible. Although the endotracheal (ET) route was previously included in resuscitation protocols, it is no longer recommended. This study aims to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of resuscitation drugs administered through different injection sites and under varying hemodynamic conditions in in vivo animal models. Methods: PubMed, CENTRAL and ClinicalTrials.gov were searched up to August 2025 for studies comparing different injection sites for the same drug (adrenaline/epinephrine, amiodarone, lidocaine and vasopressin) during CPR. Study selection, data extraction, and quality assessments were performed independently by two reviewers. Frequentist random-effects models were used to calculate mean differences and odds ratios (ORs) with 95% confidence intervals (CIs). Results: Fourteen prospective experimental studies (sample sizes ranging from 15 to 49 animals) conducted on swine were included. For epinephrine under normovolemia, humeral IO (HIO) access achieved significantly higher maximum concentrations (C_max; p = 0.0238) and a shorter time to the maximum concentration (T_max; p < 0.01) compared to IV, translating into faster return of spontaneous circulation (ROSC) (p = 0.0681). Under hypovolemia, IV access proved superiority over IO for epinephrine administration (MD = +382.80 ng/mL; p = 0.0022). The time to ROSC was significantly shorter with sternal IO (SIO) compared to tibial IO (TIO) (p = 0.0109). For amiodarone and vasopressin, no consistent or statistically significant differences were observed between administration routes, and in several cases, the findings were based on a single study. Conclusions: The injection site significantly influences the PK and PD of epinephrine during cardiac arrest. Proximal IO routes may offer advantages under normovolemic conditions, while IV access appears superior in cases of hypovolemic shock. Further research is needed to guide optimal drug delivery in varying hemodynamic conditions during cardiac arrest. Full article

Sertraline, a selective serotonin reuptake inhibitor (SSRI), has emerged as a candidate for therapeutic repurposing due to its reported antifungal activity. We systematically reviewed in vitro, in vivo, and clinical evidence up to July 2025 (PubMed, Scopus, Web of Science). As a result, 322 records were screened and 63 studies were found to meet the inclusion criteria (PRISMA 2020). We close a critical gap by consolidating relevant evidence on Candida auris, including preclinical in vivo models, which have been under-represented in previous summaries. Outcomes included minimum inhibitory and fungicidal concentrations (MIC/MFC), biofilm inhibition, fungal burden, survival, and pharmacokinetic/pharmacodynamic parameters. Preclinical data indicate its activity against clinically relevant fungi—particularly Cryptococcus neoformans and Candida spp., including C. auris—as well as consistent anti-biofilm effects and synergy with amphotericin B, fluconazole, micafungin, or voriconazole. Mechanistic evidence implicates mitochondrial dysfunction, membrane perturbation, impaired protein synthesis, and calcium homeostasis disruption. However, its potential for clinical translation remains uncertain: in cryptococcal meningitis, small phase II studies suggested improved early fungicidal activity, whereas a phase III randomized trial did not demonstrate a benefit regarding survival. Pharmacokinetic constraints at conventional doses, the absence of an intravenous formulation, and safety considerations at higher doses further limit its immediate applicability. Overall, the available evidence supports sertraline as a promising adjuvant candidate, rather than a stand-alone antifungal. Future research should define PK/PD targets, optimize doses and formulations, and evaluate rational combinations through rigorously designed trials, particularly for multidrug-resistant and biofilm-associated infections. Full article

Introduction/aim: N-acetylgalactoseamine-conjugated small interfering RNAs (GalNAc-siRNAs) are an emerging class of drugs possessing an extensive clinical potential because of their high target specificity to the asialoglycoprotein receptor (ASGPR) in hepatocytes. Overall, GalNAc-sRNAs are well-tolerated across species but differences in pharmacokinetic (PK) and pharmacodynamic (PD) properties have been observed. Furthermore, despite GalNAc-siRNA’s high liver specificity, distribution into off-target organs does occur. Through whole-body physiologically based pharmacokinetic (PBPK) modeling, this study seeks to mechanistically address species differences, establish clinical PK-PD relationships, and characterize off-target organ accumulation, ultimately expediting the preclinical-to-clinical translation of GalNAc-sRNAs in drug development. Materials/Methods: For model development, validation, and establishment of species’ translations, three in-house GalNAc-siRNAs with PK data from different biospecimens, as well as downstream effects on mRNA and target proteins in mouse, monkey, and human, were leveraged. A WB-PBPK-PD legacy model, developed as an extension to the generic model for large molecules in the platform Open Systems Pharmacology Suite, was further validated and applied to address the specific aims of this study. Results: The model successfully quantified the PK-PD relationships across species and characterized accumulation in off-target organs. The model further sheds light on species-specific differences, such as liver permeability, subcutaneous absorption rate, as well as PD-related mechanisms. Moreover, the model confirmed previously established compound-specific pharmacokinetic differences and similarities. Conclusions: This PBPK-PD can serve as a framework for future investigations of novel GalNAc-siRNAs across species. Full article

The antimicrobial concentration–time profile in humans affects antimicrobial activity, and as such, it is critical for preclinical infection models to simulate human-like dynamic concentration–time profiles for maximal translatability. This review discusses the setup, principle, and application of various dynamic in vitro PK/PD infection models commonly used in the development and optimisation of antimicrobial treatment regimens. It covers the commonly used dynamic in vitro infection models, including the one-compartment model, hollow fibre infection model, biofilm model, bladder infection model, and aspergillus infection model. It summarises the mathematical methods for the simulation of the pharmacokinetic profile of single or multiple antimicrobials when using the serial or parallel configurations of in vitro systems. Dynamic in vitro models offer reliable pharmacokinetic/pharmacodynamic data to help define the initial dosing regimens of new antimicrobials that can be developed further in clinical trials. They can also help in the optimisation of dosing regimens for existing antimicrobials, especially in the presence of emerging antimicrobial resistance. In conclusion, dynamic in vitro infection models replicate the interactions that occur between microorganisms and dynamic antimicrobial exposures in the human body to generate data highly predictive of the clinical efficacy. They are particularly useful for the development new treatment strategies against antimicrobial-resistant pathogens. Full article

Autoimmune diseases (AIDs) are a group of disorders in which the immune system attacks the body’s own tissues, leading to chronic inflammation and organ damage. These diseases are difficult to treat due to variability in drug PK among individuals, patient responses to treatment, and the side effects of long-term immunosuppressive therapies. In recent years, pharmacometrics has emerged as a critical tool in drug discovery and development (DDD) and precision medicine. The aim of this review is to explore the diverse roles that pharmacometrics has played in addressing the challenges associated with DDD and personalized therapies in the treatment of AIDs. Methods: This review synthesizes research from the past two decades on pharmacometric methodologies, including Physiologically Based Pharmacokinetic (PBPK) modeling, Pharmacokinetic/Pharmacodynamic (PK/PD) modeling, disease progression (DisP) modeling, population modeling, model-based meta-analysis (MBMA), and Quantitative Systems Pharmacology (QSP). The incorporation of artificial intelligence (AI) and machine learning (ML) into pharmacometrics is also discussed. Results: Pharmacometrics has demonstrated significant potential in optimizing dosing regimens, improving drug safety, and predicting patient-specific responses in AIDs. PBPK and PK/PD models have been instrumental in personalizing treatments, while DisP and QSP models provide insights into disease evolution and pathophysiological mechanisms in AIDs. AI/ML implementation has further enhanced the precision of these models. Conclusions: Pharmacometrics plays a crucial role in bridging pre-clinical findings and clinical applications, driving more personalized and effective treatments for AIDs. Its integration into DDD and translational science, in combination with AI and ML algorithms, holds promise for advancing therapeutic strategies and improving autoimmune patients’ outcomes. Full article

FLT3L-Fc is a half-life extended, effectorless Fc-fusion of the native human FLT3-ligand. In cynomolgus monkeys, treatment with FLT3L-Fc leads to a complex pharmacokinetic/pharmacodynamic (PK/PD) relationship, with observed nonlinear PK and expansion of different immune cell types across different dose levels. A minimal physiologically based PK/PD model with expansion-enhanced target-mediated drug disposition (TMDD) was developed to integrate the molecule’s mechanism of action, as well as the complex preclinical and clinical PK/PD data, to support the preclinical-to-clinical translation of FLT3L-Fc. In addition to the preclinical PK data of FLT3L-Fc in cynomolgus monkeys, clinical PK and PD data from other FLT3-agonist molecules (GS-3583 and CDX-301) were used to inform the model and project the expansion profiles of conventional DC1s (cDC1s) and total DCs in peripheral blood. This work constitutes an essential part of our model-informed drug development (MIDD) strategy for clinical development of FLT3L-Fc by projecting PK/PD in healthy volunteers, determining the first-in-human (FIH) dose, and informing the efficacious dose in clinical settings. Model-generated results were incorporated in regulatory filings to support the rationale for the FIH dose selection. Full article

Antibiotic development traditionally involved large Phase 3 programs, preceded by Phase 2 studies. Recognizing the high unmet medical need for new antibiotics and, in some cases, challenges to conducting large clinical trials, regulators created a streamlined clinical development pathway in which a lean clinical efficacy dataset is complemented by nonclinical data as supportive evidence of efficacy. In this context, translational Pharmacokinetic/Pharmacodynamic (PK/PD) plays a key role and is a major contributor to a “robust” nonclinical package. The classical PK/PD index approach, proven successful for established classes of antibiotics, is at the core of recent antibiotic approvals and the current antibacterial PK/PD guidelines by regulators. Nevertheless, in the case of novel antibiotics with a novel Mechanism of Action (MoA), there is no prior experience with the PK/PD index approach as the basis for translating nonclinical efficacy to clinical outcome, and additional nonclinical studies and PK/PD analyses might be considered to increase confidence. In this review, we discuss the value and limitations of the classical PK/PD approach and present potential risk mitigation activities, including the introduction of a semi-mechanism-based PK/PD modeling approach. We propose a general nonclinical PK/PD package from which drug developers might choose the studies most relevant for each individual candidate in order to build up a “robust” nonclinical PK/PD understanding. Full article

Despite the recent advances in this field, there are limited methods for translating organoid-based study results to clinical response. The goal of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to facilitate the translation, using oxaliplatin and irinotecan treatments with colorectal cancer (CRC) as examples. The PK models were developed using qualified oxaliplatin and irinotecan PK data from the literature. The PD models were developed based on antitumor efficacy data of SN-38 and oxaliplatin evaluated in vitro using tumor organoids. To predict the clinical response, translational scaling of the models was established by incorporating predicted ultrafiltration platinum in plasma or SN-38 in tumors to PD models as the driver of efficacy. The final PK/PD model can predict PK profiles and responses following treatments with oxaliplatin or irinotecan. After generation of virtual patient cohorts, this model simulated their tumor shrinkages following treatments, which were used in analyzing the efficacies of the two treatments. Consistent with the published clinical trials, the model simulation suggested similar patient responses following the treatments of oxaliplatin and irinotecan with regards to the probabilities of progression-free survival (HR = 1.05, 95%CI [0.97;1.15]) and the objective response rate (OR = 1.15, 95%CI [1.00;1.32]). This proposed translational PK/PD modeling approach provides a significant tool for predicting clinical responses of different agents, which may help decision-making in drug development and guide clinical trial design. Full article

Despite intensive monitoring of whole blood tacrolimus concentrations, acute rejection after kidney transplantation occurs during tacrolimus therapy. Intracellular tacrolimus concentrations could better reflect exposure at the site of action and its pharmacodynamics (PD). Intracellular pharmacokinetic (PK) profile following different tacrolimus formulations (immediate-release (TAC-IR) and extended-release (TAC-LCP)) remains unclear. Therefore, the aim was to study intracellular tacrolimus PK of TAC-IR and TAC-LCP and its correlation with whole blood (WhB) PK and PD. A post-hoc analysis of a prospective, open-label, crossover investigator-driven clinical trial (NCT02961608) was performed. Intracellular and WhB tacrolimus 24 h time-concentration curves were measured in 23 stable kidney transplant recipients. PD analysis was evaluated measuring calcineurin activity (CNA) and simultaneous intracellular PK/PD modelling analysis was conducted. Higher dose-adjusted pre-dose intracellular concentrations (C₀ and C₂₄) and total exposure (AUC_0–24) values were found for TAC-LCP than TAC-IR. Lower intracellular peak concentration (C_max) was found after TAC-LCP. Correlations between C₀, C₂₄ and AUC_0–24 were observed within both formulations. Intracellular kinetics seems to be limited by WhB disposition, in turn, limited by tacrolimus release/absorption processes from both formulations. The faster intracellular elimination after TAC-IR was translated into a more rapid recovery of CNA. An Emax model relating % inhibition and intracellular concentrations, including both formulations, showed an IC₅₀, a concentration to achieve 50% CNA inhibition, of 43.9 pg/million cells. Full article

Beta-lactams (BL) are the first line agents for the antibiotic management of critically ill patients with sepsis or septic shock. BL are hydrophilic antibiotics particularly subject to unpredictable concentrations in the context of critical illness because of pharmacokinetic (PK) and pharmacodynamics (PD) alterations. Thus, during the last decade, the literature focusing on the interest of BL therapeutic drug monitoring (TDM) in the intensive care unit (ICU) setting has been exponential. Moreover, recent guidelines strongly encourage to optimize BL therapy using a PK/PD approach with TDM. Unfortunately, several barriers exist regarding TDM access and interpretation. Consequently, adherence to routine TDM in ICU remains quite low. Lastly, recent clinical studies failed to demonstrate any improvement in mortality with the use of TDM in ICU patients. This review will first aim at explaining the value and complexity of the TDM process when translating it to critically ill patient bedside management, interpretating the results of clinical studies and discussion of the points which need to be addressed before conducting further TDM studies on clinical outcomes. In a second time, this review will focus on the future aspects of TDM integrating toxicodynamics, model informed precision dosing (MIPD) and “at risk” ICU populations that deserve further investigations to demonstrate positive clinical outcomes. Full article

Therapeutic drug monitoring is recommended for the use of vancomycin, but a recent widely publicized US medical society consensus statement has changed the suggested optimal method(s) of dose adjustment. Specifically, 24 h area under the curve (AUC₂₄)-based monitoring is has been recommended for vancomycin in preference to monitoring of trough concentrations. One reason cited for this change is the claim that AUC₂₄ is a superior correlate to efficacy than trough (Cmin). Evidence from a number of retrospective analyses have been critically reviewed and determined to have weaknesses. This narrative review focuses on the experimental studies performed in vivo in animal models of infection and in vitro to determine the extent to which these data may provide a compelling distinction between pharmacokinetic/pharmacodynamics (PKPD) parameters that may translate to clinical use in therapeutic drug monitoring. Animal in vivo studies have been presented at conferences, but no original peer reviewed studies could be found that compare various PKPD parameters. These conference proceeding findings were supportive but unconvincing, even though they were favorably presented subsequently in review articles and clinical practice guidelines. In vitro data are somewhat conflicting, but the range of concentrations may play a role in the discrepancies found. It has been suggested that MIC may be assumed to have a value of 1 mg/L; however, it can be demonstrated that this assumption may lead to considerable discrepancy from results with an actual MIC value. The AUC₂₄ parameter has been weighed against the percentage of time above the MIC (%T > MIC) as a comparative PKPD parameter, yet this may be an inappropriate comparison for vancomycin since all clinically useful dosing provides 100% T > MIC. Regardless, there is a distinction between clinical TDM parameters and PKPD parameters, so, in practice, the change to AUC₂₄:MIC based on animal experiments and in vitro evidence for vancomycin may be premature. Full article

Pharmacokinetic-pharmacodynamic (PK-PD) analysis is of central importance to the progress of an antifungal agent into clinical use. It is crucial to ensure that preclinical studies give the best possible prediction of the way drugs are likely to behave in a clinical setting. This review details the last 30 years of progress in terms of disease model design, efficacy outcome selection and translational modelling in antifungal PK-PD studies. The principles of how PK-PD parameters inform current clinical practice are also discussed, including a review of how these apply to existing and novel agents. Full article

The development of in vitro/in vivo translational methods and a clinical trial framework for synergistically acting drug combinations are needed to identify optimal therapeutic conditions with the most effective therapeutic strategies. We performed physiologically based pharmacokinetic–pharmacodynamic (PBPK/PD) modelling and virtual clinical trial simulations for siremadlin, trametinib, and their combination in a virtual representation of melanoma patients. In this study, we built PBPK/PD models based on data from in vitro absorption, distribution, metabolism, and excretion (ADME), and in vivo animals’ pharmacokinetic–pharmacodynamic (PK/PD) and clinical data determined from the literature or estimated by the Simcyp simulator (version V21). The developed PBPK/PD models account for interactions between siremadlin and trametinib at the PK and PD levels. Interaction at the PK level was predicted at the absorption level based on findings from animal studies, whereas PD interaction was based on the in vitro cytotoxicity results. This approach, combined with virtual clinical trials, allowed for the estimation of PK/PD profiles, as well as melanoma patient characteristics in which this therapy may be noninferior to the dabrafenib and trametinib drug combination. PBPK/PD modelling, combined with virtual clinical trial simulation, can be a powerful tool that allows for proper estimation of the clinical effect of the above-mentioned anticancer drug combination based on the results of in vitro studies. This approach based on in vitro/in vivo extrapolation may help in the design of potential clinical trials using siremadlin and trametinib and provide a rationale for their use in patients with melanoma. Full article

The peptidoglycan (PG) cell wall is an essential component of the bacterial cell structure, and crippling its synthesis is one of the most successful strategies in the continuing war against pathogenic bacteria. MurJ is a member of the multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) flippase superfamily which is critically required for the synthesis of PG from lipid II. Teixobactin (TXB) is a recently discovered, promising macrocyclic depsipeptide natural antibiotic. TXB is claimed to “kill pathogens without detectable resistance” and is considered a possible “paving stone toward a new class of antibiotics”. In the context of the current antibiotic resistance crisis, the rapid development of a plethora of TXB analogs with improved pharmacokinetics/pharmacodynamics (PK/PD) is a critical challenge. This study focuses on the computational design of new TXB analog prototypes—disruptors of PG cell wall biosynthesis by the inhibition of MurJ. A combinatorial library was generated in silico using a set of three scaffolds based on the TXB structure and a selected list of building blocks in order to avoid the molecular obesity issue and minimize the potential toxicity concerns and health risks. TXB and the combinatorial library were virtually screened with adequate drug-likeness filters and PK/PD models. The safest drug candidates were docked with PyRx v.0.9.7 against the crystal structure of MurJ. What was found was that 26 virtual analogs had better binding affinities than TXB against MurJ. Overall, the proposed computational drug design approach for novel antibiotics might be a useful asset for medicinal chemists and translational pharmacologists. Full article

Translation of the synergy between the Siremadlin (MDM2 inhibitor) and Trametinib (MEK inhibitor) combination observed in vitro into in vivo synergistic efficacy in melanoma requires estimation of the interaction between these molecules at the pharmacokinetic (PK) and pharmacodynamic (PD) levels. The cytotoxicity of the Siremadlin and Trametinib combination was evaluated in vitro in melanoma A375 cells with MTS and RealTime-Glo assays. Analysis of the drug combination matrix was performed using Synergy and Synergyfinder packages. Calculated drug interaction metrics showed high synergy between Siremadlin and Trametinib: 23.12%, or a 7.48% increase of combined drug efficacy (concentration-independent parameter β from Synergy package analysis and concentration-dependent δ parameter from Synergyfinder analysis, respectively). In order to select the optimal PD interaction parameter which may translate observed in vitro synergy metrics into the in vivo setting, further PK/PD studies on cancer xenograft animal models coupled with PBPK/PD modelling are needed. Full article