Antibacterial micro/nanomotors: current research progress, challenges, and opportunities.

Bacterial infections remain a formidable threat to human health, a situation exacerbated by the escalating problem of antibiotic resistance. While alternative antibacterial strategies such as oxidants, heat treatments, and metal nanoparticles (NPs) have shown potential, they come with significant drawbacks, ranging from non-specificity to potential environmental concerns. In the face of these challenges, the rapid evolution of micro/nanomotors (MNMs) stands out as a revolutionary development in the antimicrobial arena. MNMs harness various forms of energy and convert it into a substantial driving force, offering bright prospects for combating microbial threats. MNMs' mobility allows for swift and targeted interaction with bacteria, which not only improves the carrying potential of therapeutic agents but also narrows the required activation range for non-drug antimicrobial interventions like photothermal and photodynamic therapies, substantially improving their bacterial clearance rates. In this review, we summarized the diverse propulsion mechanisms of MNMs employed in antimicrobial applications and articulated their multiple functions, which include direct bactericidal action, capture and removal of microorganisms, detoxification processes, and the innovative detection of bacteria and associated toxins. Despite MNMs' potential to revolutionize antibacterial research, the translation from laboratory to clinical use remains challenging. Based on the current research status, we summarized the potential challenges and possible solutions and also prospected several key directions for future studies of MNMs for antimicrobial purposes. Collectively, by highlighting the important knowns and unknowns of antimicrobial MNMs, our present review would help to light the way forward for the field of antimicrobial MNMs and prevent unnecessary blindness and detours.

Ketone Monoester Plus Carbohydrate Supplementation Does Not Alter Exogenous and Plasma Glucose Oxidation or Metabolic Clearance Rate During Exercise in Men Compared with Carbohydrate Alone.

BACKGROUND: Increasing ß-hydroxybutyrate (ßHB) availability through ketone monoester (KE) plus carbohydrate supplementation is suggested to enhance physical performance by sparing glucose use during exercise. However, no studies have examined the effect of ketone supplementation on glucose kinetics during exercise. OBJECTIVES: This exploratory study primarily aimed to determine the effect of KE plus carbohydrate supplementation on glucose oxidation during steady-state exercise and physical performance compared with carbohydrate alone. METHODS: Using a randomly assigned, crossover design, 12 men consumed 573 mg KE/kg body mass plus 110 g glucose (KE+CHO) or 110 g glucose (CHO) before and during 90 min of steady-state treadmill exercise [54 ± 3% peak oxygen uptake (V˙O2peak)] wearing a weighted vest (30% body mass; 25 ± 3 kg). Glucose oxidation and turnover were determined using indirect calorimetry and stable isotopes. Participants performed an unweighted time to exhaustion (TTE; 85% V˙O2peak) after steady-state exercise and a weighted (25 ± 3 kg) 6.4 km time trial (TT) the next day after consuming a bolus of KE+CHO or CHO. Data were analyzed by paired t-tests and mixed model ANOVA. RESULTS: ßHB concentrations were higher (P < 0.05) after exercise [2.1 mM (95% CI: 1.6, .6)] and the TT [2.6 mM (2.1, 3.1)] in KE+CHO compared with CHO. TTE was lower [-104 s (-201, -8)], and TT performance was slower [141 s (19,262)] in KE+CHO than in CHO (P < 0.05). Exogenous [-0.01 g/min (-0.07, 0.04)] and plasma [-0.02 g/min (-0.08, 0.04)] glucose oxidation and metabolic clearance rate {MCR [0.38 mg·kg-1·min-1 (-0.79, 1.54)]} were not different, and glucose rate of appearance [-0.51 mg·kg-1·min-1 (-0.97, -0.04)], and disappearance [-0.50 mg·kg-1·min-1 (-0.96, -0.04)] were lower (P < 0.05) in KE+CHO compared with CHO during steady-state exercise. CONCLUSIONS: In the current study, rates of exogenous and plasma glucose oxidation and MCR were not different between treatments during steady-state exercise, suggesting blood glucose utilization is similar between KE+CHO and CHO. KE+CHO supplementation also results in lower physical performance compared with CHO alone. This trial was registered at www. CLINICALTRIALS: gov as NCT04737694.

Impact of Drug Metabolism/Pharmacokinetics and its Relevance Considering Traditional Medicine-based Anti-COVID-19 Drug Research.

BACKGROUND: The representative anti-COVID-19 herbs, i.e., Poriacocos, Pogostemon, Prunus, and Glycyrrhiza plants, are commonly used in the prevention and treatment of COVID-19, a pandemic caused by SARSCoV- 2. Diverse medicinal compounds with favorable anti-COVID-19 activities are abundant in these plants, and their unique pharmacological/pharmacokinetic properties have been revealed. However, the current trends in Drug Metabolism/Pharmacokinetic (DMPK) investigations of anti-COVID-19 herbs have not been systematically summarized. METHODS: In this study, the latest awareness, as well as the perception gaps regarding DMPK attributes, in the anti- COVID-19 drug development and clinical usage was critically examined and discussed. RESULTS: The extracts and compounds of P.cocos, Pogostemon, Prunus, and Glycyrrhiza plants show distinct and diverse absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties. The complicated herbherb interactions (HHIs) and herb-drug interactions (HDIs) of anti-COVID-19 Traditional Chinese Medicine (TCM) herb pair/formula dramatically influence the PK/pharmacodynamic (PD) performance of compounds thereof, which may inspire researchers to design innovative herbal/compound formulas for optimizing the therapeutic outcome of COVID-19 and related epidemic diseases. The ADME/T of some abundant compounds in anti-COVID-19 plants have been elucidated, but DMPK studies should be extended to more compounds of different medicinal parts, species, and formulations and would be facilitated by various omics platforms and computational analyses. CONCLUSION: In the framework of pharmacology and pharmacophylogeny, the DMPK knowledge base would promote the translation of bench findings into the clinical practice of anti-COVID-19 and speed up the anti-COVID-19 drug discovery and development.

Pharmacokinetics and metabolism of trans-emodin dianthrones in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thunb. (PM) is a common traditional Chinese medicine with diverse biological activities of resolving toxins, nourishing livers and promoting hairs. Nevertheless, in recent years hepatotoxic adverse reactions caused by the administration of PM have raised worldwide concerns. In our previous study, we found that emodin dianthrones showed hepatotoxicity and may be potential toxicity markers. However, the metabolic transformation and pharmacokinetic behavior of emodin dianthrones in vivo have still not been elucidated. AIM OF THE STUDY: Taking trans-emodin dianthrones (TED) as an example, the present study was conducted to investigate the pharmacokinetics and bioavailability of TED in rats and characterized its metabolic transformation in the plasma, urine and feces of rats. MATERIALS AND METHODS: A rapid and sensitive UPLC-qqq-MS/MS method was developed for accurate quantification of TED in plasma and successfully applied to the pharmacokinetic evaluation of TED in rats after intravenous and oral administration. A reliable UFLC-Q-TOF-MS high resolution mass spectrometry combined with a scientific metabolite identification strategy was used to comprehensively characterize the metabolic transformation of TED in plasma, urine and feces in rats. RESULTS: The established UPLC-qqq-MS/MS method had a linear range of 1-500 ng/mL, and the method was accurate and reliable to meet the quantitative requirements. When 20 mg/kg TED was given by gavage rats, it was rapidly absorbed into the circulatory system and had a long half-life time of 6.44 h and wide tissue distribution in vivo. While intravenous injection of 0.4 mg/kg TED in rats, it was rapidly metabolized and eliminated with a half-life time of 1.82 h. The oral absorption bioavailability of TED was only 2.83%. Furthermore with a sensitive UFLC-Q-TOF-MS technique and metabolite identification strategy, 21 metabolites were successfully identified, including 11 in plasma, 12 in urine and 18 in feces. The main Ⅰ and Ⅱ phase metabolic processes involved glucuronidation, oxidation, carbonylation, (de)methylation, sulfation and hydrogenation. CONCLUSION: TED could be rapidly absorbed into the blood circulation and widely distributed and slowly metabolized in the body and underwent extensive cleavage and metabolic transformation in vivo. The study provided a basis for in-depth elucidation of the toxicology and mechanism research of TED, but also laid the foundation for further research on the material basis of hepatotoxicity of PM.

Evaluation of Normothermic Machine Perfusion of Porcine Livers as a Novel Preclinical Model to Predict Biliary Clearance and Transporter-Mediated Drug-Drug Interactions Using Statins.

There is a lack of translational preclinical models that can predict hepatic handling of drugs. In this study, we aimed to evaluate the applicability of normothermic machine perfusion (NMP) of porcine livers as a novel ex vivo model to predict hepatic clearance, biliary excretion, and plasma exposure of drugs. For this evaluation, we dosed atorvastatin, pitavastatin, and rosuvastatin as model drugs to porcine livers and studied the effect of common drug-drug interactions (DDIs) on these processes. After 120 minutes of perfusion, 0.104 mg atorvastatin (n = 3), 0.140 mg pitavastatin (n = 5), or 1.4 mg rosuvastatin (n = 4) was administered to the portal vein, which was followed 120 minutes later by a second bolus of the statin coadministered with OATP perpetrator drug rifampicin (67.7 mg). After the first dose, all statins were rapidly cleared from the circulation (hepatic extraction ratio > 0.7) and excreted into the bile. Presence of human-specific atorvastatin metabolites confirmed the metabolic capacity of porcine livers. The predicted biliary clearance of rosuvastatin was found to be closer to the observed biliary clearance. A rank order of the DDI between the various systems upon coadministration with rifampicin could be observed: atorvastatin (AUC ratio 7.2) > rosuvastatin (AUC ratio 3.1) > pitavastatin (AUC ratio 2.6), which is in good agreement with the clinical DDI data. The results from this study demonstrated the applicability of using NMP of porcine livers as a novel preclinical model to study OATP-mediated DDI and its effect on hepatic clearance, biliary excretion, and plasma profile of drugs. SIGNIFICANCE STATEMENT: This study evaluated the use of normothermic machine perfusion (NMP) of porcine livers as a novel preclinical model to study hepatic clearance, biliary excretion, plasma (metabolite) profile of statins, and OATP-mediated DDI. Results showed that NMP of porcine livers is a reliable model to study OATP-mediated DDI. Overall, the rank order of DDI severity indicated in these experiments is in good agreement with clinical data, indicating the potential importance of this new ex vivo model in early drug discovery.

Effect of Nigella sativa oil on pharmacokinetics and pharmacodynamics of gliclazide in rats.

Nigella sativa oil (NSO) has been used widely for its putative anti-hyperglycemic activity. However, little is known about its potential effect on the pharmacokinetics and pharmacodynamics of antidiabetic drugs, including gliclazide. This study aimed to investigate herb-drug interactions between gliclazide and NSO in rats. Plasma concentrations of gliclazide (single oral and intravenous dose of 33 and 26.4 mg/kg, respectively) in the presence and absence of co-administration with NSO (52 mg/kg per oral) were quantified in healthy and insulin resistant rats (n = 5 for each group). Physiological and treatment-related factors were evaluated as potential influential covariates using a population pharmacokinetic modeling approach (NONMEM version 7.4). Clearance, volume of distribution and bioavailability of gliclazide were unaffected by disease state (healthy or insulin resistant). The concomitant administration of NSO resulted in higher systemic exposures of gliclazide by modulating bioavailability (29% increase) and clearance (20% decrease) of the drug. A model-independent analysis highlighted that pre-treatment with NSO in healthy rats was associated with a higher glucose lowering effect by up to 50% compared with that of gliclazide monotherapy, but not of insulin resistant rats. Although a similar trend in glucose reductions was not observed in insulin resistant rats, co-administration of NSO improved the sensitivity to insulin of this rat population. Natural product-drug interaction between gliclazide and NSO merits further evaluation of its clinical importance.

Evaluation and comparison of in vitro intrinsic clearance rates measured using cryopreserved hepatocytes from humans, rats, and rainbow trout.

In vitro and in silico methods that can reduce the need for animal testing are being used with increasing frequency to assess chemical risks to human health and the environment. The rate of hepatic biotransformation is an important species-specific parameter for determining bioaccumulation potential and extrapolating in vitro bioactivity to in vivo effects. One approach to estimating hepatic biotransformation is to employ in vitro systems derived from liver tissue to measure chemical (substrate) depletion over time which can then be translated to a rate of intrinsic clearance (CLint). In the present study, cryopreserved hepatocytes from humans, rats, and rainbow trout were used to measure CLint values for 54 industrial and pesticidal chemicals at starting test concentrations of 0.1 and 1 µM. A data evaluation framework that emphasizes the behavior of Heat-Treated Controls (HTC) was developed to identify datasets suitable for rate reporting. Measured or estimated ("greater than" or "less than") CLint values were determined for 124 of 226 (55 %) species-chemical-substrate concentration datasets with acceptable analytical chemistry. A large percentage of tested chemicals exhibited low HTC recovery values, indicating a substantial abiotic loss of test chemical over time. An evaluation of KOW values for individual chemicals suggested that in vitro test performance declined with increasing chemical hydrophobicity, although differences in testing devices for mammals and fish also likely played a role. The current findings emphasize the value of negative controls as part of a rigorous approach to data quality assessment for in vitro substrate depletion studies. Changes in current testing protocols can be expected to result in the collection of higher quality data. However, poorly soluble chemicals are likely to remain a challenge for CLint determination.

Investigation into MAO B-Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B.

Ozanimod, recently approved for treating relapsing multiple sclerosis, produced a disproportionate, active, MAO B-catalyzed metabolite (CC112273) that showed remarkable interspecies differences and led to challenges in safety testing. This study explored the kinetics of CC112273 formation from its precursor RP101075. Incubations with human liver mitochondrial fractions revealed K Mapp, V max, and intrinsic clearance (Clint) for CC112273 formation to be 4.8 µM, 50.3 pmol/min/mg protein, and 12 µl/min/mg, respectively, whereas Michaelis-Menten constant (K M) with human recombinant MAO B was 1.1 µM. Studies with liver mitochondrial fractions from preclinical species led to K Mapp, V max, and Clint estimates of 3.0, 35, and 33 µM, 80.6, 114, 37.3 pmol/min/mg, and 27.2, 3.25, and 1.14 µl/min/mg in monkey, rat, and mouse, respectively, and revealed marked differences between rodents and primates, primarily attributable to differences in the K M Comparison of Clint estimates revealed monkey to be ∼2-fold more efficient and the mouse and rat to be 11- and 4-fold less efficient than humans in CC112273 formation. The influence of stereochemistry on MAO B-mediated oxidation was also investigated using the R-isomer of RP101075 (RP101074). This showed marked selectivity toward catalysis of the S-isomer (RP101075) only. Docking into MAO B crystal structure suggested that although both the isomers occupied its active site, only the orientation of RP101075 presented the C-H on the α-carbon that was ideal for the C-H bond cleavage, which is a requisite for oxidative deamination. These studies explain the basis for the observed interspecies differences in the metabolism of ozanimod as well as the substrate stereospecificity for formation of CC112273. SIGNIFICANCE STATEMENT: This study evaluates the enzymology and the species differences of the major circulating metabolite of ozanimod, CC112273. Additionally, the study also explores the influence of stereochemistry on MAO B-catalyzed reactions. The study is of significance to the DMD readers given that this oxidation is catalyzed by a non-cytochrome P450 enzyme, and that marked species difference and notable stereospecificity was observed in MAO B-catalyzed biotransformation when the indaneamine enantiomers were used as substrates.

Population pharmacokinetic analysis and dosing guidelines for tacrolimus co-administration with Wuzhi capsule in Chinese renal transplant recipients.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is a first-line immunosuppressant which is used to prevent transplant rejection after solid organ transplantation (SOT). However, it has a narrow therapeutic index and high individual variability in pharmacokinetics (PK) and pharmacogenomics (PG). It has been reported that the metabolism of TAC can be affected by genetic factors, leading to different rates of metabolism in different subjects. Wuzhi Capsule (WZC) is a commonly used TAC-sparing agent in Chinese SOT to reduce TAC dosing due to its inhibitory effect on TAC metabolism by enzymes of the CYP3A subfamily. The aims of this study were to assess the effect of TAC+WZC co-administration and genetic polymorphism on the pharmacokinetics of TAC, by using a population pharmacokinetic (PPK) model. A dosing guideline for individualized TAC dosing is proposed based on the PPK study. METHODS: The medical records of 165 adult patients with kidney transplant and their 824 TAC concentrations from two kidney transplantation centres were reviewed. The genotypes of four single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and ABCB1 (rs1128503, rs2032582 and rs1045642) were tested by MASSARRAY. A PPK model was constructed by nonlinear mixed effect model (NONMEM® , Version 7.3). Finally, Monte Carlo simulations were employed to design initial dosing regimens based on the final model. RESULTS AND DISCUSSION: The one-compartmental PPK model with first-order absorption and elimination of TAC was established in kidney transplant recipients (KTRs). CYP3A5*3 had significant impact on the PPK model. The haematocrit (HCT), postoperative time (POD) and CYP3A5*3 genotypes had a significant influence on TAC clearance when combined with WZC. The model was expressed as 23.4 × (HCT/0.3)-0.729  × 0.837 (combination with WZC) × e-0.0875(POD/12.6) ×1.18 (CYP3A5 expressors). For patients carrying the CYP3A5*3/*3 allele and with 30% HCT, the required TAC dose to achieve target trough concentrations of 10-15 ng/ml was 4 mg twice daily (q12h). For patients with the CYP3A5*3/*3 allele, the required dose was 3 mg TAC q12h when combined with WZC, and for patients with the CYP3A5*1/*1 or *1/*3 allele, the required dose was 4 mg of TAC q12h when co-administered with WZC. WHAT IS NEW AND CONCLUSION: Wuzhi Capsule co-administration and CYP3A5 variants affect the PK of TAC Dosing guidelines are made based on the PPK model to allow individualized administration of TAC, especially when co-administered with WZC.

Micropatterned Coculture With 3T3-J2 Fibroblasts Enhances Hepatic Functions and Drug Screening Utility of HepaRG Cells.

Human liver models are useful for assessing compound metabolism/toxicity; however, primary human hepatocyte (PHH) lots are limited and highly variable in quality/viability. In contrast, cell lines, such as HepaRG, are cheaper and more reproducible surrogates for initial compound screening; however, hepatic functions and sensitivity for drug outcomes need improvement. Here, we show that HepaRGs cocultured with murine embryonic 3T3-J2 fibroblasts, previously shown to induce PHH functions, could address such limitations. We either micropatterned HepaRGs or seeded them "randomly" onto collagen-coated plates before 3T3-J2 coculture. Micropatterned cocultures (HepaRG-MPCCs) secreted 2- to 4-fold more albumin and displayed more stable cytochrome P450 activities than HepaRG conventional confluent monocultures (HepaRG-CCs) and HepaRG micropatterned hepatocytes (HepaRG-MPHs) for 4 weeks, even when excluding dimethyl sulfoxide from the medium. Furthermore, HepaRG-MPCCs had the most albumin-only positive cells (hepatic), lowest cytokeratin 19 (CK19)-only positive cells (cholangiocytic), and highest mean albumin intensity per cell than HepaRG random cocultures and monocultures; however, 80%-84% of HepaRGs remained bipotential (albumin+/CK19+) across all models. The 3T3-J2s also induced higher albumin in HepaRG spheroids than HepaRG-only spheroids. Additionally, although rifampin induced CYP3A4 in HepaRG-MPCCs and HepaRG-CCs, only HepaRG-MPCCs showed the dual omeprazole-mediated CYP1A2/3A4 induction as with PHHs. Lastly, when treated for 6 days with 47 drugs and evaluated for albumin and ATP to make binary hepatotoxicity calls, HepaRG-MPCCs displayed a sensitivity of 54% and specificity of 100% (70%/100% in PHH-MPCCs), whereas HepaRG-CCs misclassified several hepatotoxins. Ultimately, HepaRG-MPCCs could be a more cost-effective and reproducible model than PHHs for executing a tier 1 compound screen.

γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology.

Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid present endogenously in the brain and used therapeutically for the treatment of narcolepsy, as sodium oxybate, and for alcohol abuse/withdrawal. GHB is better known however as a drug of abuse and is commonly referred to as the "date-rape drug"; current use in popular culture includes recreational "chemsex," due to its properties of euphoria, loss of inhibition, amnesia, and drowsiness. Due to the steep concentration-effect curve for GHB, overdoses occur commonly and symptoms include sedation, respiratory depression, coma, and death. GHB binds to both GHB and GABAB receptors in the brain, with pharmacological/toxicological effects mainly due to GABAB agonist effects. The pharmacokinetics of GHB are complex and include nonlinear absorption, metabolism, tissue uptake, and renal elimination processes. GHB is a substrate for monocarboxylate transporters, including both sodium-dependent transporters (SMCT1, 2; SLC5A8; SLC5A12) and proton-dependent transporters (MCT1-4; SLC16A1, 7, 8, and 3), which represent significant determinants of absorption, renal reabsorption, and brain and tissue uptake. This review will provide current information of the pharmacology, therapeutic effects, and pharmacokinetics/pharmacodynamics of GHB, as well as therapeutic strategies for the treatment of overdoses. Graphical abstract.

Drug-drug interactions between salvianolate injection and aspirin based on their metabolic enzymes.

BACKGROUND: It is unclear whether the combination of traditional Chinese medicine and Western medicine leads to interactions in pharmacokinetics (PKs) and pharmacodynamics (PDs). In this study, the influence of salvianolate and aspirin on metabolic enzymes, and the relationship between the blood concentration and pharmacodynamic indexes, were determined. METHOD: In this, randomized, parallel-grouped, single-center clinical trial, 18 patients with coronary heart disease were randomly allocated into three groups: aspirin (AP) group, salvianolate (SV) group, and combination (A + S) group. All treatment courses lasted for 10 days, and blood samples were acquired before and after administration at different timepoints. The expression of catechol-O-methyltransferase (COMT), CD62p, procaspase-activating compound 1 (PAC-1), P2Y12, phosphodiesterase, and mitogen-activated protein kinase 8 (MAPK8) were compared with variance analysis The blood concentrations were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: Sixteen subjects completed the study. No significant difference in COMT was found among groups, although there was a decrease in the SV group. The PK results indicated that the absorption time of salicylic acid was shortened and the AUC0-∞ decreased and the elimination time of salvianolic acid B was prolonged and the AUC0-∞ decreased. The PD results declined after administration. A significant difference was found in MAPK8, CD62p, and P2Y12 expression. Compared with the SV group, a significant difference in P2Y12 in the A + S group was found. CONCLUSION: A pharmacokinetic drug-drug interaction was found in the aspirin and salvianolate combination. Pharmacodynamically, there was no difference between the A + S and AP groups. However, P2Y12 expression in the combination group was superior to that in the SV group. TRIAL REGISTRATION NUMBERS: The trial was registered on October 9, 2017, ClinicalTrials.gov, NCT03306550. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0007D8H&selectaction=Edit&uid=U0003QY8&ts=2&cx=oiuc9g.

The Pharmacology, Efficacy, and Safety of Rivaroxaban in Obese Patient Populations.

Cardiovascular disease (CVD) remains the leading cause of death in the USA. Several risk factors have been identified, and obesity has become one of prominent concern. Excessive weight is considered a risk factor for CVD based on evidence linking it to a hypercoagulable state. Considering the prevalence of CVD and obesity in the USA, along with the increased risk for thrombus-related events, anticoagulation plays a significant role in prevention and treatment. Direct oral anticoagulants have taken the place of many traditional anticoagulants. Considering the recently approved indications and continued postmarketing studies conducted with rivaroxaban, this updated review provides data on the overall impact of obesity on this compound. This includes data obtained from both healthy obese volunteers and obese patients with various CVD conditions enrolled in rivaroxaban clinical trials, along with data obtained from postmarketing real-world evidence studies. Assessment of the clinical pharmacology and population pharmacokinetics in obese individuals revealed no clinically relevant effects of increased weight. Additionally, subgroup analyses from each of the pivotal phase III trials supporting the current approved labeling also demonstrated consistent efficacy and safety results in obese patients. Lastly, these findings are further supported by several recent real-world evidence studies assessing the continued effectiveness and safety of rivaroxaban. In conclusion, rivaroxaban's overall pharmacological and clinical profile remained consistent in obese adults when assessed in both drug development and postmarketing studies, supporting the premise that higher weight does not necessitate adjustment in either dose strength or regimen.

Blood clearance kinetics and organ delivery of medium-chain triglyceride and fish oil-containing lipid emulsions: Comparing different animal species.

BACKGROUND & AIMS: Medium-chain triglycerides (TG) (MCT) and fish oil (FO) TG are incorporated as the core TG component into intravenous (IV) lipid emulsions for infusion in parenteral nutrition. Bolus injections of IV emulsions, on the other hand, have emerged as a novel therapeutic approach to treat various acute disorders. However, intravascular metabolism and organ delivery of acute IV injection of emulsions containing both MCT and FO are not fully defined, nor have they been characterized across common experimental animal models. We characterized and compared blood clearance kinetics and organ distribution of bolus injections of MCT/FO emulsions among different animal species. We also examined whether sex differences or feeding status can affect catabolic properties of MCT/FO lipid emulsions. DESIGN: Blood clearance rates of lipid emulsions with specific TG composition were compared in rats IV injected with [3H]cholesteryl hexadecyl ether labeled pure n-6 long-chain (LCT) and n-3 FO TG lipid emulsions, or emulsions containing MCT and FO at different ratios (wt/wt), which include 8:2 (80% MCT: 20% FO), 5:4:1 (50% MCT: 40% LCT: 10% FO) and SMOF (30% LCT: 30% MCT: 25% olive oil: 10% FO). Dose-response effects (0.016 mg-1.6 mg TG/g body weight) of the MCT/FO 8:2 emulsions on blood clearance properties and organ delivery were determined in both mice and rats. Blood clearance kinetics and organ uptake of MCT/FO 8:2 emulsions were compared between male and female rats and between fed and fasted rats. Changes in plasma lipid profiles after acute injections of MCT/FO 8:2 lipid emulsion at different doses (0.043, 0.133, and 0.4 mg TG/g body weight) were characterized in non-human primates (Cynomolgus monkeys). RESULTS: MCT/FO 8:2 emulsion was cleared faster in rats when compared with other emulsions with different TG contents. Mice had faster blood clearance and higher fractional catabolic rates (FCR) when compared with the rats injected with MCT/FO 8:2 emulsions regardless of the injected doses. Mice and rats had similar plasma TG and free fatty acid (FFA) levels after low- or high-dose injections of the MCT/FO emulsion. Tissue distribution of the MCT/FO 8:2 lipid emulsion are comparable between mice and rats, where liver had the highest uptake per recovered dose among all organs (>60%). Feeding status and sex differences did not alter the blood clearance rate of the MCT/FO 8:2 emulsion in rats. In a nonhuman primate model, dose-response increases in plasma TG and FFA were observed after IV injection of MCT/FO 8:2 emulsions within the 1st 10 min. CONCLUSION: A lipid emulsion containing both MCT and FO TG is cleared rapidly in blood and readily available for organ uptake in rodent and primate animal models. Characterization of the blood clearance properties of the MCT/FO 8:2 emulsion administered in various animal models may provide further insight into the safety and efficacy profiles for future therapeutic use of bolus injections of MCT/FO emulsions in humans.

Population Pharmacokinetics and Exposure-Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With ß-Thalassemia.

ß-Thalassemia is an inherited blood disorder resulting from defects in hemoglobin production, leading to premature death of red blood cells (RBCs) or their precursors. Patients with transfusion-dependent ß-thalassemia often need lifelong regular RBC transfusions to maintain adequate hemoglobin levels. Frequent transfusions may lead to iron overload and organ damage. Thus, there is a large unmet need for alternative therapies. Luspatercept, a first-in-class erythroid maturation agent, is the first approved therapy in the United States for the treatment of anemia in adult patients with ß-thalassemia who require regular RBC transfusions. The population pharmacokinetics and exposure-response relationship of luspatercept were evaluated in 285 patients with ß-thalassemia. Luspatercept displayed linear and time-invariant pharmacokinetics when administered subcutaneously once every 3 weeks. Body weight was the only clinically relevant covariate of luspatercept clearance, favoring weight-based dosing. Magnitude and frequency of hemoglobin increase, if not influenced by RBC transfusions, was positively correlated with luspatercept area under the serum concentration-time curve (AUC), 0.2-1.25 mg/kg, whereas a significant reduction in RBC units transfused was observed in frequently transfused patients. The probability of achieving ≥33% or ≥50% reduction in RBC transfusion burden was similar across the time-averaged AUC (0.6-1.25 mg/kg), with the 1 mg/kg starting dose sufficient for most early responders (71%-80%). Increasing luspatercept AUC (0.2-1.25 mg/kg) did not increase incidence or severity of treatment-emergent adverse events. These results provide a positive benefit-risk profile for the recommended luspatercept doses (1-1.25 mg/kg) in treating adult patients with ß-thalassemia who require regular RBC transfusions.

Optimal Dosing of Meropenem in a Small Cohort of Critically Ill Children Receiving Continuous Renal Replacement Therapy.

Severe sepsis is an important cause of mortality and morbidity in critically ill children. Meropenem is a broad-spectrum antibiotic commonly used to treat sepsis. Current meropenem dosage recommendations for children on continuous renal replacement therapy are extrapolated from pharmacokinetic (PK) studies done in adults. Our study aims to determine the optimal dosing in critically ill septic children receiving continuous renal replacement therapy. A prospective single-center PK study was performed in 9 children in the intensive care unit on continuous renal replacement therapy. Meropenem concentrations were measured from blood and effluent fluid samples. A population PK model was developed using nonlinear mixed-effects modeling software (NONMEM, AstraZeneca UK Ltd, Cheshire, UK). Monte Carlo simulations were performed. The PK/pharmacodynamic target aimed for plasma concentrations above minimum inhibitory concentration of 4 mg/L for 100% of dosing interval (100%ƒT>MIC ). A 2-compartment model best characterized meropenem PK. Mean (range) clearance and elimination half-life was 0.091 L/h/kg (0.04-0.157) and 3.9 hours (2.1-7.5), respectively. Dosing of 40 mg/kg/dose every 12 hours over 30 minutes achieved PK/PD target in only 32% while 20 mg/kg every 8 hours over 4 hours or 40 mg/kg every 8 hours over 2 hours achieved 100% ƒT>MIC target for at least 90% of simulated patients.

Development and optimization of sitagliptin and dapagliflozin loaded oral self-nanoemulsifying formulation against type 2 diabetes mellitus.

Control of hyperglycemia and prevention of glucose reabsorption (glucotoxicity) are important objectives in the management of type 2 diabetes. This study deals with an oral combined dosage form design for two anti-diabetic drugs, sitagliptin and dapagliflozin using self-nanoemulsifying drug delivery systems (SNEDDS). The SNEDDS were developed using naturally obtained bioactive medium-chain/long-chain triglycerides oil, mixed glycerides and nonionic surfactants, and droplet size was measured followed by the test for antioxidant activities. Equilibrium solubility and dynamic dispersion experiments were conducted to achieve the maximum drug loading. The in vitro digestion, in vivo bioavailability, and anti-diabetic effects were studied to compare the representative SNEDDS with marketed product Dapazin®. The representative SNEDDS containing black seed oil showed excellent self-emulsification performance with transparent appearance. Characterization of the SNEDDS showed nanodroplets of around 50-66.57 nm in size (confirmed by TEM analysis), in addition to the high drug loading capacity without causing any precipitation in the gastro-intestinal tract. The SNEDDS provided higher antioxidant activity compared to the pure drugs. The in vivo pharmacokinetic parameters of SNEDDS showed significant increase in C max (1.99 ± 0.21 µg mL-1), AUC (17.94 ± 1.25 µg mL-1), and oral absorption (2-fold) of dapagliflozin compared to the commercial product in the rat model. The anti-diabetic studies showed the significant inhibition of glucose level in treated diabetic mice by SNEDDS combined dose compared to the single drug therapy. The combined dose of sitagliptin-dapagliflozin using SNEDDS could be a potential oral pharmaceutical product for the improved treatment of type 2 diabetes mellitus.

Position paper on the safety/efficacy profile of direct oral anticoagulants in patients with chronic kidney disease. Consensus document from the SIN, FCSA and SISET.

Direct oral anticoagulants (DOAC) are mostly prescribed to prevent cardioembolic stroke in patients with non-valvular atrial fibrillation (AF). An increasing number of guidelines recommend DOAC in AF patients with preserved renal function for the prevention of thromboembolism, and an increased use of DOAC in daily practice has been recorded also in elderly patients. Ageing is associated with a reduction in glomerular filtration rate, and impaired renal function, regardless of the cause, increases the risk of bleeding. Multiple medication use (polypharmacy) for treating superimposed co-morbidities is common in both elderly and chronic kidney disease (CKD) patients and drug-drug interaction may cause accumulation of DOAC, thereby increasing the risk of bleeding. The safety profile of DOAC in patients with CKD has not been defined with any certainty, particularly in those with severely impaired renal function or end stage renal disease. This has been due to the heterogeneity of studies and the relative paucity of data. This document reports the position of three Italian scientific societies engaged in the management of patients with atrial fibrillation who are treated with DOAC and present with CKD.

Characterization of Seasonal Pharmacokinetic Variability in Woodchucks.

The eastern woodchuck (Marmota monax) is a hibernating species extensively used as an in vivo efficacy model for chronic human hepatitis B virus infection. Under laboratory conditions, woodchucks develop a pseudohibernation condition; thus, the pharmacokinetics (PK) of small-molecule therapeutics may be affected by the seasonal change. The seasonal PK of four probe compounds were characterized over 12 months in seven male and nine female laboratory-maintained woodchucks. These compounds were selected to study changes in oxidative metabolism [antipyrine (AP)], glucuronidation [raltegravir (RTG)], renal clearance [lamivudine (3TC)], and hepatic function [indocyanine green (ICG)]. Seasonal changes in physiologic parameters and PK were determined. Seasonal body weight increases were ≥30%. Seasonal changes in body temperature and heart rate were <10%. The mean AP exposure remained unchanged from April to August 2017, followed by a significant increase (≥1.0-fold) from August to December and subsequent decrease to baseline at the end of study. A similar trend was observed in RTG and 3TC exposures. The ICG exposure remained unchanged. No significant sex difference in PK was observed, although female woodchucks appeared to be less susceptible to seasonal PK and body weight changes. Significant seasonal PK changes for AP, RTG, and 3TC indicate decreases in oxidative metabolism, phase II glucuronidation, and renal clearance during pseudohibernation. The lack of seasonal change in ICG exposure suggests there are no significant changes in hepatic function. This information can be used to optimize the scheduling of woodchuck studies to avoid seasonally driven variation in drug PK. SIGNIFICANCE STATEMENT: Woodchuck is a hibernating species and is commonly used as a nonclinical model of hepatitis B infection. Investigation of seasonal PK changes is perhaps of greater interest to pharmaceutical industry scientists, who use the woodchuck model to optimize the scheduling of woodchuck studies to avoid seasonally driven variation in drug PK and/or toxicity. This information is also valuable to drug metabolism and veterinary scientists in understanding woodchuck's seasonal metabolism and behavior under the pseudohibernation condition.

In Vitro Human Cell-Based Experimental Models for the Evaluation of Enteric Metabolism and Drug Interaction Potential of Drugs and Natural Products.

Elements of key enteric drug metabolism and disposition pathways are reviewed to aid the assessment of the applicability of current cell-based enteric experimental systems for the evaluation of enteric metabolism and drug interaction potential. Enteric nuclear receptors include vitamin D receptor, constitutive androstane receptor, pregnane X receptor, farnesoid X receptor, liver X receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor. Enteric drug metabolizing enzyme pathways include both cytochrome P450 (P450) and non-P450 drug metabolizing enzymes based on gene expression, proteomics, and activity. Both uptake and efflux transporters are present in the small intestine, with P-glycoprotein found to be responsible for most drug-drug and food-drug interactions. The cell-based in vitro enteric systems reviewed are 1) immortalized cell line model: the human colon adenocarcinoma (Caco-2) cells; 2) human stem cell-derived enterocyte models: stem cell enteric systems, either from intestinal crypt cells or induced pluripotent stem cells; and 3) primary cell models: human intestinal slices, cryopreserved human enterocytes, permeabilized cofactor-supplemented (MetMax) cryopreserved human enterocytes, and cryopreserved human intestinal mucosa. The major deficiency with both immortalized cell lines and stem cell-derived enterocytes is that drug metabolizing enzyme activities, although they are detectable, are substantially lower than those for the intestinal mucosa in vivo. Human intestine slices, cryopreserved human enterocytes, MetMax cryopreserved human enterocytes, and cryopreserved human intestinal mucosa retain robust enteric drug metabolizing enzyme activity and represent appropriate models for the evaluation of metabolism and metabolism-dependent drug interaction potential of orally administered xenobiotics including drugs, botanical products, and dietary supplements. SIGNIFICANCE STATEMENT: Enteric drug metabolism plays an important role in the bioavailability and metabolic fate of orally administered drugs as well as in enteric drug-drug and food-drug interactions. The current status of key enteric drug metabolism and disposition pathways and in vitro human cell-based enteric experimental systems for the evaluation of the metabolism and drug interaction potential of orally administered substances is reviewed.