Candida auris is an emergent fungal pathogen that causes severe infectious outbreaks globally. The public health concern when dealing with this mainly due to reduced susceptibility current antifungal drugs. A valuable alternative overcome problem investigate the efficacy of combination therapy. aim study was determine in vitro interactions isavuconazole echinocandins against C. auris. Interactions were determined using a checkerboard method, and absorbance data analyzed different approaches:...

The high failure rate of central nervous system (CNS) drugs is partly associated with an insufficient understanding target site exposure. Blood–brain barrier (BBB) permeability evaluation tools are needed to explore drugs’ ability access the CNS. An outstanding aspect physiologically based pharmacokinetic (PBPK) models integration knowledge on drug-specific and system-specific characteristics, allowing identification relevant factors involved in distribution. We aimed qualify a PBPK platform...

Aims Residual neuromuscular blockade (RNB) commonly occurs when using blockers and increases the risk for pulmonary complications, such as airway obstruction severe hypoxemia, in extubated patients. Rocuronium exhibits a high variability recovery time, contributing to an increased RNB. This study aimed identify characterize sources of rocuronium exposure response via population pharmacokinetic/pharmacodynamic (PK/PD) analysis apply developed PK/PD model investigate clinical implications....

ABSTRACT Neuropathic pain, often associated with diabetic neuropathy or nerve compression injuries, arises from damage dysfunction in the somatosensory nervous system. Tramadol, frequently prescribed for this has its fraction unbound and that of active metabolite (M1) significantly altered by diabetes. Yet, dosing adjustments neuropathic pain remain underexplored. This study developed a comprehensive population pharmacokinetics/pharmacodynamics (PK/PD) model tramadol major metabolites,...

Objectives: It is a common yet optimistic assumption that pharmacokinetic (PK) and pharmacodynamic (PD) studies are error-free when employing nonlinear mixed-effect approach. However, errors can arise at any phase of clinical drug development studies, potentially influencing the residual unexplained variability (RUV). Previous research highlighted neglecting these could lead to biased PK estimates [1]. We aim 1) assess impact manufacturing(ME), dosing time(DE), sampling time(SE),...

Objectives: Recombinant human erythropoietin (rHuEPO) is indicated to treat anemia in chronic kidney disease (CKD) [1]. Nevertheless, due its short half-life requires frequent administration. Pegylation an efficient method improve therapeutic proteins' pharmacokinetics (PK). However, pegylation can also affect protein biologic properties, including potency [2]. A semi-mechanistic PK/PD model was previously developed evaluate four rHuEPO (ior®EPOCIM, MIRCERA®, and PEG-EPO 32 40 kDa) rabbits...

Objectives: Spironolactone (SP) is a potassium-sparing diuretic medication that has been in the market for more than 60 years. SP complex pharmacokinetics (PK) which includes poor solubility, metabolism, and multiple active metabolites. Limited research comprehensively addressed clinical PK, efficacy safety, resulting persisting knowledge gaps. Additionally, used off-label pediatrics since its approval. Several challenges are thus faced to inform use derived from this lack of substantial...

Background/Objectives: Spironolactone (SP) has been used off-label in pediatrics since its approval, but use is challenged by limited pharmacokinetic (PK) data adults and especially children. Methods: Physiologically based (PBPK) models for SP active metabolites, canrenone (CAN) 7α thio-methyl spironolactone (TMS), were developed. These aim to enhance understanding of SP’s PK provide a basis predicting optimizing dosing infants neonates. Given complex metabolism, we assumed complete...

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by dopaminergic cell death in the substantia nigra. While interplay between dopamine loss and symptoms well‐recognized, respective quantitative link has yet to be established. The objective was establish biomarker‐directed clinical endpoint model for early‐stage PD patients. We developed disease progression using DATscan data 196 healthy subjects 419 patients characterize onset of This then linked MDS‐UPDRS Parts I, II,...

Background/Objectives: Omeprazole is widely used for managing gastrointestinal disorders like GERD, ulcers, and H. pylori infections. However, its use in pediatrics presents challenges due to drug interactions (DDIs), metabolic variability, safety concerns. Omeprazole’s pharmacokinetics (PK), primarily influenced by CYP2C19 metabolism, affected ontogenetic changes enzyme expression, complicating dosing children. Methods: This study aimed develop validate a physiologically based...

Physiologically based pharmacokinetic (PBPK) models are increasingly used to support pediatric dose selection for small molecule drugs. In contrast, only a few PBPK therapeutic antibodies have been published recently, and the knowledge on maturation of processes relevant antibody pharmacokinetics (PK) is limited compared molecules. The aim this study was, thus, evaluate predictions from children which were scaled adults in order identify respective gaps. For this, we generic model...

Fentanyl is a synthetic opioid commonly used as an anesthetic and also increasingly popular sedative agent in neonates. Initial dosage regimens this population are often empirically derived from adults on body weight basis. However, ontogenic maturation processes related to drug disposition not necessarily always correlates. We developed predictive pharmacokinetic/pharmacodynamic model that includes growth physiologic changes for fentanyl neonatal care. Key pharmacokinetic variables...

In vitro combination of echinocandins and isavuconazole against the emerging species Candida auris is mainly synergistic. However, this has not been evaluated in clinical settings. A pharmacokinetic/pharmacodynamic modeling simulation approach based on data may be helpful to further study therapeutic potential these combinations. Therefore, aims were characterize time course growth killing C. response three approved using a semimechanistic model perform model-based simulations order predict...

Abstract Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria adults children aged ≥ 6 years. Pharmacokinetic data 6–11 years were extracted post hoc from study which (2–11 years) with or received oral bilastine (10 mg/day). Maximum plasma concentration ( C max ) area under curve (AUC) compared adult pharmacokinetic seven clinical studies (bilastine 20 Safety phase III randomized controlled trial chronic receiving...

Levonorgestrel (LNG) is the active moiety in many hormonal contraceptive formulations. It typically coformulated with ethinyl estradiol (EE) to decrease intermenstrual bleeding. Due its widespread use and CYP3A4-mediated metabolism, there concern regarding drug-drug interactions (DDIs), particularly a suboptimal LNG exposure when co-administered CYP3A4 inducers, potentially leading unintended pregnancies. The goal of this analysis was determine impact DDIs on systemic LNG. To end, we...

Hormonal contraceptive agents (HCAs) are widely used throughout the world, and women taking HCAs likely to take other medications. However, little is known about clinical effect of most drug-drug interactions (DDIs) associated with HCAs. A team interdisciplinary outcomes pharmacometric researchers from academia industry jointly engage in a research project (i) quantitatively elucidate DDI impacts on unintended pregnancies breakthrough bleeding, (ii) establish DDI-prediction framework inform...

Abstract Pharmacometrics is the science of quantifying relationship between pharmacokinetics and pharmacodynamics drugs in combination with disease models trial information to aid drug development dosing optimization for clinical practice. Considering variability dose–concentration–effect drugs, an opportunity exists linking pharmacokinetic pharmacodynamic model-based estimates pharmacoeconomic models. This link may provide early cost effectiveness therapies, thus informing late-stage...

Aims A population‐based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux‐en‐Y gastric bypass (RYGB) on PK ( R )‐ and S )‐carvedilol. We aimed optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model. Methods PopPK models were developed data from 52 subjects, including nonobese, obese, post‐ RYGB who received rac ‐ orally. Covariate analysis included anthropometric laboratory data, history surgery,...

Abstract This study employed physiologically‐based pharmacokinetic–pharmacodynamics (PBPK/PD) modeling to predict the effect of obesity and gastric bypass surgery on pharmacokinetics intragastric pH following omeprazole treatment. The simulated plasma concentrations closely matched observed data from non‐obese, morbidly obese, post‐gastric populations. Obesity significantly reduces CYP3A4 CYP2C19 activities, as reflected by metabolic ratio [omeprazole sulphone]/[omeprazole]...