Safflower yellow for injection enhances anti-coagulation of warfarin in rats: implications in pharmacodynamics and pharmacokinetics.

This study investigated whether Safflower Yellow for injection (SYI) would affect the anticoagulation of warfarin in rats.Wistar male rats were divided into six groups randomly and administered with SYI (9 mg/kg, intraperitoneal injection) in single-dose and steady-dose warfarin (0.2 mg/kg, oral gavage), respectively. The pharmacodynamic parameters of PT and APTT were measured by a coagulation analyser. R/S-warfarin concentration was measured by UHPLC-MS/MS, and pharmacokinetic parameters calculated using DAS 2.0 software.The single-dose study demonstrated that SYI, alone or co-administered with warfarin, could significantly increase PT, INR, and APTT values (p < 0.01). R-warfarin Cmax, AUC, and t1/2 values increased by 9.25% (p > 0.05), 25.96% (p < 0.01), and 26.17% (p < 0.01), respectively, whereas the CL/F value reduced by 22.22% (p < 0.01) in the presence of SYI. Meanwhile, S-warfarin Cmax, AUC, and t1/2 values increased by 37.41%, 32.11%, and 31.73% (all p < 0.01), respectively, whereas the CL/F value reduced by 33.33% (p < 0.01). The steady-dose study showed that PT, INR, APTT, and the concentrations of R/S-warfarin increased significantly when SYI was co-administered with warfarin (p < 0.01).SYI can enhance warfarin's anticoagulation intensity and decelerate its metabolism in rats.

Pharmacogenetic considerations in therapy with novel antiplatelet and anticoagulant agents.

Antiplatelets and anticoagulants are extensively used in cardiovascular medicine for the prevention and treatment of thrombosis in the venous and arterial circulations. Wide inter-individual variability has been observed in response to antiplatelets and anticoagulants, which triggered researchers to investigate the genetic basis of this variability. Data from extensive pharmacogenetic studies pointed to strong evidence of association between polymorphisms in candidate genes and the pharmacokinetics and pharmacodynamic action and clinical response of the antiplatelets clopidogrel and the anticoagulant warfarin. In this review, we conducted an extensive search on Medline for the time period of 2009-2023. We also searched the PharmGKB website for levels of evidence of variant-drug combinations and for drug labels and clinical guidelines. We focus on the pharmacogenetics of novel antiplatelets and anticoagulants while excluding acetylsalicylic acid, warfarin and heparins, and discuss the current knowledge with emphasis on the level of evidence.

Factors Influencing Unfractionated Heparin Pharmacokinetics and Pharmacodynamics During a Cardiopulmonary Bypass.

BACKGROUND: Unfractionated heparin (UFH) is commonly used during cardiac surgery with a cardiopulmonary bypass to prevent blood clotting. However, empirical administration of UFH leads to variable responses. Pharmacokinetic and pharmacodynamic modeling can be used to optimize UFH dosing and perform real-time individualization. In previous studies, many factors that could influence UFH pharmacokinetics/pharmacodynamics had not been taken into account such as hemodilution or the type of UFH. Few covariates were identified probably owing to a lack of statistical power. This study aims to address these limitations through a meta-analysis of individual data from two studies. METHODS: An individual patient data meta-analysis was conducted using data from two single-center prospective observational studies, where different UFH types were used for anticoagulation. A pharmacodynamic/pharmacodynamic model of UFH was developed using a non-linear mixed-effects approach. Time-varying covariates such as hemodilution and fluid infusions during a cardiopulmonary bypass were considered. RESULTS: Activities of UFH's anti-activated factor/anti-thrombin were best described by a two-compartment model. Unfractionated heparin clearance was influenced by body weight and the specific UFH type. Volume of distribution was influenced by body weight and pre-operative fibrinogen levels. Pharmacodynamic data followed a log-linear model, accounting for the effect of hemodilution and the pre-operative fibrinogen level. Equations were derived from the model to personalize UFH dosing based on the targeted activated clotting time level and patient covariates. CONCLUSIONS: The population model effectively characterized UFH's pharmacokinetics/pharmacodynamics in cardiopulmonary bypass patients. This meta-analysis incorporated new covariates related to UFH's pharmacokinetics/pharmacodynamics, enabling personalized dosing regimens. The proposed model holds potential for individualization using a Bayesian estimation.

Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients.

AIMS: Genotype-guided dosing algorithms can explain about half of the interindividual variability in prothrombin time-international normalized ratio (PT-INR) under warfarin treatment. This study aimed to refine a published kinetic-pharmacodynamic model and guide warfarin dosage for an optimal PT-INR based on renal function. METHODS: Using a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT-INR measurements, we refined the kinetic-pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear-mixed-effect modelling programme. We searched the significant covariates for parameters, such as the dose rate for 50% inhibition of coagulation (EDR50 ), using a stepwise forward and backward method. Monte Carlo simulation determined a required daily dose of warfarin with a target range of PT-INR (2.0-3.0 or 1.6-2.6) based on the significant covariates. RESULTS: A total of 350 patients with 2762 PT-INR measurements were enrolled (estimated glomerular filtration rate [eGFR]: 47.5 [range: 2.6-199.0] mL/min/1.73 m2 ). The final kinetic-pharmacodynamic model showed that the EDR50 changed power functionally with body surface area, serum albumin level and eGFR. Monte Carlo simulation revealed that a lower daily dose of warfarin was required to attain the target PT-INR range as eGFR decreased. CONCLUSIONS: Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment.

The Safety, Pharmacokinetics, and Pharmacodynamics of SHR2285, an Oral Small Molecule Factor XIa Inhibitor, in Healthy Chinese Volunteers.

BACKGROUND AND OBJECTIVE: There is an unmet need for a safer anticoagulant since bleeding remains a concern with currently approved anticoagulants. Coagulation factor XI (FXI) is an attractive anticoagulant drug target with limited a role in physiological hemostasis. The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of SHR2285, a novel small molecule FXIa inhibitor, in healthy Chinese volunteers. METHODS: The study consisted of single ascending doses part (part 1: 25-600 mg) and multiple ascending doses part (part 2: 100, 200, 300, and 400 mg). In both parts, subjects were randomized in a 3:1 ratio to receive SHR2285 or placebo orally. Blood, urine and feces samples were collected to describe its pharmacokinetic and pharmacodynamic profile. RESULTS: In total, 103 healthy volunteers completed the study. SHR2285 was well tolerated. SHR2285 was absorbed rapidly with median time to maximum plasma concentration (Tmax) of 1.50 to 3.00 h. The geometric median half-life (t1/2) of SHR2285 varied from 8.74 to 12.1 h across 25-600 mg single dose. Total systemic exposure of metabolite SHR164471 was approximately 1.77- to 3.61-fold that of the parent drug. The plasma concentration of SHR2285 and SHR164471 reached steady state by the morning of Day 7, with low accumulation ratio (0.956-1.20 and 1.18-1.56, respectively). The increase in pharmacokinetic exposure of SHR2285 and SHR164471 was less than dose proportional. Food has minimal effect on the pharmacokinetics of SHR2285 and SHR164471. SHR2285 produced an exposure-dependent prolongation of activated partial thromboplastin time (APTT) and a decrease in FXI activity. The maximum FXI activity inhibition rate (geometric mean) at steady state was 73.27%, 85.58%, 87.77% and 86.27% for 100-400 mg, respectively. CONCLUSIONS: SHR2285 was generally safe and well tolerated in healthy subjects across a wide range of doses. SHR2285 exhibited a predictable pharmacokinetic profile and an exposure-related pharmacodynamic profile. CLINICALTRIALS: gov Identifier NCT04472819; registered on July 15, 2020.

Population Pharmacokinetics and Probability of Target Attainment Analysis of Nadroparin in Different Stages of COVID-19.

BACKGROUND AND OBJECTIVE: The risk of thrombotic complications in critical patients with COVID-19 remains extremely high, and multicenter trials failed to prove a survival benefit of escalated doses of low-molecular-weight heparins (nadroparin calcium) in this group. The aim of this study was to develop a pharmacokinetic model of nadroparin according to different stages of COVID-19 severity. METHODS: Blood samples were obtained from 43 patients with COVID-19 who received nadroparin and were treated with conventional oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation. We recorded clinical, biochemical, and hemodynamic variables during 72 h of treatment. The analyzed data comprised 782 serum nadroparin concentrations and 219 anti-Xa levels. We conducted population nonlinear mixed-effects modeling (NONMEM) and performed Monte Carlo simulations of the probability of target attainment for reaching 0.2-0.5 IU/mL anti-Xa levels in study groups. RESULTS: We successfully developed a one-compartment model to describe the population pharmacokinetics of nadroparin in different stages of COVID-19. The absorption rate constant of nadroparin was 3.8 and 3.2 times lower, concentration clearance was 2.22 and 2.93 times higher, and anti-Xa clearance was 0.87 and 1.1 times higher in mechanically ventilated patients and the extracorporeal membrane oxygenation group compared with patients treated with conventional oxygen, respectively. The newly developed model indicated that 5.900 IU of nadroparin given subcutaneously twice daily in the mechanically ventilated patients led to a similar probability of target attainment of 90% as 5.900 IU of subcutaneous nadroparin given once daily in the group supplemented with conventional oxygen. CONCLUSIONS: Different nadroparin dosing is required for patients undergoing mechanical ventilation and extracorporeal membrane oxygenation to achieve the same targets as those for non-critically ill patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier no. NCT05621915.

Evaluation of safety, pharmacokinetics, and pharmacodynamics of apixaban in pediatric subjects at risk of venous or arterial thrombotic disorder.

Apixaban is an oral small-molecule, direct factor Xa (FXa) inhibitor approved in adults for treatment of deep vein thrombosis and pulmonary embolism, and for reducing risk of venous thromboembolism recurrence after initial anticoagulant therapy. This phase I study (NCT01707394) evaluated the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of apixaban in pediatric subjects (<18 years), enrolled by age group, at risk of venous or arterial thrombotic disorder. A single apixaban dose, targeting adult steady-state exposure with apixaban 2.5 mg, was administered using two pediatric formulations: 0.1 mg sprinkle capsule (age <28 days); 0.4 mg/ml solution (age 28 days to <18 years; dose range, 1.08-2.19 mg/m2 ). End points included safety, PKs, and anti-FXa activity. For PKs/PDs, four to six blood samples were collected ≤26 h postdosing. A population PK model was developed with data from adults and pediatric subjects. Apparent oral clearance (CL/F) included fixed maturation function based on published data. From January 2013 to June 2019, 49 pediatric subjects received apixaban. Most adverse events were mild/moderate, and the most common was pyrexia (n = 4/15). Apixaban CL/F and apparent central volume of distribution increased less than proportionally with body weight. Apixaban CL/F increased with age, reaching adult values in subjects aged 12 to <18 years. Maturation affected CL/F most notably in subjects aged <9 months. Plasma anti-FXa activity values were linearly related to apixaban concentrations, with no apparent age-related differences. Pediatric subjects tolerated single apixaban doses well. Study data and population PK model supported phase II/III pediatric trial dose selection.

Pharmacokinetics of a microdosed cocktail of three direct oral anticoagulants in children with congenital heart defects: study protocol for a single-centre clinical trial (DOAC-Child).

INTRODUCTION: Direct oral anticoagulants (DOACs) are direct inhibitors of coagulation factor Xa and are frequently used in adults for different indications such as deep vein thrombosis or non-valvular atrial fibrillation. Paediatric patients might benefit as well from DOACs because the simplicity and convenience of their use is likely to decrease physical and psychological stress related to invasive procedures associated with phenprocoumon and heparin therapy. Thus, it is expected that the future use of DOACs will ultimately improve compliance and overall safety of anticoagulant therapies in paediatric populations. To assure safe and effective use the clinical pharmacology and pharmacokinetics (PK) of these drugs need to be evaluated in children. METHODS AND ANALYSIS: This study is a single-centre, open-label, clinical trial in a paediatric population with non-cyanotic congenital heart defects. After having obtained informed consent from the parents, each participant will receive a single oral administration of a drinkable solution of a microdose cocktail of three FXa inhibitors consisting of apixaban (12.5 µg), rivaroxaban (12.5 µg), edoxaban (50 µg), plus a microdose of the two probe drugs midazolam (10 µg) and yohimbine (25 µg). Serial blood samples (n=up to 20) will be collected at specified time points before and up to 25 hours after cocktail administration. The primary PK endpoint will be the area under the plasma concentration time curve of apixaban, rivaroxaban and edoxaban. Secondary PK outcomes will be Cmax, tmax, t1/2, Cl/F and Vss/F. Safety and tolerability of the microdose cocktail will be evaluated as well by a collection of adverse events. ETHICS: This study has been approved by the responsible Ethics Committee of the Medical Faculty of Heidelberg University. DISSEMINATION: Study results will be presented at international scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT 2019-001759-38 16, DRKS00021455.

A Physiological-Based Pharmacokinetic Model Embedded with a Target-Mediated Drug Disposition Mechanism Can Characterize Single-Dose Warfarin Pharmacokinetic Profiles in Subjects with Various CYP2C9 Genotypes under Different Cotreatments.

Warfarin, a commonly prescribed oral anticoagulant medication, is highly effective in treating deep vein thrombosis and pulmonary embolism. However, the clinical dosing of warfarin is complicated by high interindividual variability in drug exposure and response and its narrow therapeutic index. CYP2C9 genetic polymorphism and drug-drug interactions (DDIs) are substantial contributors to this high variability of warfarin pharmacokinetics (PK), among numerous factors. Building a physiology-based pharmacokinetic (PBPK) model for warfarin is not only critical for a mechanistic characterization of warfarin PK but also useful for investigating the complicated dose-exposure relationship of warfarin. Thus, the objective of this study was to develop a PBPK model for warfarin that integrates information regarding CYP2C9 genetic polymorphisms and their impact on DDIs. Generic PBPK models for both S- and R-warfarin, the two enantiomers of warfarin, were constructed in R with the mrgsolve package. As expected, a generic PBPK model structure did not adequately characterize the warfarin PK profile collected up to 15 days following the administration of a single oral dose of warfarin, especially for S-warfarin. However, following the integration of an empirical target-mediated drug disposition (TMDD) component, the PBPK-TMDD model well characterized the PK profiles collected for both S- and R-warfarin in subjects with different CYP2C9 genotypes. Following the integration of enzyme inhibition and induction effects, the PBPK-TMDD model also characterized the PK profiles of both S- and R-warfarin in various DDI settings. The developed mathematic framework may be useful in building algorithms to better inform the clinical dosing of warfarin. SIGNIFICANCE STATEMENT: The present study found that a traditional physiology-based pharmacokinetic (PBPK) model cannot sufficiently characterize the pharmacokinetic profiles of warfarin enantiomers when warfarin is administered as a single dose, but a PBPK model with a target-mediated drug disposition mechanism can. After incorporating CYP2C9 genotypes and drug-drug interaction information, the developed model is anticipated to facilitate the understanding of warfarin disposition in subjects with different CYP2C9 genotypes in the absence and presence of both cytochrome P450 inhibitors and cytochrome P450 inducers.

Rivaroxaban Pharmacokinetics in Obese Subjects: A Systematic Review.

INTRODUCTION: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality globally. The direct oral anticoagulants, including rivaroxaban, are relatively novel therapeutic options in the treatment and prevention of VTE. There is a conflicting and inconclusive evidence surrounding the pharmacokinetics (PK) of rivaroxaban in patients with VTE who are obese. OBJECTIVES: We conducted a systematic review to provide an overview, and to synthesize the available evidence in the current literature pertaining to rivaroxaban PK in obese subjects who are healthy or diseased. METHODS: The PubMed, Embase, ScienceDirect, Rayyan, and Cochrane Library databases were systematically searched from 1 May 2021 through 28 February 2022. Studies investigating rivaroxaban PK in adult obese subjects were included in the review. Pertinent data, including anthropometric parameters, rivaroxaban dosage regimen, PK parameters, PK model, and outcome measures were extracted. Reference values of rivaroxaban PK parameters in the general population were used for comparison purposes. The review protocol was registered in the PROSPERO database (CRD42020177770). RESULTS: In the 11 studies included in this systematic review, over 7140 healthy or diseased subjects received rivaroxaban therapy, with varying clinical indications in the diseased population. The reported PK parameters of rivaroxaban in obese subjects compared with reference values in the general population were variable. The reported values of the volume of distribution (Vd) among obese subjects (73.4-82.8 L) fell within the range of values reported/calculated for the general population (59.4-104 L), assuming complete bioavailability. However, some of the reported values of clearance (CL) in obese subjects (7.86-16.8 L.h-1) do not fall within the range of values reported/calculated for the general population (5.57-11.3 L.h-1). The reported maximum plasma concentrations in obese subjects versus the general population following a 10 mg dose were 149 vs. 143-180 µg.L-1, and following a 20 mg dose were 214-305 vs. 299-360 µg.L-1, respectively. The area under the plasma concentration versus time curves (AUC) over different intervals in obese subjects versus the general population following a 10 mg dose were 1155 (AUC from time zero to infinity [AUC∞]) vs. 1029 (AUC∞) µg.h.L-1; and 1204-2800 (AUC from time zero to 24 h [AUC24]) vs. 3200 (AUC24) µg.h.L-1, respectively, following a 20 mg dose. The reported values of half-life and time to reach the maximum plasma concentration in obese subjects versus the general population were not consistent across studies. CONCLUSION: Variable changes and inconsistencies in different rivaroxaban PK parameters were reported in obese subjects. Further well-designed studies are warranted to better characterize the PK and clinical outcomes of rivaroxaban in subjects with obesity.

Phenytoin Metabolic Ratio, a Marker of CYP2C9 Activity, is Superior to the CYP2C9 Genotype as a Predictor of (S)-Warfarin Clearance.

BACKGROUND: CYP2C9 is a member of the cytochrome P450 (CYP) superfamily responsible for the metabolism of 16% of drugs that undergo oxidative metabolism. The activity of CYP2C9 exhibits marked inter-individual variability, which translates into prominent differences in the pharmacokinetics of CYP2C9 substrates, some of which are characterized by a narrow therapeutic window. Genetic polymorphisms in the gene encoding for CYP2C9 account for a fraction of the variability in CYP2C9 activity. The phenytoin metabolic ratio (PMR) is a marker of CYP2C9 activity in vivo, which correlates with CYP2C9 genetic polymorphisms. OBJECTIVE: The purpose of the current study was to evaluate the ability of the PMR to predict the oral clearance of (S)-warfarin (SWOCL) and its formation clearance towards its CYP2C9-mediated metabolites (SWCLf) [i.e., 6- and 7-hydroxy-(S)-warfarin]. METHODS: The study was conducted in 150 healthy non-smoker subjects (segment 1) and 60 patients treated with warfarin (segment 2). In the first segment, the participants received on two separate occasions a single 300-mg dose of phenytoin and at least 7 days later a single dose of warfarin (5 or 10 mg). The same PMR procedure was performed in the second segment, except that it was performed either before warfarin initiation or after the patients had reached stable anticoagulation. The PMR was derived from the ratio of 5-(4-hydroxyphenyl)-5-phenyl-hydantoin content in a 24-hour urine collection to plasma phenytoin concentration 12- (PMR24/12) or 24- (PMR24/24) post-dosing. In segment 1, SWOCL was calculated from the ratio of (S)-warfarin dose to the warfarin area under the plasma concentration-time curve extrapolated to infinity and the SWCLf from the ratio of urine content of 6- and 7-hydroxy-(S)-warfarin to (S)-warfarin area under the (S)-warfarin plasma concentration-time curve until the last measured timepoint. In segment 2, estimated SWOCL was derived from the ratio of (S)-warfarin dose to the mid-interval plasma concentration of (S)-warfarin. RESULTS: The PMR, SWOCL, and SWCLf varied significantly between carriers of different CYP2C9 genotypes in both healthy subjects (p < 0.001) and patients (p < 0.005). However, PMR and SWOCL values exhibited substantial intra-genotypic variability. PMR24/12 and PMR24/24 were significantly correlated with SWOCL both in healthy subjects (r = 0.62 and r = 0.67, respectively, p < 0.001) and in patients (r = 0.57 and r = 0.61, respectively, p < 0.001). In a multiple regression model that included all variables that correlated with SWOCL, PMR was the strongest predictor, explaining 44% and 38% of the variability in SWOCL among healthy subjects and patients, respectively, and accounting for 95.7% (44%/46%) and 90.5% (38%/42%) of the total explained variability in SWOCL among healthy subjects and patients, respectively. CONCLUSIONS: The PMR is the strongest predictor of SWOCL, and as such, it exhibits a significant advantage over the CYP2C9 genotype. The inclusion of PMR in future dosing algorithms of CYP2C9 substrates characterized by a narrow therapeutic window should be encouraged and further investigated.

Evaluating pharmacokinetic drug-drug interactions of direct oral anticoagulants in patients with renal dysfunction.

INTRODUCTION: Drug transporters, metabolic enzymes, and renal clearance play significant roles in the pharmacokinetics of direct oral anticoagulants (DOACs). Recommendations for DOAC drug-drug interactions (DDIs) by the product labeling are limited to selected CYP3A4 and P-glycoprotein inhibitors and lack considerations for concomitant renal dysfunction. AREAS COVERED: This review focuses on: 1) current recommendations for the management of pharmacokinetic DOAC DDIs and the evidence used to support them; 2) alterations in DOAC exposure in the setting of concomitant DDIs and mild, moderate, and severe renal impairment; 3) clinical outcomes associated with this combination; and 4) expert recommendations for the management of pharmacokinetic DOAC DDIs. English-language, full-text articles on apixaban, dabigatran, rivaroxaban, and edoxaban with a publication date up to 30 September 2021 were retrieved from PubMed. EXPERT OPINION: Given the lack of supporting clinical data, empiric dose adjustments based on pharmacokinetic data alone should be avoided. When a considerable increase in a DOAC exposure is anticipated, it may be advisable to use an alternative DOAC or anticoagulant from a different class. Future research on identification of DOAC therapeutic ranges and target patient populations is needed to inform clinical utility of DOAC level monitoring to guide the management of DDIs.

The Impact of CYP2C9*11 Allelic Variant on the Pharmacokinetics of Phenytoin and (S)-Warfarin.

Cytochrome P450 2C9 (CYP2C9) is responsible for the oxidative metabolism of about 15% of commonly used drugs, some of which are characterized by a narrow therapeutic window. CYP2C9 is highly polymorphic, and over 60 alleles have been described. CYP2C9*2 and CYP2C9*3 are the most common polymorphisms among White patients and both are associated with decreased activity. The evidence concerning the functional importance of less frequent variant alleles is scarce. The objective of the current study was to characterize the in vivo activity of CYP2C9 among carriers of CYP2C9*11, one of the "African" alleles and the fourth most common CYP2C9 variant allele among White patients by using two prototype substrates, phenytoin and (S)-warfarin. Single 300-mg phenytoin and 20-mg warfarin doses were given to 150 healthy Ethiopian Jewish participants who were nonsmokers, at least one week apart. (S)-warfarin oral clearance and phenytoin metabolic ratio (PMR) derived from the ratio of 5-(4-hydroxyphenyl)-5-phenylhydantoin in 24-hour urine collection to plasma phenytoin 12 hours (PMR 24/12) or 24 hours (PMR 24/24) post dosing, were used as markers of CYP2C9 activity. PMR 24/12 and PMR 24/24 were reduced by 50% and 62.2%, respectively, among carriers of CYP2C9*1/*11 (n = 13) as compared with carriers of CYP2C9*1/*1 (n = 127) (false discovery rate (FDR) q < 0.001). The respective decrease in (S)-warfarin oral clearance was 52.6% (FDR q < 0.001). In conclusion, the enzyme encoded by CYP2C9*11 is characterized by a more than 50% decrease in the enzymatic activity, resembling the extent of decrease associated with CYP2C9*3 ("no-function allele"). Among patients of African ancestry, CYP2C9*11 genetic analysis should be considered prior to prescribing of narrow therapeutic window drugs such as phenytoin, warfarin, nonsteroidal anti-inflammatory drugs, or siponimod.

Population Pharmacokinetics of Rivaroxaban in Chinese Patients with Non-Valvular Atrial Fibrillation: A Prospective Multicenter Study.

BACKGROUND AND OBJECTIVE: Rivaroxaban is a novel oral anticoagulant widely used for thromboprophylaxis in patients with non-valvular atrial fibrillation (NVAF). The present study aimed to develop a population pharmacokinetic (PPK) model for rivaroxaban in Chinese patients with NVAF. METHODS: We performed a prospective multicenter study. The plasma concentration of rivaroxaban was directly detected by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and indirectly by rivaroxaban-calibrated chromogenic anti-Xa assay (STA®). Gene polymorphisms were detected by MassARRAY single nucleotide polymorphism genotyping technology. Nonlinear mixed-effects modeling was used to develop the PPK model for rivaroxaban in patients with NVAF, and we simulated the steady-state rivaroxaban exposures under different dosing strategies in different covariate levels. RESULTS: A total of 150 patients from five centers were recruited, including 263 plasma concentrations detected by HPLC-MS/MS, 2626 gene polymorphisms, and 131 plasma concentrations detected by anti-Xa assay. In our study, an oral one-compartment model was used to describe the pharmacokinetics of rivaroxaban in patients with NVAF. In the final model, the estimated apparent clearance (CL/F) and volume of distribution (V/F) were 5.79 L/h (relative standard error [RSE] 4.4%) and 51.5 L (RSE 5.0%), respectively. Covariates in the final model included creatinine clearance, total bilirubin, rs4728709, and body weight. The simulation results showed that in the 15 mg once-daily dosing regimen, in most instances the maximum plasma concentration at steady state (Cmax,ss) and trough plasma concentration at steady state (Cmin,ss) were in the target range for different covariate levels. When patients were administered rivaroxaban 15 or 20 mg once daily, the Cmax,ss and Cmin,ss in the different bodyweight levels were also in the target range. For patients with the ABCB1 rs4728709 mutation, the Cmin,ss in the 10, 15, and 20 mg once-daily dosing regimens were lower than the target range. The anti-Xa assay was highly linearly correlated with the HPLC-MS/MS method [y = 1.014x - 2.4648 (R2 = 0.97)]. CONCLUSIONS: Our study was the first multicenter PPK model for rivaroxaban in Chinese patients with NVAF (Alfalfa-RIVAAF-PPK). The study found that 15 mg once daily may be suitable as the principal rivaroxaban dose for Chinese patients with NVAF. For patients with the rs4728709 mutation, it may be necessary to examine insufficient anticoagulation. We found that the rivaroxaban-calibrated chromogenic anti-Xa assay and HPLC-MS/MS method were highly linearly correlated. Prospective studies with larger sample sizes and real-world studies are needed for further verification.

Evaluation of DOAC Dipstick Test for Detecting Direct Oral Anticoagulants in Urine Compared with a Clinically Relevant Plasma Threshold Concentration.

Measuring direct oral anticoagulant (DOAC) concentrations might be necessary in certain clinical situations but is not routinely performed. The DOAC Dipstick is a new rapid test for detecting DOACs in urine. The aim of this study was to evaluate the possible uses and limitations of the DOAC Dipstick and to compare visual analysis and DOASENSE Reader analysis of DOAC Dipstick pads. Plasma and urine samples were collected from 23 patients taking DOACs. DOAC concentrations in plasma and urine were measured by chromogenic substrate assays and in urine also by the DOAC Dipstick. Plasma concentrations were dichotomized at a threshold of ≥30 ng/mL. Patient samples were compared with samples from control individuals not using anticoagulants (n = 10) and with DOASENSE control urines. The Combur-10 test was used to measure parameters that may affect urine color and hence the interpretation of the DOAC Dipstick result. DOAC Dipstick test results were positive in 21/23 patient urine samples at a plasma DOAC concentration of ≥30 ng/mL and in 2/23 patient urine samples at a plasma DOAC concentration of <30 ng/mL. Inter-observer agreement was above 90% for visual analysis of patient urine samples and was 100% for DOASENSE Reader analysis of patient urines and for analysis of control group urines and DOASENSE control urines. Abnormalities in urine color detected by the Combur-10 test did not affect the DOAC Dipstick results. DOAC Dipstick detects DOACs in urine at a plasma threshold of ≥30 ng/mL. Positive DOAC Dipstick results should be confirmed by measuring DOAC plasma concentration.

Citrate pharmacokinetics in critically ill liver failure patients receiving CRRT.

Citrate has been proposed as anticoagulation of choice in continuous renal replacement therapy (CRRT). However, little is known about the pharmacokinetics (PK) and metabolism of citrate in liver failure patients who require CRRT with regional citrate anticoagulation (RCA). This prospective clinical PK study was conducted at King Chulalongkorn Memorial Hospital between July 2019 to April 2021, evaluating seven acute liver failure (ALF) and seven acute-on-chronic liver failure (ACLF) patients who received CRRT support utilizing RCA as an anticoagulant at a citrate dose of 3 mmol/L. For evaluation of the citrate PK, we delivered citrate for 120 min and then stopped for a further 120 min. Total body clearance of citrate was 152.5 ± 50.9 and 195.6 ± 174.3 mL/min in ALF and ACLF, respectively. The ionized calcium, ionized magnesium, and pH slightly decreased after starting citrate infusion and gradually increased to baseline after stopping citrate infusion. Two of the ACLF patients displayed citrate toxicity during citrate infusion, while, no ALF patient had citrate toxicity. In summary, citrate clearance was significantly decreased in critically ill ALF and ACLF patients receiving CRRT. Citrate use as an anticoagulation in these patients is of concern for the risk of citrate toxicity.

Qualitative and Quantitative Analysis of Secondary Metabolites in Morphological Parts of Paulownia Clon In Vitro 112® and Their Anticoagulant Properties in Whole Human Blood.

It is not easy to find data in the scientific literature on the quantitative content of individual phytochemicals. It is possible to find groups of compounds and even individual compounds rather easily, but it is not known what their concentration is in cultivated or wild plants. Therefore, the subject of this study was to determine the content of individual compounds in the new Paulownia species, Oxytree, developed in a biotechnology laboratory in 2008 at La Mancha University in Spain. Six secondary metabolites were isolated, and their chemical structure was confirmed by spectral methods. An analytical method was developed, which was then used to determine the content of individual compounds in leaves, twigs, flowers and fruits of Paulownia Clon in Vitro 112®. No flavonoids were found in twigs and fruits of Oxytree, while the highest phenylethanoid glycosides were found in twigs. In this study, we also focused on biological properties (anticoagulant or procoagulant) of extract and four fractions (A-D) of different chemical composition from Paulownia Clon in Vitro 112 leaves using whole human blood. These properties were determined based on the thrombus-formation analysis system (T-TAS), which imitates in vivo conditions to assess whole blood thrombogenecity. We observed that three fractions (A, C and D) from leaves decrease AUC10 measured by T-TAS. In addition, fraction D rich in triterpenoids showed the strongest anticoagulant activity. However, in order to clarify the exact mechanism of action of the active substances present in this plant, studies closer to physiological conditions, i.e., in vivo studies, should be performed, which will also allow to determine the effects of their long-term effects.

Comparative pharmacokinetics of difethialone stereoisomers in male and female rats and mice: development of an intra- and inter-species model to predict the suitable formulation mix.

The ecotoxicity of anticoagulants used for rodent pests' management is a major concern, particularly with second generation anticoagulants, which are more persistent in the body of rodents and therefore more likely to cause secondary exposure in their predators. One of the solutions envisaged to mitigate this risk is to use stereoisomers of these anticoagulants, each of which has particular pharmacokinetics. However, the few studies published to date have considered only one species and one sex. Here, we study the pharmacokinetics of the 4 stereoisomers of 3.4 mg/kg of difethialone in rats (Rattus norvegicus) and 3 mg/kg in mice (Mus musculus) in both sexes and propose a model to choose the optimal stereoisomer efficacy/ecotoxicity mixture for the management of all these animals. Our results show that while the most persistent stereoisomer (E3-cis) is common to both species and sexes, the pharmacokinetics of the other stereoisomers show marked differences between sexes and species. Thus, the area under curve (AUC) of E4-trans in male rats is four times lower than in females or mice, making it a priori unusable in male rats. Conversely, our modeling seems to show that the E1-trans stereoisomer seems to offer the best compromise AUC persistence. In conclusion, we highlight that studies on anticoagulants must necessarily integrate research on the effect of gender and species both on efficacy and with regard to the ecotoxicity of these molecules.

Evaluating the effects of anticoagulant rodenticide bromadiolone in Wistar rats co-exposed to vitamin K: impact on blood-liver axis and brain oxidative status.

The aim of this study was to investigate the beneficial effects of vitamin K relate to protection against detrimental effects of bromadiolone. Wistar rats (n = 30) were divided in three groups (n = 10): control group and two groups treated with bromadiolone (0.12 mg/kg) and bromadiolone + vitamin K (0.12 mg/kg + 100 mg/kg) over the period of four days. The main findings in the bromadiolone-exposed rats, such as damaged hepatocytes, high levels of globulin, total proteins and lymphocytes, and altered albumin/globulin ratio, collectively indicate an acute inflammatory process. Morphological changes in erythrocytes include microcytosis, hypochromia, hyperchromia, hemolysis, stomatocytosis, and spherocytosis. Significantly low values of RBC, Hct, and hemoglobin concentrations indicate impairments of the hematopoietic pathway causing combined anemia. The selected dose of bromadiolone caused a non-significant increase of catalase activity and a significant increase of the total protein content in brain tissue homogenates. Vitamin K supplementation reduced many of the harmful effects of bromadiolone. The cytoprotective role of vitamin K was proved to be of great importance for the preservation of structural changes on the membranes of hepatocytes and erythrocytes, in addition to the known role in the treatment of coagulopathies. The results of the study suggest valuable properties of vitamin K in the prevention and treatment of various types of anemia caused by bromadiolone toxicity. Future research is necessary to determine the adequate dose and treatment duration with vitamin K in disorders caused by the cumulative action of bromadiolone and possibly other pesticides.