ABCG2 polymorphism and rivaroxaban pharmacokinetics in healthy individuals after a single dose.

Rivaroxaban is a direct factor Xa inhibitor. Its interindividual variability is large and may be connected to the occurrence of adverse drug reactions or drug inefficacy. Pharmacogenetics studies concentrating on the reasons underlying rivaroxaban's inadequate response could help explain the differences in treatment results and medication safety profiles. Against this background, this study evaluated whether polymorphisms in the gene encoding the ABCG2 transporter modify the pharmacokinetic characteristics of rivaroxaban. A total of 117 healthy volunteers participated in two bioequivalence experiments with a single oral dose of 20 mg rivaroxaban, with one group fasting and the other being fed. Ultra-high-performance liquid chromatography coupled with mass spectrometry was employed to determine the plasma concentrations of rivaroxaban, and the WinNonlin program was used to calculate the pharmacokinetics parameters. In the fasting group, the rivaroxaban pharmacokinetic parameters of Vd (508.27 vs 334.45 vs 275.59 L) and t1/2 (41.04 vs 16.43 vs 15.47 h) were significantly higher in ABCG2 421 A/A genotype carriers than in ABCG2 421 C/C and 421 C/A genotype carriers (P<0.05). The mean values of Cmax (145.81 vs 176.27 vs 190.19 ng/mL), AUC0-t (1193.81 vs 1374.69 vs 1570.77 ng/mL·h), and Cl (11.82 vs 14.50 vs 13.01 mL/h) for these groups were lower, but this difference was not statistically significant (P>0.05). These findings suggested that the ABCG2 421 A/A genotype may impact rivaroxaban parameters after a single dose in healthy subjects. This finding must be validated before it is applied in clinical practice.

Apixaban plasma concentrations before and after catheter ablation for atrial fibrillation.

BACKGROUND: Catheter ablation in patients with atrial fibrillation is associated with a transient increase in thromboembolic risk and adequate anticoagulation is highly important. When patients are anticoagulated with apixaban, monitoring of plasma concentrations of the drug is not routinely performed. This study aimed to assess the influence of clinical patient characteristics, concomitant drug treatment and self-reported adherence on apixaban concentrations, and to describe the intra- and inter-individual variability in apixaban concentrations in this group of patients. Method Apixaban concentrations from 141 patients were measured in plasma one week before ablation and two, six and ten weeks after ablation, employing ultra-high performance liquid chromatography coupled with tandem mass spectrometry. In samples not obtained at trough, apixaban concentrations were adjusted to trough levels. Self-reported adherence was registered by means of the 8-item Morisky Medication Adherence Scale before and after ablation. RESULTS: There were statistically significant, positive correlations between apixaban concentrations and increased age, female sex, lower glomerular filtration rate, higher CHA2DS2-VASc score, use of cytochrome P450 3A4 and/or p-glycoprotein inhibitors, and use of amiodarone. Self-reported adherence was generally high. The mean intra-individual and inter-individual coefficients of variation were 29% and 49%, respectively. CONCLUSION: In patients undergoing catheter ablation for atrial fibrillation, age, sex, renal function, interacting drugs and cerebrovascular risk profile were all associated with altered plasma apixaban concentration. In this group of patients with a generally high self-reported adherence, intra-individual variability was modest, but the inter-individual variability was substantial, and similar to those previously reported in other patient apixaban-treated populations. If a therapeutic concentration range is established, there might be a need for a more flexible approach to apixaban dosing, guided by therapeutic drug monitoring.

Effects of the antitumor drugs adagrasib and asciminib on apixaban metabolism in vitro and in vivo.

Apixaban is an oral anticoagulant that directly inhibits the target Factor Xa (FXa). In this study, we focused on the in vivo and in vitro effects of adagrasib and asciminib on apixaban metabolism, to discover potential drug-drug interactions (DDI) and explore their inhibitory mechanisms. The levels of apixaban and its metabolite, O-desmethyl-apixaban (M2), were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In vitro evaluation, the maximum half inhibitory concentration (IC50) of adagrasib in rat liver microsomes (RLM) and human liver microsomes (HLM) against apixaban was 7.99 µM and 117.40 µM, respectively. The IC50 value of asciminib against apixaban in RLM and HLM was 4.28 µM and 18.42 µM, respectively. The results of the analysis on inhibition mechanisms showed that adagrasib inhibited the metabolism of apixaban through a non-competitive mechanism, while asciminib inhibited the metabolism of apixaban through a mixed mechanism. Moreover, the interaction of apixaban with adagrasib and asciminib in Sprague-Dawley (SD) rats was also investigated. It was found that the pharmacokinetic characteristics of apixaban were significantly changed when combined with these two antitumor drugs, where AUC(0-t), AUC(0-∞), t1/2, Tmax, and Cmax were increased, while CLz/F was significantly decreased. But both drugs did not appear to affect the metabolism of M2 in a significant way. Consistent results from in vitro and in vivo demonstrated that both adagrasib and asciminib inhibited the metabolism of apixaban. It provided reference data for the future clinical individualization of apixaban.

Pharmacokinetics of single-dose rivaroxaban under fed state in obese vs. non-obese subjects: An open-label controlled clinical trial (RIVOBESE-PK).

The evidence of rivaroxaban's pharmacokinetics in obese compared with non-obese populations remains inconclusive. We aimed to compare the pharmacokinetic profile of rivaroxaban between obese and non-obese populations under fed state. Participants who met the study's eligibility criteria were assigned into one of two groups: obese (body mass index ≥35 kg/m2) or non-obese (body mass index 18.5-24.9 kg/m2). A single dose of rivaroxaban 20 mg was orally administered to each participant. Nine blood samples over 48 h, and multiple urine samples over 18 h were collected and analyzed for rivaroxaban concentration using ultra-performance liquid chromatography coupled with tandem mass detector. Pharmacokinetic parameters were determined using WinNonlin software. Thirty-six participants were recruited into the study. No significant changes were observed between obese and non-obese participants in peak plasma concentration, time to reach peak plasma concentration, area under the plasma concentration-time curve over 48 h or to infinity, elimination rate constant, half-life, apparent volume of distribution, apparent clearance, and fraction of drug excreted unchanged in urine over 18 h. Rivaroxaban's exposure was similar between the obese and non-obese subjects, and there were no significant differences in other pharmacokinetic parameters between the two groups. These results suggest that dose adjustment for rivaroxaban is probably unwarranted in the obese population.

[Interference of oral anti-Xa anticoagulants during monitoring of unfractionated heparin treatments: practical and future attitudes]. / Interférence des anticoagulants oraux directs anti-Xa lors de la surveillance des traitements par héparine non-fractionnée : attitudes pratiques et à venir.

Contrary to direct oral anticoagulants (DOAC), unfractionated heparin (UFH) requires daily monitoring when administered at therapeutic dose. At present, UFH monitoring is preferably carried out by measuring plasma anti-Xa activity, however, in patients previously treated with an anti-Xa DOAC and switched to UFH, there is a high risk of DOAC interfering with the measurement of UFH anti-Xa activity. Residual anti-Xa DOAC in the sample can lead to an overestimation of the anticoagulant activity attributed to heparin and thus to incorrect anticoagulation. This risk of interference should not be overlooked because interference may occur even at concentration of DOAC below the hemostatic safety threshold and can last several days. To overcome this issue, several alternatives are being studied. This note provides an update on anti-Xa DOAC interference and different strategies available in current practice. It also underlines the importance of communication between biologists and clinicians on anticoagulant treatments received by patients.

Apixaban plasma concentrations in patients with obesity.

PURPOSE: Routine therapeutic drug monitoring of apixaban is currently not recommended but may however be warranted in some situations and for some patient groups to provide better and safer treatment. Due to limited data on apixaban concentrations in different subpopulations, it is still unclear which group of patients could possibly gain from monitoring. The purpose of this study was to examine apixaban exposure in patients with obesity compared with normal-weight patients. METHODS: Forty patients with obesity (mean BMI 39.4 kg/m2) and 40 controls with normal weight (mean BMI 23.4 kg/m2), treated with apixaban 5 mg twice daily were included. The patients were matched for age, sex, and renal function. Trough and peak apixaban concentrations were measured with LC‒MS/MS methodology. RESULTS: The median trough concentrations in patients with obesity (58.7, range 10.7-200.7 ng/ml) were slightly higher than those in patients with normal weight (52.0, range 31.0-150.9 ng/ml) (p < 0.05). Notably, the variability in trough concentration was considerably higher in patients with obesity. Peak concentrations were similar in both groups, with a median of 124.5 ng/ml (range 82.0-277.5) and 113.5 ng/ml (range 75.5-334.6) in patients with obesity and normal weight, respectively. CONCLUSION: Apixaban exposure did not vary substantially between obese and normal weight matched controls, implying that general dose adjustments are not required. However, vast interindividual variability was observed in patients with obesity, suggesting that measuring the concentrations could be valuable for specific patients. Further research is needed to identify which specific patients may benefit from this approach.

Proactive monitoring of drug-drug interactions between direct oral anticoagulants and small-molecule inhibitors in patients with non-small cell lung cancer.

BACKGROUND: Small-molecule inhibitors (SMIs) have revolutionised the treatment of non-small cell lung cancer (NSCLC). However, SMI-induced drug-drug interactions (DDIs) with frequently co-administered direct oral anticoagulants (DOACs), increase thromboembolic and bleeding risks. This study investigated and proactively managed the consequences of DOAC-SMI DDIs. METHODS: This prospective, observational study enrolled patients with NSCLC concomitantly using a DOAC and SMI. The primary outcome was the proportion of patients with DOAC plasma trough (Ctrough) and peak (Cpeak) concentrations outside expected ranges. Secondary outcomes included DOAC treatment modifications, incidence of bleeding and thromboembolic events and feasibility evaluation of pharmacokinetically guided DOAC dosing. RESULTS: Thirty-three patients were analysed. Thirty-nine percent (13/33) had DOAC Ctrough and/or Cpeak were outside the expected ranges in 39% (13/33). In 71% (5/7) of patients with DOAC concentrations quantified before and during concurrent SMI use, DOAC Ctrough and/or Cpeak increased or decreased >50% upon SMI initiation. In all patients in whom treatment modifications were deemed necessary, DOAC concentrations were adjusted to within the expected ranges. CONCLUSION: Proactive monitoring showed that a substantial proportion of patients had DOAC concentrations outside the expected ranges. DOAC concentrations were successfully normalised after treatment modifications. These results highlight the importance of proactive monitoring of DOAC-SMI DDIs to improve treatment in patients with NSCLC.

The impact of ABCB1, CYP3A4 and CYP3A5 gene polymorphisms on apixaban trough concentration and bleeding risk in patients with atrial fibrillation.

OBJECTIVES: Apixaban, a direct oral anticoagulant, is increasingly used worldwide for the treatment and prevention of venous thromboembolism and ischemic stroke in patients with nonvalvular atrial fibrillation (AF). Obviously, one of the ways to enhance effectiveness and safety of drug therapy is a personalized approach to therapy, which involves pharmacogenetic and pharmacokinetic tests. The study aims to investigate the effect of CYP3A4*22, CYP3A5*3 and ABCB1 polymorphisms on the pharmacokinetics of apixaban and the risk of bleeding. METHODS: A total of 84 patients were enrolled in this prospective observational study. All patients received apixaban 5 or 2.5 mg twice daily. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G. A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. RESULTS: The C/D ratio was higher in patients aged >80 years (F(1)=11.209, p=0.00124) and was affected by serum creatinine (>133 µmol/L, F(1)=6.7, p=0.01124). ABCB1 (rs1045642 and rs4148738), CYP3A5 (rs776746) and CYP3A4 (rs35599367) polymorphisms did not show a correlation with C/D ratio of apixaban. Multivariate logistic regression analyses showed that none of the clinical or genetic factors predicted the fact of bleeding. CONCLUSIONS: We report no significant association between ABCB1 gene polymorphisms (rs1045642 and rs4148738), CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G and bleeding events on apixaban treatment. Complementing the existing criteria with pharmacogenetic and pharmacokinetics information for the patients with AF will enable further individualization of apixaban.

Clinical guidance for unfractionated heparin dosing and monitoring in critically ill patients.

INTRODUCTION: Unfractionated heparin is a widely used anticoagulant in critically ill patients. It has a well-established safety profile and remains an attractive option for clinicians due to its short half-life and reversibility. Heparin has a unique pharmacokinetic profile, which contributes to significant inter-patient and intra-patient variability in effect. The variability in anticoagulant effect combined with heparin's short half-life mean close monitoring is required for clinical efficacy and preventing adverse effects. To optimize heparin use in critically ill patients, effective monitoring assays and dose adjustment strategies are needed. AREAS COVERED: This paper explores the use of heparin as an anticoagulant and optimal approaches to monitoring in critically ill patients. EXPERT OPINION: Conventional monitoring assays for heparin dosing have significant limitations. Emerging data appear to favor using anti-Xa assay monitoring for heparin anticoagulation, which many centers have successfully adopted as the standard. The anti-Xa assay appears have important benefits relative to the aPTT for heparin monitoring in critically ill patients, and should be considered for broader use.

Comparative Bleeding Risk of Brand Vs Generic Rivaroxaban in Elderly Inpatients with Atrial Fibrillation.

Objective: Atrial fibrillation (AF) is the most common abnormal heart rhythm in elderly patients. Rivaroxaban has been widely used for stroke prevention. The anticoagulant response to rivaroxaban increases with age, which may make elderly patients susceptible to adverse outcomes resulting from small differences in bioavailability between generic and brand products. Methods: We designed a cohort study of ≥65-year-old inpatients with AF. Sociodemographic and laboratory measures of qualified patients who received brand or generic rivaroxaban for at least 72 hours at the study hospital from January 2021 to June 2023 were collected retrospectively. The primary outcome was the incidence of bleeding. Results: A total of 1008 qualifying patients were included for analysis, with 626 (62.1%) receiving brand rivaroxaban and 382 (37.9%) receiving generic rivaroxaban. After propensity score matching and weighting to account for confounders, the odds ratios comparing brand vs generic rivaroxaban (95% confidence intervals) for the bleeding was 1.15 (0.72-1.82). Results from subgroup analyses of patients with age ≥85, HAS-BLED score ≥ 3, containment of antiplatelet drugs, and female patients were consistent with the primary analysis. Conclusion: It provides evidence regarding the clinical safety outcome of generic rivaroxaban in the elderly AF population that may be particularly susceptible to adverse outcomes resulting from small allowable differences in pharmacokinetics.

Physiologically based absorption modeling to predict the bioequivalence of two apixaban formulations.

The equivalence of absorption rates and extents between generic drugs and their reference formulations is crucial for ensuring therapeutic comparability. Bioequivalence (BE) studies are widely utilized and play a pivotal role in substantiating the approval and promotional efforts for generic drugs. Virtual BE simulation is a valuable tool for mitigating risks and guiding clinical BE studies, thereby minimizing redundant in vivo BE assessments. Herein, we successfully developed a physiologically based absorption model for virtual BE simulations, which precisely predicts the BE of the apixaban test and reference formulations. The modeling results confirm that the test and reference formulations were bioequivalent under both fasted and fed conditions, consistent with clinical studies. This highlights the efficacy of physiologically based absorption modeling as a powerful tool for formulation screening and can be adopted as a methodological and risk assessment strategy to detect potential clinical BE risks.

Development of immediate-release formulation with reliable absorption of rivaroxaban in various meal regimes.

The bioavailability of rivaroxaban at the higher doses (15 and 20 mg) is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients. Therefore, the aim of this study was to evaluate innovative rivaroxaban-containing formulations designed to eliminate the food effect to ensure reliable absorption and thus to improve patient adherence with the treatment. Three prototypes (Cocrystal, HPMCP and Kollidon) with rivaroxaban were developed and their bioavailability and food effect in comparison to the reference product was tested in open label, randomized, single oral dose, crossover studies, where test products were administered under fasting and fed conditions and the reference product was administered under fed conditions. Comparable bioavailability for all tested prototypes both under fed and fasting conditions was demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the concentration-time curve remained within the standard acceptance range of 80.00%-125.00%. An innovative immediate release form of rivaroxaban with no food effect on drug bioavailability has been developed, which may represent an important step toward increasing adherence, improving treatment outcome and reducing health care costs.

Anti-Xa Monitoring of Apixaban (ZyQuis) in Venous Thrombo-Embolism and Atrial Fibrillation.

Apixaban is a direct oral Xa inhibitor and is indicated for the treatment of venous thrombo-embolism (VTE) and prevention of stroke in atrial fibrillation (AF). Recently, a generic (ZyQuis, Zydus Lifesciences Limited, India) has received Food and Drug Administration approval. While bioequivalence has been demonstrated with Eliquis (Bristol-Myers Squibb/Pfizer, UK), it is necessary to monitor its effectiveness prior to acceptance in medical practice. This prospective study independently evaluated Apixaban (ZyQuis) at two accredited laboratories. Participants were converted from Warfarin or Rivaroxaban to Apixaban 5 mg bd for a duration of one month. Peak anti-Xa levels were measured 3-4 h post the morning dose. The samples were processed on the Atellica COAG 360 (Siemens Healthineers, Marburg, Germany) analyzers with a chromogenic anti-Xa assay (Innovance, reference interval 69-321 ng/mL). There were 26 participants; 5 men, 21 women; mean ± standard deviation age of 46 ± 12 years. Indications for anticoagulation included: VTE (88.5%) and AF (11.5%). 69.2% of the participants had at least one comorbidity. 96.2% of the anti-Xa levels were within the laboratory's 95% reference interval. Mean anti-Xa activity was 191 ± 69 ng/mL and 186 ± 68 ng/mL measured at respective laboratories. Mean differences in anti-Xa measurements represented by Bland-Altman statistics were small (bias of -2.6%, 95% confidence interval -1.11 to -4.09) and a strong correlation was observed on Deming regression analysis (0.995). Apixaban (ZyQuis) was effective for the management of VTE and AF as evidenced by anti-Xa activity.

Pharmacokinetics of apixaban in patients undergoing pancreaticoduodenectomy (PAP-UP).

OBJECTIVE: The impact of pancreaticoduodenectomy on absorption of drugs in the duodenum remains largely unknown. We aim to characterize the pharmacokinetics of apixaban in patients who had previously undergone pancreaticoduodenectomy. MATERIALS AND METHODS: A single 10-mg dose of apixaban was administered to 4 volunteers who underwent pancreaticoduodenectomy at least 6 months prior. The maximum plasma apixaban concentration (Cmax) and area under the plasma concentration time-curve (AUC0-24, AUC0-inf) were compared against healthy historical control subjects (N = 12). Geometric mean ratios (GMR) with 90% confidence interval (CI) were calculated for determination of comparative bioequivalence. RESULTS: In pancreaticoduodenectomy patients, AUC0-24 and AUC0-inf were 1,861 and 2,080 ng×h/mL, respectively. The GMRs of AUC0-24 and AUC0-inf between study subjects and healthy controls were 1.27 (90% CI 0.88 - 1.83) and 1.18 (90% CI 0.82 - 1.72). The mean Cmax of apixaban was 201 ng/mL (SD 15.6) occurring at a median tmax of 3.25 hours (range 2.5 - 4 hours). The GMR of Cmax between study subjects and healthy controls was 1.12 (90% CI 0.77 - 1.63). CONCLUSION: The pharmacokinetic characteristics of apixaban in subjects who had undergone pancreaticoduodenectomy are not significantly different from those of healthy controls. Though the sample size of this study is small, results suggest that no change to apixaban dose regimen is needed in patients who have had a pancreaticoduodenectomy.

Potential treatment option of rivaroxaban for breastfeeding women: A case series.

The use of direct oral anticoagulants (DOACs) in breastfeeding women is currently challenging due to limited safety data for breastfeeding infants, and there have been no previous studies on the drug concentration in breastfeeding infants. We treated 2 patients (one case was twin pregnancy) with venous thromboembolisms in breastfeeding women administered rivaroxaban at our institution. Blood samples from the mothers and breastmilk samples were collected at time 0 and 2 h after the rivaroxaban administration, breastfeeding was conducted 2 h after the rivaroxaban administration, and blood samples from the infants were collected 2 h after breastfeeding (4 h after maternal rivaroxaban administration). The milk-to-plasma (M:P) ratios were 0.27 in Case 1 and 0.32 in Case 2. The estimated relative infant dose (RID) was 0.82 % in Case 1 Children 1 and 2, and 1.27 % in Case 2. The rivaroxaban concentration in the infant plasma was below the lower limit of quantification in all infants. In addition, even in the high-exposure case simulation based on 5 days of breastfeeding in Case 2, the infant plasma concentration level was below the lower limit of quantification. At 3 months of follow-up, breastfeeding was continued, and all infants grew and developed without any health problems including bleeding events. The current case series showed that there were no pharmacokinetic or clinical concerns for breastfeeding women or breastfed infants, and provides support for rivaroxaban as a safe treatment option for these patients.

Apixaban Pharmacokinetics and Bioequivalence of Two Tablet Formulations: A Randomized, Open-Label, Crossover Study, Fasting Condition in Healthy Indonesian Volunteers.

The present study aimed to assess the bioequivalence of a new apixaban generic with reference formulation. Twenty-six healthy volunteers were recruited for an open-label, balanced, randomized, 2-treatment, 2-sequence, 2-period, single oral dose study. Following overnight fasting, each volunteer received 5 mg of apixaban test and reference formulations as single doses, separated by a 1-week washout period. Twenty blood samples were collected at predose and multiple time points between 0.5 and 72 hours after dosing. A validated ultra-performance liquid chromatography-tandem mass spectrometry detection method following a protein precipitation step was implemented to determine apixaban concentrations. Noncompartmental analysis was used to derive the pharmacokinetic parameters, which were then compared between the test and reference products using a multivariate analysis of variance. The pharmacokinetic parameters of the test product were not statistically different from the reference product, and the 90% confidence intervals of apixaban natural log-transformed area under the concentration-time curve from time 0 to infinity, area under the concentration-time curve from time 0 to the last measurable concentration, and maximum concentration were within 80%-125% based on the bioequivalence acceptance range criteria. The test and reference formulations of apixaban are bioequivalent in healthy subjects under fasting conditions.

The Pharmacogenetic Variability Associated with the Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Healthy Chinese Subjects: A National Multicenter Exploratory Study.

PURPOSE: This study aimed to explore the pharmacogenetic variability associated with the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in healthy Chinese subjects. METHODS: This was a multicenter study that included 304 healthy adults aged 18 to 45 years with unknown genotypes. All participants were administered a single dose of rivaroxaban at 10 mg, 15 mg, or 20 mg. PK and PD parameters were measured, and exome-wide association analysis was conducted. FINDINGS: Sixteen SNPs located on 11 genes influenced the AUC0-t. Among these, the 3 most influential genes were MiR516A2, PARP14, and MIR618. Thirty-six SNPs from 28 genes were associated with the PD of rivaroxaban. The 3 most influential genes were PKNOX2, BRD3, and APOL4 for anti-Xa activity, and GRIP2, PLCE1, and MLX for diluted prothrombin time (dPT). Among them, BRD3 played an important role in both the PK and PD of rivaroxaban. Anti-Xa activity (ng/mL) differed significantly among subjects with BRD3 rs467387: 145.1 ± 55.5 versus 139.9 ± 65.1 versus 164.0 ± 68.6 for GG, GA, and AA carriers, respectively (P = 0.0002). IMPLICATIONS: This study found that that the regulation of the BRD3 gene might affect the PK and PD of rivaroxaban, suggesting that it should be studied as a new pharmacologic target. The correlation between this gene locus and clinical outcomes has yet to be verified in patients undergoing clinical treatment.

Enoxaparin thromboprophylaxis in hospitalized obese pediatric patients.

BACKGROUND: Enoxaparin is an anticoagulant used for pharmacologic thromboprophylaxis in pediatrics. Enoxaparin pharmacokinetics can be altered in the setting of obesity. Optimal enoxaparin dosing for thromboprophylaxis in children with obesity remains unclear. PROCEDURE: A retrospective review was conducted of pediatric patients who weighed ≥60 kg with BMI ≥ 95th percentile, received enoxaparin for thromboprophylaxis, and had at least one appropriately drawn anti-factor Xa (anti-Xa) from 2013 to 2022. Anti-Xa levels were reviewed for patients initially treated with enoxaparin 30 mg every 12 h. The average daily enoxaparin dose required to achieve an anti-Xa of 0.2-0.4 unit/mL, which was stratified by BMI percentile and weight, was calculated. RESULTS: Of 116 patients (median age 15.8 years) included for analysis, 106 patients were initially treated with enoxaparin 30 mg every 12 h. Anti-Xa levels were <0.2 unit/mL in 53% of patients with BMI > 99th percentile and 54% of patients >100 kg. Ninety-one patients had at least one anti-Xa 0.2-0.4 unit/mL with an average daily enoxaparin dosing of 66 mg. When stratified by severity of obesity, higher doses were required to attain an anti-Xa 0.2-0.4 unit/mL in patients with BMI > 99th percentile compared with those with 95th-99th percentile (67.8 ± 15.7 vs. 62 ± 5.6 mg/day, p = .01). Patients > 100 kg required significantly higher dose than those ≤100 kg (69.1 ± 15.5 vs 61.2 ± 7.3 mg/day, p = .002). CONCLUSIONS: Increased initial dosing and/or anti-Xa level monitoring should be considered in adolescents with severe obesity receiving enoxaparin thromboprophylaxis.

Time Course of the Interaction Between Oral Short-Term Ritonavir Therapy with Three Factor Xa Inhibitors and the Activity of CYP2D6, CYP2C19, and CYP3A4 in Healthy Volunteers.

BACKGROUND: We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed. METHODS: In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses. RESULTS: Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration-time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined. CONCLUSION: This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation. CLINICAL TRIAL REGISTRATION: EudraCT number: 2021-006643-39.

Pharmacokinetics, Pharmacodynamics, and Safety of Edoxaban in Pediatric Subjects: A Phase I Single-Dose Study.

This was an open-label, single-dose, phase I study to characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of edoxaban in pediatric subjects from birth to 18 years at risk for venous thromboembolism (VTE). Children requiring anticoagulant therapy were enrolled into 5 age cohorts (0 to < 6 months (N = 12), 0.5 to < 2 years (N = 13), 2 to < 6 years (N = 13), 6 to < 12 years (N = 13), and 12 to < 18 years (N = 15)) receiving tablet or oral suspension of edoxaban at doses expected to be equivalent to 30 or 60 mg once daily (q.d.) in adult subjects with VTE. Sixty-six pediatric subjects were enrolled and completed the study. Edoxaban plasma concentration peaked between 1 and 3 hours and declined rapidly until 4-8 hours. The range of mean total apparent clearance across 5 age cohorts at low and high doses was 0.47 to 1.11 L/h/kg. The ranges of mean volume of central compartment and apparent peripheral volume were 2.31 to 3.59 L/kg and 1.92 to 4.14 L/kg, respectively. Across all age groups, the estimated median exposures were within the 0.5- to 1.5-fold of the median area under the plasma drug concentration-time curve (AUC) in adult subjects receiving corresponding doses (30 mg q.d. for low dose and 60 mg q.d. for high dose). In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time, and anti-Factor Xa activity) showed a linear PK-PD relationship and were in line with previous adult data. The results support further evaluation of the pediatric doses in larger pivotal trials.