Pharmacokinetic Studies Research Articles

At-Home Self-Collection of Pharmacokinetic Data: Design and Results From a Phase 1 Open-Label Feasibility Trial.

Pharmacokinetic (PK) studies pose unique technical challenges. We present the design of a Phase 1, open-label, fixed-sequence, PK trial that aimed to compare the timing accuracy of participant- versus staff-collected data, and we provide safety and tolerability outcomes for centanafadine treatment. Healthy adults aged 18-55 years received a single 100-mg centanafadine sustained-release tablet at Visits 1, 2, and 4. PK samples (venous sampling and blood microsampling) and safety assessments (12-lead electrocardiograms [ECGs] and vital signs) were collected by clinical site staff only at Visit 1. At Visit 2, site staff collected venous blood, and participants obtained blood microsamples, a 6-lead ECG, and vital signs under staff supervision. At Visit 4, participants obtained blood microsamples, a 6-lead ECG, and vital signs remotely. The absolute differences between actual and scheduled collection times for PK samples, ECGs, and vital signs are reported descriptively. Of the 20 participants, at least 75% obtained blood microsamples within 10 minutes of the planned nominal time. Absolute differences between actual and scheduled collection times of ECGs and vital signs were small. No adverse events were related to treatment. Overall, results support the feasibility of at-home collection of PK samples, ECGs, and vital signs.

Development of an HPLC–UV method for quantification of posaconazole in low-volume plasma samples: design of experiments and machine learning models

Posaconazole (PCZ) is a triazole antifungal agent with a broad-spectrum activity. Our research aims to present a novel approach by combining a 2-level fractional factorial design and machine learning to optimize both chromatography and extraction experiments, allowing for the development of a rapid method with a low limit of quantification (LOQ) in low-volume plasma samples. The PCZ retention time at the optimized condition (organic phase 58%, methanol 6%, mobile pH = 7, column temperature: 39 °C, and flow rate of 1.2 mL/min) was found to be 8.2 ± 0.2 min, and the recovery of the PCZ at the optimized extraction condition (500 µL extraction solvent, NaCl 10% w/v, plasma pH = 11, extraction time = 10 min, and centrifuge time = 1 min) was calculated above 98%. The results of machine learning models were in line with the results of experimental design. Method validation was performed according to ICH guideline. The method was linear in the range of 50–2000 ng/mL and LOQ was found to be 50 ng/mL. Additionally, the validated method was applied to analyze PCZ nanomicelles and conduct pharmacokinetic studies on rats. Half-life (t1/2), mean residence time (MRT), and the area under the drug concentration–time curve (AUC) were found to be 7.1 ± 0.6 h, 10.5 ± 0.9 h, and 1725.7 ± 44.1 ng × h/mL, respectively.Graphical

Buprenorphine Salivary Gland Accumulation Sustaining High Oral Fluid Exposure and Increasing the Risk of Streptococcus mutans Biofilm Formation.

The US Food and Drug Administration (FDA) issued a warning about buprenorphine-induced dental caries of unknown mechanism in 2022. To investigate the potential mechanism, the association between local buprenorphine exposure and dental biofilm formation will be explored in this study. Female F344 rats were dosed with sublingual buprenorphine film or intravenous injection to explore the oral cavity exposure of the buprenorphine. The buprenorphine distribution in salivary glands after the sublingual and intravenous administration was also evaluated. To investigate the effects of buprenorphine exposure on dental caries formation, buprenorphine's impact on the biofilm formation of S. mutans in vitro was measured. The absolute sublingual bioavailability of buprenorphine in rats was 17.8% with a high ratio of oral fluid exposure to blood concentration in the pharmacokinetic study. Salivary gland concentrations of buprenorphine and its active metabolite norbuprenorphine were significantly higher than their blood concentrations after both sublingual (s.l.) and intravenous (i.v.) administration. Correlation analysis showed that the oral fluid concentration of buprenorphine and norbuprenorphine was highly correlated to salivary gland concentration rather than blood concentration. These data indicate that the salivary gland serves as an accumulation organ for buprenorphine, allowing prolonged oral fluid exposure to buprenorphine. Lastly, buprenorphine and its metabolites contributed to the biofilm formation of S. mutans in high concentration. Sublingual administration substantially increased the salivary gland distribution of buprenorphine and norbuprenorphine. Depot effects following sublingual dosing and salivary gland accumulation likely sustained high oral fluid exposure to buprenorphine and stimulated the biofilm formation of S. mutans.

Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects

We aimed to prepare novel dibenzo[a,d][7]annulen derivatives that act on N-methyl-D-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Our in silico analyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds 3l and 6f to penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy, 6f showed high relative inhibition (∼90% for GluN1/GluN2A), while 3l showed moderate inhibition (∼50%). An in vivo toxicity study determined that compounds 3l and 6f were safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compound 3l at a concentration of 30 μM significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzo[a,d][7]annulen derivatives are promising candidates for developing NMDA receptor-targeted therapies with minimal psychotomimetic side effects.

Strategic Establishment of a High-throughput Photosafety Assessment System

Chemical phototoxicity is elicited after exposure of skin to photosensitive chemicals, followed by exposure to sunlight. The intensity of ultraviolet light has increased due to ozone layer destruction; therefore, interest in avoidance of the phototoxicity risk of chemicals has increased in drug discovery and product development. Based on the mechanism of chemical phototoxicity, a photosafety screening strategy focusing on the photoreactivity of chemicals and skin exposure to chemicals was proposed. In an initially-developed photosafety screening system, a reactive oxygen species (ROS) assay and an in vivo cassette-dosing pharmacokinetic study were employed to evaluate the photoreactivity of chemicals and skin exposure to chemicals, respectively, and previous investigations yielded reliable photosafety predictions. On the other hand, the tools in the photosafety screening system have some issues, such as low applicability to poorly water-soluble chemicals in the ROS assay and unsatisfactory animal welfare in in vivo cassette-dosing pharmacokinetic studies. The present study aimed to overcome these issues. A micellar ROS (mROS) assay was newly developed to evaluate photoreactivity of poorly water-soluble chemicals, resulting in an increase in the number of evaluable chemicals by ROS assay systems. An in vitro permeation test was applied to the proposed photosafety screening strategy as an alternative to the in vivo pharmacokinetic study for evaluating chemical exposure of the skin. Combined use of the ROS assay system and in vitro permeation test provided reliable photosafety evaluations. These findings would contribute to drug discovery and product development with high photosafety and improved animal welfare.

Nanostructured Lipid Carrier-Mediated Transdermal Delivery System of Glibenclamide for Gestational Diabetes: Pharmacokinetic and Pharmacodynamic Evaluation.

Gestational diabetes mellitus (GDM) poses significant risks during pregnancy for both mother and fetus. Adherence to oral antidiabetic medications, like glibenclamide (GB), can be challenging, necessitating novel drug delivery methods. Nanostructured lipid carriers (NLC) offer a promising approach by efficiently permeating the skin due to their small size and lipid-based composition. This study aimed to develop and evaluate transdermal patches loaded with glibenclamide NLCs to treat GDM. Glibenclamide NLCs were prepared using hot homogenization with ultrasonication and melt dispersion method. A central composite design was utilized to optimize the formulations. Transdermal patches containing optimized NLCs were developed using HPMC K 100 and Eudragit L polymers. The patches were evaluated for various parameters, and their pharmacokinetic and pharmacodynamic studies were carried out to assess their safety and efficacy. Optimized NLCs efficiently permeated rat skin. Cell viability studies indicated the nontoxicity of the formulations. NLC-loaded transdermal patches (F2 and F7) showed drug release of 1098 μg/cm2 and 1001.83 μg/cm2 in 24 h, with a 2.5-fold higher flux and permeation coefficient than the GB patch. Pharmacokinetic analysis revealed Tmax of 8 and 10 h and Cmax of 7127 ng/ml and 7960 ng/ml for F2 and F7, respectively, ensuring sustained drug action. AUC0-α was 625681 ng/ml·h and 363625 ng/ml·h for F2 and F7, respectively, indicating improved bioavailability. Transdermal patches incorporating NLCs hold promise for enhancing glibenclamide's therapeutic efficacy in GDM treatment. Improved skin permeation, sustained drug release, and enhanced bioavailability make NLC-based transdermal patches a potential alternative with better patient compliance.

In vivo pharmacokinetic and pharmacodynamic study and cutoff of florfenicol against Riemerella anatipestifer in ducks

In vivo pharmacokinetic and pharmacodynamic study and cutoff of florfenicol against Riemerella anatipestifer in ducks

Self-assembled sustainable bionanocomposite hydrogels from chitosan for the combination chemotherapy of hydrophobic and hydrophilic drugs.

Self-assembled hydrogels derived from naturally sourced polymers have gained significant interest in drug delivery applications, owing to their potential, exceptional biocompatibility and sustainable properties. This work presents the development and application of self-assembled nanocomposite hydrogels from chitosan and nanosilver as a pH responsive drug delivery system for the controlled release of doxorubicin and paclitaxel in anticancer therapy. Chitosan was functionalized with 4-formyl benzoic acid for incorporating both hydrophobic and hydrophilic anticancer drugs. The self-assembled nanocomposite hydrogels formed from chitosan and 4-formyl benzoic acid by various non-covalent interactions were studied by FT-IR, Dynamic Light Scattering (DLS), and rheology analysis. Rheology studies demonstrated the hydrogel's shear-thinning nature, enabling easy injection. The antibacterial activity can be evidenced by agar-well diffusion assay and MIC values were measured. The antibacterial effect was analyzed by agar-well diffusion assays and H2-DCFDA assay, providing a comprehensive understanding. In-vivo pharmacokinetic studies on Wistar rats demonstrated promising and effective systemic circulation of drug loaded material in blood, thus supporting its potential for therapeutic applications. All these studies and results demonstrates feasibility and a novel synergistic dual drug delivery approach, promising the synergy between hydrophobic paclitaxel (PTX) and hydrophilic Doxorubicin hydrochloride (Dox.HCl), for improved anticancer efficacy.

Highly sensitive ultra-high-performance liquid chromatography coupled with tandem mass spectrometry method for the multiplex analysis of levosimendan and its metabolites OR-1855 and OR-1896 in human plasma

Levosimendan is a positive inotrope and vasodilator used in patients with acute and chronic decompensated heart failure. It is metabolized into OR-1855 (inactive metabolite), which is further acetylated into OR-1896 (active metabolite having a prolonged half-life, hence a sustained effect). Levosimendan represents a valuable alternative to traditional inotropes with broad clinical applications in critically ill patients with cardiogenic shock, advanced heart failure and post-cardiac surgery. However, while levosimendan demonstrates dose-dependent hemodynamic effects, its pharmacokinetics has not yet been investigated in adult critically ill patients, a vulnerable population characterized by complex and unstable conditions that may significantly alter drug disposition. Therefore, pharmacokinetics studies of levosimendan and metabolites in critically ill patients require a reliable and sensitive quantification method.We developed and validated a highly sensitive method using ultra-high-performance liquid-chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) for the quantification of levosimendan, OR-1855 and OR-1896 in human plasma. To achieve the required analytical sensitivity, plasma sample preparation included protein precipitation with acetonitrile, subsequent supernatant’s evaporation to dryness under nitrogen, and reconstitution of the solid residues with a solution of H2O:MeOH 4:1, followed by a 40 µL-aliquot injection into the LC column. Chromatographic separation of the three analytes was achieved in a 6-minute run in gradient mode, using an Acquity UPLC BEH C18 1.7µm, 2.1 ×150mm column. The method was extensively validated according to international bioanalytical assay guidelines, on a clinically relevant concentration range of 0.1 to 100ng/mL, for each analyte. Considering these very low concentrations, the assay showed excellent performances in terms of trueness (94.3-105.3%), repeatability (1.9-7.2%) and intermediate fidelity (2.3-9.7%).Of note, during our ex vivo studies on whole blood samples stability, acetylation of the metabolite OR-1855 into the active OR-1896 metabolite was observed in the presence of red blood cells.The UHPLC method is being applied for a prospective observational pharmacokinetics study of levosimendan in patients undergoing extracorporeal membrane oxygenation support. The benefit of levosimendan therapeutic drug monitoring in intensive care patients remains to be assessed.

Synchronization of extraction and chromatographic conditions of diverse physicochemical behavior of pseudoephedrine, loratadine and desloratadine for their simultaneous determination in human plasma: Application to pharmacokinetic study

A selective, sensitive, and rapid LC-MS/MS method has been developed, optimized, and validated for the simultaneous determination of pseudoephedrine (PSE), loratadine (LOR), and LOR active metabolite, desloratadine (DES) in K3EDTA human plasma. A simple liquid–liquid extraction method was adopted for extraction of the 3 analytes and their internal standards; chlorpheniramine (CLP), loratadine D4 (LOR-D4), and desloratadine D4 (DES-D4), respectively, giving consistent recovery results (78.38––88.23 %) using diethyl ether: dichloromethane (80:20, v/v) as the extraction solvent. The chromatographic separation was challenging due to the polarity differences between PES, which is more polar, and LOR and DES, which are less polar that affected their physicochemical properties including the retention of the drugs on C18 column. The separation was achieved using of isocratic elution of 20 mM ammonium formate and 2 mM trifluoracetic acid ammonium salt: acetonitrile containing 0.15 % formic acid (12:88, v/v) as a mobile phase pumped onto a Supelco Discovery® C18 (4.6 mm x 100 mm, 5 µm) at 35 °C with a flow rate of 0.8 mL/min. The use of trifluoracetic acid ammonium salt as an ion pair reagent in the selected mobile phase allowed good retention of the polar PSE on the used C18 column with a reasonable retention time. Positive Electrospray ionization was employed followed by detection using a tandem mass spectrometer in multiple reactions monitoring (MRM) mode. The sample analysis of this study was conducted in compliance with ICH guideline M10 on bioanalytical method validation and study sample analysis. The method was linear over the concentration range of (4–1200) ng/mL for PSE, (50–15000) pg/mL for both LOR, and DES. The developed method was accurate (91.14–110.30 %), precise (0.53–7.86 %), and was applied to study the pharmacokinetic profile of the cited drugs in the plasma of healthy human volunteers after single oral administration of the fixed-dose combination Claritin D® tablet, (240/10 mg) of PSE, and LOR, respectively.

1,3-Naphthoxazine derivatives: Synthesis, in silico pharmacokinetic studies, antioxidant and photoprotective properties

Investigation into the interactions between photoprotective agents and skin can offer a precise understanding of their biological behaviors in vitro and in vivo, providing crucial insights for generating new substances. For this purpose, we designed and synthesized a series of naphthoxazine derivatives and examined their photoprotective properties. 1,3-naphthoxazine derivatives were synthesized through the multi-component reaction of 2-naphthol, arylamines and aromatic aldehydes in the presence of copper(II) trifluoromethanesulfonate (Cu(OTf)2) and (±)-Camphor-10-sulfonic acid ((±)-CSA) catalyst system under sonication. The potential of these synthesized 1,3-naphthoxazine derivatives as antioxidants and viable organic structural-based sunscreen ingredients has been investigated. Sun protection factor (SPF) assay results showed that especially compounds 4i, 4c, 4k, 4d, 4r, and 4h had remarkably high activity (23.65, 23.57, 23.04, 21.94, 20.80, and 20.26, respectively at 900 µg/mL concentration). Additionally, antioxidant activity of the synthesized compounds was evaluated and compounds 4h, 4e, 4b, and 4j exhibited the highest activities in DPPH scavenging activity assay (86.46 %, 82.83 %, 80.78 %, and 80.65 % respectively at 400 µg/mL concentration). The synthesized compounds exhibit promising characteristics for effective UV radiation absorption, suggesting their suitability for inclusion in sunscreen formulations. Cytotoxic activity of compound 4k against normal human fibroblast cell line (MRC-5) was determined by CVDK-8 method. The results revealed that the compound provided remarkable viability (87.55 %) of MRC-5 cells at concentration of 100 µM. The study explores their efficacy in providing broad-spectrum protection against UVA and UVB rays, degradation and photostability, ADMET profile, and other pharmacokinetic properties.

Clinical Pharmacology and Side Effects of Venetoclax in Hematologic Malignancies

Venetoclax is a first-in-class B-cell lymphoma/lymphoma-2 (BCL-2) inhibitor that induces apoptosis in malignant cells through the inhibition of BCL-2. The clinical response to venetoclax exhibits heterogeneity, and its sensitivity and resistance may be intricately linked to genetic expression. Pharmacokinetic studies following doses of venetoclax (ranging from 100 to 1200mg) revealed a time to maximum observed plasma concentration of 5-8 hours, with a maximum blood concentration of 1.58-3.89 μg/mL, and a 24-hour area under the concentration-time curve of 12.7-62.8 μg·h/mL. Population-based pharmacokinetic investigations highlighted that factors such as low-fat diet, race, and severe hepatic impairment play pivotal roles in influencing venetoclax dose selection. Being a substrate for CYP3A4, P-glycoprotein, and breast cancer resistance protein, venetoclax undergoes primary metabolism and clearance in the liver, displaying low accumulation in the body.The significance of dose modifications (a 50% decrease with moderate and a 75% reduction with strong CYP3A inhibitors) and a cautious two-hour interval when co-administered with P-glycoprotein inhibitors are highlighted by insights from clinical medication interaction studies. Moreover, an exposure-response relationship analysis indicates that venetoclax exposure significantly correlates not only with overall survival and total response rate but also with the occurrence of ≥ 3-grade neutropenia. In real-world studies, common or severe side effects of venetoclax include tumor lysis syndrome, myelosuppression, nausea, diarrhea, constipation, infection, autoimmune hemolytic anemia, and cardiac toxicity, among others. In this review, we summarize the current clinical pharmacology studies and side effects of venetoclax, which showed that the approved dosage of venetoclax is relatively wide, and the dosage for different hematologic populations can be streamlined in the future.

Evaluation of the effect of milk casein on the pharmacokinetics of rutin

Rutin, often referred to as vitamin P, possesses numerous pharmaceutical applications, yet its market availability is restricted due to poor bioavailability. Recent interest has focused on exploiting rutin's therapeutic potential, prompting efforts to enhance its bioavailability. This study aimed to enhance the bioavailability of rutin by formulating tablet dosage forms using cow milk casein as a matrix-forming agent. Tablet formulations containing rutin and milk casein were prepared, and their physicochemical properties were evaluated through in vitro tests, including hardness, friability, and dissolution. Pharmacokinetic studies were conducted using Wistar rat models, analyzing plasma drug concentrations and urine excretion. Stability studies were also performed to assess the tablets' shelf life under various conditions. The results of the study revealed that the incorporation of milk casein significantly improved the bioavailability of rutin, both in vitro and in vivo. Physicochemical evaluations demonstrated satisfactory tablet properties, while pharmacokinetic studies indicated enhanced plasma drug concentrations and reduced urine excretion of rutin with milk casein formulations. Stability studies further supported the suitability of the formulated tablets for long-term storage. In conclusion, milk casein proved effective as a matrix-forming agent for improving the bioavailability of rutin. The formulated tablets exhibited favorable physicochemical properties and enhanced drug absorption characteristics, suggesting the potential utility of milk casein in enhancing the therapeutic efficacy of rutin formulations.

Population Pharmacokinetic and Pharmacodynamic Study of Palbociclib in Children and Young Adults with Recurrent, Progressive, or Refractory Brain Tumors

Population Pharmacokinetic and Pharmacodynamic Study of Palbociclib in Children and Young Adults with Recurrent, Progressive, or Refractory Brain Tumors

Bioadhesive film for the delivery of local anesthetics to the buccal mucosa: ex-vivo and in-vivo evaluation

The aim of this work was the preparation and characterization of two bioadhesive films (with different drug loadings) containing a combination of lidocaine and prilocaine hydrochloride to be applied on the buccal mucosa to reduce the pain sensation associated with needle insertion during dental procedures. The films were tested ex-vivo to determine the amount of drug permeated/retained in buccal mucosa, and, in-vivo to assess the extent and duration of anesthetic effect on the mucosa and pharmacokinetic parameters. As a reference, the commercial formulation EMLA® cream was used. Ex-vivo studies were conducted on porcine esophageal epithelium, an accepted model for buccal mucosa, and in-vivo studies on human volunteers. The ex-vivo results obtained show that the retention of both drugs into the mucosa resulted comparable after the application of the films or EMLA® cream for 10 min; on the contrary, the amounts of drug permeated from the commercial formulation was higher, suggesting the possibility to achieve systemic effect. In-vivo experiments showed that the intensity of anesthesia, evaluated by VAS during needle insertion, was much higher for EMLA® cream (the median value was zero for EMLA® and 0.15–0.3 cm for the two films); however, the film and EMLA® cream resulted equivalent in terms of duration of anesthesia, from 25 to 40 min. The pharmacokinetic study showed that both films tested produced very low plasma concentration (zero for most of experimental data point), thus guaranteeing no risk of systemic effects, whereas EMLA® cream demonstrated measurable plasma levels for both drugs (lidocaine Cmax was 4 ng/ml, prilocaine Cmax was 1.5 ng/ml). Moreover, a correlation between ex-vivo drug tissue concentration and duration of the anesthetic effect in-vivo was found. Although this correlation is limited to a small number of formulations, it supports the validity of pig esophageal epithelium in the development of formulation to be used on human buccal mucosa.

Population Pharmacokinetics and Dose Optimization of Piperacillin in Infants and Children with Pneumonia.

We aimed to determine the piperacillin disposition and optimize the dosing regimens for infants and children with pneumonia. An opportunistic sampling strategy was used in this pharmacokinetic study. High-performance liquid chromatography was used to measure the concentrations of piperacillin in plasma samples. A population pharmacokinetic model was conducted using NONMEM. The pharmacokinetic data of 90 samples from 64 infants and children with pneumonia (age range: 0.09-1.72 years for infants and 2.12-11.10 years for children) were available. A two-compartment model with first-order elimination was the most suitable model to describe the population pharmacokinetics of piperacillin. A covariate analysis indicated that body weight and age were significant factors affecting clearance. Monte Carlo simulations showed that a 50-mg/kg every 8 h or every 12 h dosing regimen results in underdosing. Results both in infants and children showed that an extended infusion (3 h) of various dosing regimens (80, 100, or 130 mg/kg) three times daily or a 300-mg/kg continuous infusion can reach a therapeutic level based on the chosen target for the probability of target attainment threshold of 70%, 80%, and 90% at minimum inhibitory concentration breakpoints of 8 mg/L and 16 mg/L. A population pharmacokinetic model was obtained to evaluate the disposition of piperacillin, and the optimal dosing regimens were provided for use in infants and children with pneumonia.

Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia.

Histone deacetylase inhibitors (HDACi) are established anticancer drugs, especially in hematological cancers. This study aimed to design, synthesize, and evaluate a set of HDACi featuring a pentyloxyamide connecting unit linker region and substituted phenylthiazole cap groups. A structural optimization program yielded HDACi with nanomolar inhibitory activity against histone deacetylase class I/IIb enzymes. The novel inhibitors (4d and 4m) showed superior antileukemic activity compared to several approved HDACi. Furthermore, 4d and 4m displayed synergistic activity when combined with chemotherapeutics, decitabine, and clofarabine. In vitro pharmacokinetic studies showed the most promising profile for 4d with intermediate microsomal stability, excellent plasma stability, and concentration-independent plasma protein binding. Additionally, 4d demonstrated comparable in vivo pharmacokinetics to vorinostat. When administered in vivo, 4d effectively inhibited the proliferation of leukemia cells without causing toxicity. Furthermore, the binding modes of 4d and 4m to the catalytic domain 2 of HDAC6 from Danio rerio were determined by X-ray crystallography.

One Concentration Does Not Fit All: It is Time to Personalize the Therapeutic Range of Infliximab in Crohn Disease.

Therapeutic drug monitoring of infliximab is commonly performed based on trough concentration. However, doses and dosing intervals may be adapted to patient outcomes, and this trough concentration target may correspond to a large range of exposures in terms of the area under the concentration-time curve (AUC). The objectives of this study were to assess the real-life exposure to intravenous infliximab in patients with Crohn disease in remission at year 1 and to assess the evolution of exposure in patients who switched to subcutaneous infliximab. The authors conducted a retrospective observational pharmacokinetic study in patients with Crohn disease who had available infliximab concentrations during intravenous and subcutaneous infliximab maintenance therapy as per the standard of care. Infliximab exposure parameters (AUCs and trough concentrations, C0) were compared for different dosing regimens of intravenous infliximab before (intravenous) and after (subcutaneous) the switch. A total of 113 patients had 383 intravenous infliximab concentrations. Dosing intervals ranged from 4 to 12 weeks. The median/range/CV% C0, AUC0-t, and AUC0-8weeks were 5.3 mcg/mL [<LLoQ-49.6]/71.6%, 37,792 mcg.h/mL [4971-116,366]/33.1%, and 41,582 mcg.h/mL [7953-232,048]/43.9%, respectively. Forty-one patients had available paired C0 after both intravenous and subcutaneous administration. A poor correlation was found between preswitch intravenous infliximab C0 and postswitch subcutaneous infliximab C0. In this study, the authors suggested that in patients treated with IV IFX, different targets of C0 should be proposed according to treatment schemes and that AUC0-t might be a relevant determinant of clinical remission. Moreover, exposure did not remain stable throughout the switch from IV to SC IFX in any patient. These variations may depend on the intravenous dosing interval before switching.

Population pharmacokinetics and dose optimization of ceftazidime in critically ill children

ObjectiveThe aim of this study was to develop a population pharmacokinetic model for ceftazidime in critically ill children in the pediatric intensive care unit (PICU) and optimize an appropriate dosing regimen for this population.MethodsWe performed a prospective pharmacokinetic study on critically ill children aged 0.03–15 years. A population pharmacokinetic model was developed using the NLME program. Statistical and graphical methods were used to assess the stability and predictive performance of the model. Monte Carlo simulations were conducted to determine the optimal ceftazidime dosing regimen to achieve 70% fT &amp;gt; minimum inhibitory concentration (MIC).ResultsThis study included 88 critically ill children and 100 ceftazidime serum concentrations. The pharmacokinetic characteristics of ceftazidime were best described by a one-compartment linear elimination model. The weight and estimated glomerular filtration rate (eGFR) were determinant covariates for the clearance (CL) of ceftazidime. The recommended ceftazidime dosage regimens achieved a probability of target attainment (PTA) &amp;gt;90% for critically ill children at MIC values of 2, 4, and 8 mg/L. For bacterial infection at an MIC of 16 mg/L, it is difficult to achieve effective pharmacodynamic (PD) targets in vivo with the commonly used dose of ceftazidime.ConclusionThe population pharmacokinetic model of ceftazidime was established in critically ill children. Based on this model, we recommend evidence-based, individualized dosing regimens for subgroups with different weights and renal functions. The current daily dosage for children adequately meets the treatment requirements for MICs of 2, 4, and 8 mg/L, while for bacterial infection at an MIC of 16 mg/L, an elevated dosage regimen may be required.Clinical Trial Registrationhttps://www.medicalresearch.org.cn/login, Identifier MR-42-22-000220.

A comprehensive pharmacokinetic strategy for systematic evaluation of whole interaction of different constituents in Astragali Radix -Fructus Corni to improve diabetic kidney disease

Ethnopharmacological relevanceAstragali-Radix (the dried root of Astragalus mongholicus Bunge, AR) - Fructus Corni (the dried ripe fruit of Cornus officinalis Sieb. et Zucc., FC) has been used as a herb-pair remedy to treat diabetic kidney disease (DKD) for hundred years. Polysaccharides, saponins, and flavonoids in AR, and the iridoid glycosides in FC were deemed as the main bioactive constituents that can offer beneficial nephroprotective activities. A systematic evaluation of the nephroprotective effects of AR-FC herb pair, the main bioactive constituents extracted from the herb pair, and their combinations in different ratios was performed, CG6 (polysaccharides, flavonoids, saponins, and iridoid glycosides, in a ratio of 2:3:1:2) as the best compatibility proportion was screened out in our previous study. Aim of the studyThis study aimed to investigate the pharmacokinetic characteristics of AR-FC herb-pair in DKD rats, and explore the interactions between constituents from AR-FC and the rational compatibility of different constituents. Materials and methodsThe protective effect of AR-FC and CG6 on renal injury caused by DKD was first verified by histopathological examination. Then, an analytical method based on UHPLC-Q-TOF-MS and UHPLC-QqQ-MS/MS for qualitative and quantitative metabolites without reference standards was established and applied to pharmacokinetic (PK) studies in following different aspects: between single groups (polysaccharides, flavonoids, saponins and iridoid glycosides) and compatibility groups (AR-FC, CG6), in normal and DKD rats, in single-dose administration and long-term administration. ResultsPathological observations confirmed that AR-FC could improve renal injury in DKD rats. PK profiles of nine prototypes and four metabolites in various groups were obtained, revealing the compatibility of multiple constitutes, pathological states, and long-term administration could alter PK characteristics of the main components from AR-FC, and promoting the absorption of them (Cmax, AUC0-t, and AUC0-t increased). Notably, co-administration of iridoid glycosides could significantly increase the absorption of flavonoids and saponins in vivo. The pharmacokinetics based on homologous compounds revealed that saponins first acted, then its initial metabolites affected flavonoids, and ultimately the metabolites of flavonoids influenced iridoid glycosides. ConclusionThis study demonstrated the existence of interactions between constituents from AR-FC herb-pair and the importance of their rational compatibility. It provides experimental evidence for developing a therapeutic agent based on AR-FC (especially CG6) to treat DKD. It is also expected to provide a reference for the multi-component pharmacokinetic study of other herbal medicines.