European Journal of Drug Metabolism and Pharmacokinetics最新文献

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. Among the aforementioned nanosystems, quercetin phytosomes are attracting more interest and are available on the market. The present review covers insights into the possibilities of harnessing quercetin for several therapeutic applications and a special focus on anticancer applications and the clinical benefits of nanoquercetin formulations.

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. The objective of this study was to develop  a physiologically based pharmacokinetic (PBPK) model to predict fentanyl concentrations in different newborn tissues due to intrauterine exposure.

Methods: A fentanyl PBPK model in adults after intravenous and epidural administration was built, validated, and scaled to pregnancy and newborn populations. The dose that the newborn received transplacentally at birth was calculated using the pregnancy model. Then, the newborn bECF, saliva, plasma, and urine concentrations after such a dose were predicted using the newborn PBPK model.

Results: After a maternal epidural dose of fentanyl 245 µg, the predicted newborn plasma and bECF levels were below the toxicity thresholds. Furthermore, the salivary threshold levels in newborns for fentanyl analgesic and respiratory depression effects were estimated to be 0.39 and 14.7-18.2 ng/ml, respectively.

Conclusion: The salivary TDM of fentanyl in newborns can be useful in newborns exposed to intrauterine exposure from parturient females dosed with epidural fentanyl. However, newborn-specific values of µ-opioid receptors IC₅₀ for respiratory depression are needed.

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). High-performance liquid chromatography was used for measuring serum concentrations. We used nonlinear mixed-effect modeling for estimating the primary pharmacokinetic parameters of acetaminophen and its metabolites. The effect of covariates was evaluated followed by dose optimization using Monte Carlo simulation. Patient factors such as demographic information, liver and renal function tests were used as covariates in population pharmacokinetic analysis. The therapeutic range for serum acetaminophen concentration was considered to be 66-132 μM, while 990 μM was considered as the threshold for toxic concentration.

Results: Eighty-seven participants were recruited. A joint two-compartment acetaminophen pharmacokinetic model linked to glucuronide and sulfate metabolite compartments was used. The central and peripheral volume distributions were 7.87 and 8.87 L/70 kg, respectively. Estimated clearance (CL) was 0.58 L/h/70 kg, while intercompartmental clearance was 44.2 L/h/70 kg. The glucuronide and sulfate metabolite CL were 22 and 94.7 L/h/70 kg, respectively. Monte Carlo simulation showed that twice-daily administration of acetaminophen would result in a relatively higher proportion of patient population achieving and retaining serum concentrations in the therapeutic range, with reduced risk of concentrations remaining in the toxic range.

Conclusion: A joint pharmacokinetic model for intravenous acetaminophen and its principal metabolites in a critically ill patient population has been developed. Acetaminophen CL in this patient population is reduced. We propose a reduction in the frequency of administration to reduce the risk of supra-therapeutic concentrations in this population.

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, 0.7-1.0) and a two-compartment model reported for mAbs. The pharmacokinetic profiles following subcutaneous (SC) dosing were predicted by simple dose normalisation from monkeys or using the geometric means of the absorption rate constant (Ka) and bioavailability (BA) for mAbs or Fc-fusion proteins in humans and compared.

Results: In the case of IV administration, the area under the curve could be predicted for more than 85% of Fc-fusion proteins within a twofold difference from the observed value using the species-invariant time method (scaling exponent for CL, 0.95). For SC dosing, incorporating the geometric means of absorption parameters for both mAbs (BA 68.2%, Ka 0.287 day^-1) and Fc-fusion proteins (BA 63.0%, Ka 0.209 day^-1) in humans provided better accuracy than simple normalisation from monkeys.

Conclusion: We have successfully predicted the human pharmacokinetic profiles of Fc-fusion proteins for both IV and SC administration within twofold of the observed value from monkey pharmacokinetic data by extending on reported methods for mAbs. This method will facilitate drug discovery and development of Fc-fusion proteins.

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. Thus, the present review aims to provide the latest innovations that incrementally overcome these issues and future directions in the context of ongoing clinical trials against infectious diseases and beyond.

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. Several factors can affect the accuracy and reliability of the DBS sampling method, including haematocrit (HCT), blood volume, sampling paper and chromatographic effects. It is crucial to evaluate the correlation between DBS concentrations and conventional plasma/serum concentrations, as the latter has traditionally been used for clinical decision. The feasibility of using DBS sampling method as an option for home-based TDM is also discussed. Furthermore, DBS has also been used as a matrix for monitoring the drug or disease responses (DRM) through various approaches such as genotyping, viral load measurement, assessment of inflammatory factors, and more recently, metabolic profiling. Although this research is still in the development stage, advancements in technology are expected to lead to the identification of surrogate biomarkers for drug treatment in DBS and a better understanding of the correlation between DBS drug levels and drug responses. This will make DBS a valuable matrix for TDM and DRM, facilitating the achievement of pharmacokinetic and pharmacodynamic correlations and enabling personalised therapy.

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. In part A, participants received (3:1) a single ascending dose (SAD) of 1, 3, 10, 20, 40, 80, 160, 320, 640 and 1000 mg MHV370 or placebo. In part B, participants received (3:1) multiple ascending doses (MAD) of 25, 50, 100, 200 and 400 mg MHV370 twice daily (b.i.d) or placebo for 14 days. In part C, participants received an open-label single dose of 200 mg MHV370 under fasted or fed conditions. Safety, pharmacokinetic and pharmacodynamic parameters were evaluated.

Results: MHV370 was well tolerated, and no safety signal was observed in the study. No dose-limiting adverse events occurred across the dose range evaluated. Plasma concentrations of MHV370 increased with dose (mean [SD] maximum plasma concentrations ranged from 0.97 [0.48] to 1670 [861.0] ng/mL for SAD of 3-1000 mg, 29.5 [7.98] to 759 [325.0] ng/mL for MAD of 25-400 mg b.i.d. on day 1). The intake of food did not have a relevant impact on the pharmacokinetics of MHV370. Pharmacodynamic data indicated time- and dose-dependent inhibition of TLR7-mediated CD69 expression on B cells (100% inhibition at 24 h post-dose starting from SAD 160 mg and MAD 50 mg b.i.d.) and TLR8-mediated TNF release after ex vivo stimulation (>90% inhibition at 24 h post-dose starting from SAD 320 mg and MAD 100 mg b.i.d.).

Conclusion: The safety, pharmacokinetic and pharmacodynamic data support the further development of MHV370 in systemic autoimmune diseases driven by the overactivation of TLR7 and TLR8.

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. Additionally, plasma protein binding and pharmacokinetics in mice were investigated.

Results: Microsomal stability assay corroborated moderate to high clearance of FHND5071, and the use of UPLC-Q-TOF-MS identified a total of six metabolites and suggested a possible metabolic pathway involving oxidation, demethylation, and N-dealkylation. Primary contributors to the CYP-mediated metabolism of FHND5071 were found to be CYP2C8 and CYP3A4, and FHND5071 displayed low permeability and acted as a substrate for the P-glycoprotein (P-gp). FHND5071 had a moderate to high binding in plasma and exhibited a moderate absorption degree (absolute bioavailability > 60%) The distribution of FHND5071 in mouse tissues was rapid (mostly peaking at 1-4 h) and wide (detectable in almost all tissues and organs), with the highest exposure in the spleen. A small fraction of FHND5071 was excreted via the urine and feces, and a presumed metabolic pathway involving 20 metabolites in mice is proposed.

Conclusion: Pharmacokinetic characteristics of FHND5071 were systemically profiled, which may lay the foundation for further clinical development as a drug candidate.

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.

Methods: Male and female Sprague Dawley rats were treated with a single, equivalent oral dose of CBD delivered as isolate, broad-spectrum, or full-spectrum product. An additional study using an in-house preparation of CBD isolate plus 0.2% THC was performed. A permeability assay was also conducted to investigate whether the presence of THC alters the intestinal permeability of CBD.

Results: There was an increase in the oral bioavailability of CBD (12% and 21% in male and female rats, respectively) when administered as a full-spectrum product compared with the isolate and broad-spectrum products. There was no difference in the bioavailability of CBD between the commercially available full-spectrum formulation (3.1% CBD; containing 0.2% THC plus terpenes and other minor cannabinoids) versus the in-house preparation of CBD full-spectrum (CBD isolate 3.2% plus 0.2% THC isolate). In vitro permeability assays demonstrated that the presence of THC increases permeability of CBD while also decreasing efflux through the gut wall.

Conclusions: The presence of 0.2% THC increased the oral bioavailability of CBD in male and female rats, indicating that full-spectrum products may produce increased effectiveness of CBD due to a greater exposure available systemically.