European Journal of Drug Metabolism and Pharmacokinetics

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UNLABELLED: BACKGROUND AND OBJECTIVES: Acute inflammation caused by infections or sepsis can impact pharmacokinetics. We used a model-based analysis to evaluate the effect of acute inflammation as represented by interleukin-6 (IL-6) levels on drug clearance, focusing on renal glomerular filtration rate (GFR) and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. METHODS: A physiologically based model incorporating renal and hepatic drug clearance was implemented...

BACKGROUND: Moderate malnutrition is a common problem in young children. It is observed that severe malnutrition affects the pharmacokinetics of chemotherapy drugs in pediatric cancer patients, but moderate malnutrition is not well studied in this context. OBJECTIVES: In this study, we aimed to understand how moderate malnutrition affects the pharmacokinetics of two chemotherapy drugs, etoposide and vincristine, using a murine model of early age moderate malnutrition...

BACKGROUND AND OBJECTIVE: It remains unclear whether sepsis in patients with malignancy interferes with the predictive performance of the dose-estimation formulas. The quick sequential organ failure assessment (qSOFA) score can help identify patients with poor outcomes because of sepsis-associated organ damage. Vancomycin, an important antibiotic, treats systemic infections (sepsis) caused by methicillin-resistant Staphylococcus aureus. We aimed to clarify whether including the qSOFA score in a standard population pharmacokinetic (PopPK) assessment may improve the predictive performance of vancomycin doses in patients with malignancy...

BACKGROUND AND OBJECTIVE: All latanoprost formulations currently available for the treatment of glaucoma or ocular hypertension contain the same concentration of latanoprost (0.005%) but differ in excipients, which may affect corneal drug permeability or stability. This study aimed at comparing corneal penetration of three marketed latanoprost solutions with different excipient formulations in in vitro and in vivo drug permeability studies. METHODS: Three latanoprost formulations were tested under good laboratory practice conditions: a formulation containing benzalkonium chloride (BAK) but no surfactant (Preserved latanoprost); the same formulation except preservative-free (PF) without BAK or surfactant (SF) (PF SF latanoprost); and a different formulation without BAK but containing a non-ionic surfactant (MGHS 40 at 5%) combined with thickening agents (Carbomer 974P, Macrogol 4000) (PF latanoprost)...

Messenger RNA (mRNA) has emerged as a new therapeutic agent for the prevention and treatment of a wide range of diseases. The recent achievement of the two lipid nanoparticle-mRNA vaccines developed by Moderna and Pfizer-BioNTech against coronavirus 2019 (COVID-19) disease in record time highlights the huge potential of mRNA technology and reshaping the landscape of vaccine development and the future of gene therapies. Challenges related to translational efficacy, mRNA stability, immunogenicity, and ensuring the quality of final products have been significantly improved by recent advancements in mRNA engineering and delivery...

BACKGROUND: In pediatric drug development, the selection of first-in-pediatric dose is of immense importance. Generally, the pharmacokinetic information and a safe and efficacious dose of a drug in adults are already known and this information can then be used to select first-in-pediatric dose. The objective of this study was to predict the pediatric dose of antimalarial drugs and compare the predicted dose with the recommended dose. METHODS: In this study, two simple methods to project a first-in-pediatric dose to initiate a clinical trial for antimalarial drugs were evaluated...

BACKGROUND AND OBJECTIVE: Fentanyl can mitigate the mother and newborn complications resulting from labor pain. However, fentanyl shows a narrow therapeutic index between its respiratory depressive and analgesic effects. Thus, prenatally acquired high fentanyl levels in the newborn brain extracellular fluid (bECF) may induce respiratory depression which requires therapeutic drug monitoring (TDM). TDM using saliva and urine in newborns can reduce the possibility of infections and distress associated with TDM using blood...

BACKGROUND AND OBJECTIVE: MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and  has demonstrated efficacy in murine models of lupus. This first-in-human study aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of MHV370 in healthy adults, as well as the effects of food consumption on a single dose of MHV370. METHODS: This was a phase 1, randomised, placebo-controlled study conducted in three parts...

BACKGROUND AND OBJECTIVE: Fc fusion is an effective strategy for extending the half-lives of therapeutic proteins. This study aimed to evaluate the applicability of a human pharmacokinetics prediction method for Fc-fusion proteins by extending on reported methods for monoclonal antibodies (mAbs). METHODS: To predict human pharmacokinetic profiles following intravenous (IV) dosing, the pharmacokinetic data for 11 Fc-fusion proteins in monkeys were analysed by two approaches: a species-invariant time method with a range of allometric exponents in clearance (CL, 0...

BACKGROUND AND OBJECTIVES: Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase that plays a crucial role in tumorigenesis. FHND5071, a potent and selective RET kinase inhibitor, could exert antitumor effects by inhibiting RET autophosphorylation. The present work aims to profile the pharmacokinetics of FHND5071 in in vivo and in vitro experiments as a ground work for further clinical research. METHODS: The absorption, distribution, metabolism, and excretion properties of FHND5071 were examined, along with metabolite production and cytochrome P450 (CYP) phenotyping assay...

Quercetin, a naturally occurring flavonoid, has been credited with a wide spectrum of therapeutic properties. However, the oral use of quercetin is limited due to its poor water solubility, low bioavailability, rapid metabolism, and rapid plasma clearance. Quercetin has been studied extensively when used with various nanodelivery systems for enhancing quercetin bioavailability. To enhance its oral bioavailability and efficacy, various quercetin-loaded nanosystems such as nanosuspensions, polymer nanoparticles, metal nanoparticles, emulsions, liposomes or phytosomes, micelles, solid lipid nanoparticles, and other lipid-based nanoparticles have been investigated in in-vitro cells, in-vivo animal models, and humans...

This review provides an overview on the current applications of dried blood spots (DBS) as matrices for therapeutic drug (TDM) and drug or disease response monitoring (DRM). Compared with conventional methods using plasma/serum, DBS offers several advantages, including minimally invasiveness, a small blood volume requirement, reduced biohazardous risk, and improved sample stability. Numerous assays utilising DBS for TDM have been reported in the literature over the past decade, covering a wide range of therapeutic drugs...

BACKGROUND AND OBJECTIVE: Acetaminophen (paracetamol) is a ubiquitously administered drug in critically ill patients. Considering the dearth of literature, we evaluated the population pharmacokinetics of intravenous acetaminophen and its principal metabolites (sulfate and glucuronide) in this population. METHODS: Critically ill adults receiving intravenous acetaminophen were included in the study. One to three blood samples were withdrawn per patient for the estimation of acetaminophen, and its metabolites (acetaminophen glucuronide and acetaminophen sulfate)...

BACKGROUND AND OBJECTIVE: Therapeutic drug monitoring (TDM) is an effective tool for the management of patients who are administered linezolid. The use of saliva for TDM has potential advantages over the use of plasma; however, only a few reports have compared drug concentrations in the saliva and plasma. Moreover, there are no reports on the salivary concentration of tedizolid, an oxazolidinone antibiotic similar to linezolid. In the present study, the concentrations of tedizolid and linezolid in rat submandibular saliva were compared with those measured in the plasma...

BACKGROUND AND OBJECTIVES: Current anticoagulants pose an increased risk of bleeding. The development of drugs targeting factor XIa, like asundexian, may provide a safer treatment option. A human mass‑balance study was conducted to gain a deeper understanding of the absorption, distribution, metabolism, excretion, and potential for drug-drug interaction of asundexian. Additionally, an overview of the biotransformation and clearance pathways for asundexian in humans and bile-duct cannulated (BDC) rats in vivo, as well as in vitro in hepatocytes of both species, is reported...

BACKGROUND AND OBJECTIVES: Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. This study evaluated the involvement of cytochrome P450 (CYP) isozymes and drug transporters in the biotransformation of ocedurenone, and whether ocedurenone inhibited or induced CYP enzymes and transporters. Clinical pharmacokinetic drug-drug interaction (DDI) of ocedurenone with CYP3A inhibitor and inducer were investigated in healthy volunteers...

BACKGROUND AND OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients that require respiratory and/or cardiac support. Cefiderocol is a novel siderophore antibiotic that may require use in infected critically ill patients supported by ECMO. The objective of this study was to determine the loss of cefiderocol through an ex vivo adult ECMO circuit using a Quadrox-iD oxygenator. METHODS: A 3/8-inch, simulated, ex vivo closed-loop ECMO circuit was prepared with a Quadrox-iD adult oxygenator and primed with fresh whole blood...

BACKGROUND AND OBJECTIVES: The oral bioavailability of withangulatin A (WA) is low and may undergo first-pass metabolism because of the presence of two esters bonds. This study aimed to identify the hydrolysis behavior and mechanism of WA, thus enriching its structure-pharmacokinetic relationship. METHODS: The in vivo pharmacokinetic studies of WA in rats were first investigated, followed by in vitro assays including metabolic stability, phenotyping identification and metabolic kinetics assays...

BACKGROUND AND OBJECTIVES: A wide variety of products containing cannabidiol (CBD) are available on the commercial market. One of the most common products, CBD oil, is administered to self-treat a variety of conditions. These oils are available as CBD isolate, broad-spectrum [all terpenes and minor cannabinoids except Δ-9-tetrahydrocannabinol (THC)], or full-spectrum (all terpenes and minor cannabinoids with THC < 0.3% dried weight) products. A systematic pharmacokinetic study was performed to determine whether there are differences in the pharmacokinetic parameters and systemic exposure of CBD after oral dosing as an isolate, broad-spectrum, or full-spectrum product...