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.

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.

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.

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.

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.

Bioequivalence Study of Capsules versus Film Tablets Containing Rivaroxaban in Healthy Caucasian Subjects under Fasting and Fed Conditions.

The bioequivalence (BE) of orally administered capsules versus film tablets containing 20  and 10 mg of rivaroxaban was assessed in 2 single-dose, open-label, randomized 2-way crossover trials with a washout period of at least 1 week. The study for the 10 mg strength was conducted under fasting conditions (n = 68) and the study for the 20 mg strength under fed conditions (n = 52). Blood samples were collected over a 36-hour period and concentrations were assayed using a liquid chromatography tandem mass spectrometry method. Pharmacokinetic (PK) evaluation was performed with the program Phoenix WinNonlin, for non-compartmental assessment of data. After administration of 10 mg rivaroxaban under fasting conditions, mean Area Under the time - concentration Curve until the last blood sampling point (AUCt ), Area Under the time - concentration Curve until infinity (AUC∞ ), and maximum plasma concentration (Cmax ) were comparable (972 ng/mL*h, 1048 ng/mL*h, and 111 ng/mL, respectively, for the test and 1013 ng/mL*h, 1070 ng/mL*h and 130 ng/mL, respectively, for the reference formulation). Mean AUCt , AUC∞ , and Cmax were also comparable under fed conditions after administration of 20 mg rivaroxaban (2145 ng/mL*h, 2198 ng/mL*h and 275 ng/mL, respectively, for the test and 1856 ng/mL*h, 1916 ng/mL*h and 240 ng/mL, respectively, for the reference formulation). The 90% confidence intervals for all PK parameters were within the acceptance range of 80%-125%, suggesting BE between the generic product and the innovator product in healthy Caucasian male subjects. A clinically relevant difference in the tolerability and safety of the treatments was not detected. Study results indicated that the capsule formulations were bioequivalent with the film tablet formulations.

Apixaban and rivaroxaban's physiologically-based pharmacokinetic model validation in hospitalized patients: A first step for larger use of a priori modeling approach at bed side.

When used in real-world conditions, substantial interindividual variations in direct oral anticoagulant (DOAC) plasma concentrations are observed for a given dose, leading to a risk of over- or under-exposure and clinically significant adverse events. Physiologically-based pharmacokinetic (PBPK) models could help physicians to tailor DOAC prescriptions in vulnerable patient populations, such as those in the hospital setting. The present study aims to validate prospectively PBPK models for rivaroxaban and apixaban in a large cohort of elderly, polymorbid, and hospitalized patients. In using a model of geriatric population integrating appropriate physiological parameters into models first optimized with healthy volunteer data, observed plasma concentration collected in hospitalized patients on apixaban (n = 100) and rivaroxaban (n = 100) were adequately predicted (ratio predicted/observed area under the concentration curve for a dosing interval [AUCtau ] = 0.97 [0.96-0.99] geometric mean, 90% confidence interval, ratio predicted/observed AUCtau = 1.03 [1.02-1.05]) for apixaban and rivaroxaban, respectively. Validation of the present PBPK models for rivaroxaban and apixaban in in-patients represent an additional step toward the feasibility of bedside use.

The impact of ABCB1, CYP3A4/5 and ABCG2 gene polymorphisms on rivaroxaban trough concentrations and bleeding events in patients with non-valvular atrial fibrillation.

BACKGROUND: The influence of genetic factors on the pharmacokinetics and clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) is poorly understood. This study aimed to explore the effects of CYP3A4/5, ABCB1, and ABCG2 gene polymorphisms on the trough concentrations and the bleeding risk of rivaroxaban in NVAF patients. PATIENTS AND METHODS: This study is a prospective multicenter study. The patient's blood samples were collected to detect the steady-state trough concentrations of rivaroxaban and gene polymorphisms. We visited the patients regularly at month 1, 3, 6, and 12 to record bleeding events and medications. RESULTS: A total of 95 patients were enrolled in this study, and 9 gene loci were detected. For the dose-adjusted trough concentration ratio (Ctrough/D) of rivaroxaban, the homozygous mutant type was significantly lower than wild type at ABCB1 rs4148738 locus (TT vs. CC, P = 0.033), and the mutant type was significantly lower than the wild type at ABCB1 rs4728709 locus (AA + GA vs. GG, P = 0.008). ABCB1 (rs1045642, rs1128503), CYP3A4 (rs2242480, rs4646437), CYP3A5 (rs776746), and ABCG2 (rs2231137, rs2231142) gene polymorphisms had no significant effect on the Ctrough/D of rivaroxaban. For the bleeding events, we found that there were no significant differences among genotypes of all gene loci. CONCLUSION: This study found for the first time that ABCB1 rs4148738 and rs4728709 gene polymorphisms had a significant impact on the Ctrough/D of rivaroxaban in NVAF patients. CYP3A4/5, ABCB1, and ABCG2 gene polymorphisms were not associated with the bleeding risk of rivaroxaban.

Coming full circle: The potential utility of real-world evidence to discern predictions from a physiologically based pharmacokinetic model.

Today real word data (RWD) are playing a greater role in informing health care decisions. A physiologically based pharmacokinetic model (PBPK) and observed exposure-risk relationship predicted an increased bleeding risk induced by rivaroxaban (RXB) in patients with mild to moderate chronic kidney disease (CKD) taking concomitant medications that are combined Pgp-CYP3A inhibitors. In this commentary, we explore the potential use of RWD to assess the clinical consequence of this complex drug-drug interaction predicted from PBPK. This is a retrospective, case control, pilot study using a RWD dataset of 896,728 patients with mild to moderate chronic kidney disease and rivaroxaban use that was refined based upon combined Pgp-CYP3A inhibitor exposure and report of drug-induced bleeding (DIB). The odds ratio of patients with mild to moderate chronic kidney disease taking rivaroxaban with or without concurrent Pgp-CYP3A inhibitor use having a DIB was calculated. The odds ratio for DIB was 2.04 (CI95 1.82, 2.3; p < 0.001) suggesting an approximate doubling of bleeding risk which is consistent with the rivaroxaban exposure changes predicted by the published PBPK model and observed exposure-risk relationship. This exploratory analysis demonstrated the potential utility of RWD to assess model-based predictions as part of a drugs life cycle management.

Rivaroxaban-loaded SLNs with treatment potential of deep vein thrombosis: in-vitro, in-vivo, and toxicity evaluation.

OBJECTIVES: Rivaroxaban (RXB), a novel Xa inhibitor having groundbreaking therapeutic potential. However, this drug is associated with few limitations, including its pharmacokinetics related toxicities. Here, we developed RXB-loaded SLNs (RXB-SLNs) to improve its biopharmaceutical profile. Methods: High pressure homogenizer was used to prepare RXB-SLNs, followed by their particle characterization, Transmission electron microscopy (TEM), Dynamic light scattering (DSC), and Powder X-ray diffraction (PXRD) analysis. Beside this, in-vitro, ex-vivo, and in-vivo evaluation, prothrombin time assessment and toxicity was investigated. RESULTS: RXB-SLNs had their particle size in nano range (99.1 ± 5.50 nm) with excellent morphology and low polydispersity index (0.402 ± 0.02) and suitable zeta potential (-25.9 ± 1.4 mV). The incorporation efficiency was observed around 95.9 ± 3.9%. In-vitro release profiles of the RXB-SLNs exhibited enhanced dissolution (89 ± 9.91%) as compared to pure drug (11 ± 1.43%) after 24 h of the study. PK study demonstrated a seven times enhanced bioavailability of RXB-SLNs when compared with pure drug. Furthermore, RXB-SLNs exhibited an expressive anti-coagulant behavior in human and rat blood plasma. Also, the final formulation exhibited no toxicity after oral administration of the SLNs. CONCLUSIONS: All together, these studies revealed the capability of the SLNs for carrying the RXB with enhanced therapeutic efficacy and no toxicity, most importantly for the treatment of deep vein thrombosis.

Pharmacokinetic drug-drug interactions with direct anticoagulants in the management of cancer-associated thrombosis.

Drug-drug interactions (DDIs) are common in cancer management and complicate the choice of anticoagulation in cancer-associated thrombosis. Cancer confers an increased risk of thrombotic events. Also, more bleeding events are observed in those who receive anticoagulation compared to those without cancer. In the treatment of cancer-associated thrombosis, direct oral anticoagulants (DOACs) have been found to be at least as effective as low-molecular weight heparins, which became the standard of care after several trials demonstrated superiority over vitamin K antagonists. Non-inferiority compared to low-molecular weight heparins has been shown for rivaroxaban, edoxaban and apixaban with a signal of fewer recurrent thrombotic events, albeit with an increase in bleeding events. Yet, potentially major pharmacokinetic drug-drug interactions have been identified as a reason to withhold DOACs and to rather choose an alternative. Practical guidance on what constitutes a major pharmacokinetic interaction and/or how to deal with these interactions in clinical practice is limited. Hence, here we have provided a framework to allow clinicians to better deal with pharmacokinetic drug-drug interactions between DOACs and cancer therapies in the management of cancer-associated thrombosis. In this review we have discussed the current literature, how the pharmacokinetic profile links to the label information on DDI, and have provided a practical proposal, applied to a clinical case.

Population Pharmacokinetics of Rivaroxaban in Real-World Patients.

The pharmacokinetics (PK) of rivaroxaban have been studied in different populations, and there were differences in the PK parameters. However, most of these studies were conducted on healthy subjects from different ethnic groups. Thus, this study aimed to investigate the PK of rivaroxaban in real-world patients to determine the covariates that may cause differences in the pharmacokinetics of rivaroxaban. This was a prospective observational study. Five blood samples were collected at different time points after starting the rivaroxaban dose. Plasma concentrations were analyzed, and population PK models were developed using Monolix version 4.4 software. In total, 100 blood samples from 20 patients (50% men/50% women) were analyzed. The patients' mean (±standard deviation) age was 53.1 (±15.5) years and their mean body weight was 81.7 (±27.2) kg. The PK of rivaroxaban were described by a 1-compartment model. The initial estimates for the absorption rate constant, apparent clearance (CL/F), and apparent volume of distribution were 1.8/h, 4.46 L/h, and 21.7 L, respectively. The interindividual variability for absorption rate constant, CL/F, and volume of distribution was 14%, 24%, and 29.3%, respectively. Covariates were tested for their influence on rivaroxaban pharmacokinetics. The aspartate aminotransferase, alanine aminotransferase, body mass index, and albumin concentrations had an effect on the CL/F of rivaroxaban. In this analysis, the population PK model of rivaroxaban found significant interindividual variability. Several covariates influenced the clearance of rivaroxaban and contributed to this variability. The results may provide a guide that can aid the clinician during the initiation and adjustment of therapeutic regimens.

Development and verification of a physiologically based pharmacokinetic model of dronedarone and its active metabolite N-desbutyldronedarone: Application to prospective simulation of complex drug-drug interaction with rivaroxaban.

AIMS: Despite potential enzyme- and transporter-mediated drug-drug interactions (DDIs) between dronedarone and rivaroxaban in atrial fibrillation (AF) patients, pharmacokinetic/pharmacodynamic data remain limited to guide clinical practice. We aimed to develop, verify and validate a physiologically based pharmacokinetic (PBPK) model of dronedarone and its major metabolite, N-desbutyldronedarone (NDBD), to prospectively interrogate this clinically relevant DDI in healthy and mild renal impairment populations. METHODS: The middle-out development of our PBPK model combined literature-derived or in-house in vitro data, predicted in silico data and in vivo clinical data. Model verification was performed for intravenous and oral (single and multiple) dosing regimens. Model validation for the accurate prediction of cytochrome P450 (CYP)3A4- and P-glycoprotein-mediated DDI utilized simvastatin and digoxin as respective victim drugs. Rivaroxaban-specific inhibitory parameters of dronedarone and/or NDBD against CYP3A4, CYP2J2, OAT3 and P-glycoprotein were incorporated into the PBPK-DDI model for prospective dronedarone-rivaroxaban DDI simulation. RESULTS: Dronedarone and NDBD PK following clinically relevant doses of 400 mg dronedarone across single and multiple oral dosing were accurately simulated by incorporating effect of auto-inactivation on dose nonlinearities. Following successful model validation, nondose-adjusted rivaroxaban-dronedarone DDI in healthy and mild renal impairment populations revealed simulated rivaroxaban area under the plasma concentration-time curve up to 24 h fold change greater than dose exposure equivalence (0.70-1.43) at 1.65 and 1.84, respectively. Correspondingly, respective major bleeding risk was 4.24 and 4.70% compared with threshold of 4.5% representing contraindicated rivaroxaban-ketoconazole DDI. CONCLUSION: Our PBPK-DDI model predicted clinically significant dronedarone-rivaroxaban DDI in both healthy and mild renal impairment subjects. Greater benefit vs. risk could be achieved with rivaroxaban dose reductions to at least 15 mg in mild renal impairment subjects on concomitant dronedarone and rivaroxaban.

Physiologically-based pharmacokinetic modeling to predict drug-drug interactions of dabigatran etexilate and rivaroxaban in the Chinese older adults.

INTRODUCTION: Drug-drug interaction (DDI) is one of the major concerns for the clinical use of NOACs in the older adults considering that coexistence of multiple diseases and comorbidity were common. Current guidelines on the DDI management were established based on clinical studies conducted in healthy adults and mainly focus on the Caucasians, whereas systemic and ethnic differences may lead to distinct management in the Chinese older adults. OBJECTIVES: To investigate the impact of aging on the DDI magnitude between P-gp and/or CYP3A4 inhibitors with dabigatran etexilate and rivaroxaban in older adults, providing additional information for the use in clinical practice. RESULTS: Compared with the simulated adult, the AUC of the simulated older adults increased by 42-88% (DABE) and 21-60% (rivaroxaban), respectively, during NOACs monotherapy. Simulation on DDIs predicted that verapamil and clarithromycin further increase the exposure of dabigatran by 29-72% and 40-47%, whereas clarithromycin, fluconazole, and ketoconazole increase the exposure of rivaroxaban by 21-30%, 16-24%, and 194-247% in the older adults. Overall, our simulation result demonstrated that aging and DDIs both increased the exposure of NOACs. However, aging does not have a drastic impact on the extent of DDIs. The DDI ratios of young and old older adults were similar to the adults and were also similar between Caucasians and Chinese. DISCUSSION: We further simulated the interactions under steady-state based on the EHRA guideline (2021). Our simulation results revealed that recommended reduced dosing regimen of dabigatran etexilate during comedication with verapamil and clarithromycin (110 and 75 mg BID for Chinese young and old older adults) will result in exposure (trough concentration) that was either slightly higher or similar to the trough concentration of patients with any bleeding events. Routine monitoring of bleeding risk is encouraged. Further studies on the use of rivaroxaban in Chinese older adults are warranted. CONCLUSION: Aging and DDI increases exposure of drug in Chinese older adults. However, aging does not have a drastic impact on the extent of DDIs. Clinical management of DDIs in Chinese older adults in the absence of complex polypharmacy can a priori be similar to the EHRA guideline but routine monitoring of bleeding risk is encouraged when dabigatran etexilate given with verapamil and clarithromycin.

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.

Application of physiologically-based pharmacokinetic model approach to predict pharmacokinetics and drug-drug interaction of rivaroxaban: A case study of rivaroxaban and carbamazepine.

Rivaroxaban (RIV; Xarelto; Janssen Pharmaceuticals, Beerse, Belgium) is one of the direct oral anticoagulants. The drug is a strong substrate of cytochrome P450 (CYP) enzymes and efflux transporters. This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model for RIV. It contained three hepatic metabolizing enzyme reactions (CYP3A4, CYP2J2, and CYP-independent) and two active transporter-mediated transfers (P-gp and BCRP transporters). To illustrate the performance of the developed RIV PBPK model on the prediction of drug-drug interactions (DDIs), carbamazepine (CBZ) was selected as a case study due to the high DDI potential. Our study results showed that CBZ significantly reduces the exposure of RIV. The area under the concentration-time curve from zero to infinity (AUCinf ) of RIV was reduced by 35.2% (from 2221.3 to 1438.7 ng*h/ml) and by 25.5% (from 2467.3 to 1838.4 ng*h/ml) after the first dose and at the steady-state, respectively, whereas the maximum plasma concentration (Cmax ) of RIV was reduced by 37.7% (from 266.3 to 166.1 ng/ml) and 36.4% (from 282.3 to 179.5 ng/ml), respectively. The developed PBPK model of RIV could be paired with PBPK models of other interested perpetrators to predict DDI profiles. Further studies investigating the extent of DDI between CBZ and RIV should be conducted in humans to gain a full understanding of their safety and effects.

The Influence of ABCB1 (rs1045642 and rs4148738) Gene Polymorphisms on Rivaroxaban Pharmacokinetics in Patients Aged 80 Years and Older with Nonvalvular Atrial Fibrillation.

INTRODUCTION: ABCB1 gene polymorphisms are associated with rivaroxaban distribution changes and adverse reactions but the data are controversial. AIM: To evaluate the influence of ABCB1 (rs1045642 and rs4148738) gene polymorphisms on rivaroxaban pharmacokinetics in patients aged 80 years and older with nonvalvular atrial fibrillation (NAF). METHODS: 128 patients aged 80 years and older (median [Me] age 87.5 [83.0-90.0] years) with NAF were included. We performed ABCB1 (rs1045642 and rs4148738) genotyping, measured the trough steady-state plasma concentration (Cmin,ss) of rivaroxaban and prothrombin time (PT) and analyzed prior medical records for clinically relevant non-major bleeding (CRNMB). RESULTS: CC genotype carriers had no differences in Cmin,ss (p > 0.05) compared with the CT and TT rs1045642 and rs4148738 genotypes carriers. CC genotype carriers had no differences in PT (p > 0.05) compared with the CT rs1045642 and rs4148738 and TT rs4148738 genotypes carriers. In the TT genotype PT levels were higher than in the CC rs1045642 genotype: Me 14.2 [13.0-16.1] sec vs 13.3 [12.4-14.5] sec (p = 0.049). Incidence of CRNMB was higher in patients with the TT genotype compared with the CC rs1045642 (29.3% vs 4.5%, p = 0.021) and rs4148738 (39.3% vs 8.1%, p = 0.008) and the CT genotype rs4148738 (39.3% vs 14.3%, p = 0.002). CONCLUSION: ABCB1 (rs1045642 and rs4148738) polymorphisms didn't influence rivaroxaban pharmacokinetics in patients aged 80 years and older with NAF. TT carriers developed CRNMB more frequently compared with the CC rs1045642 and the CC and CT rs4148738 genotypes. The haplotype TT-TT haplotype was associated with a higher frequency of CRNMB.

Predicting drug-drug interactions with physiologically based pharmacokinetic/pharmacodynamic modelling and optimal dosing of apixaban and rivaroxaban with dronedarone co-administration.

BACKGROUND: The concurrent administration of dronedarone and oral anti-coagulants is common because both are used in managing atrial fibrillation (AF). Dronedarone is a moderate inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme and P-glycoprotein (P-gp). Apixaban and rivaroxaban are P-gp and CYP3A4 substrates. This study aims to investigate the impact of exposure and bleeding risk of apixaban or rivaroxaban when co-administered with dronedarone using physiologically based pharmacokinetic/pharmacodynamic analysis. METHODS: Modeling and simulation were conducted using Simcyp® Simulator. The parameters required for dronedarone modeling were collected from the literature. The developed dronedarone physiologically based pharmacokinetic (PBPK) model was verified using reported drug-drug interactions (DDIs) between dronedarone and CYP3A4 and P-gp substrates. The model was applied to evaluate the DDI potential of dronedarone on the exposure of apixaban 5 mg every 12 h or rivaroxaban 20 mg every 24 h in geriatric and renally impaired populations. DDIs precipitating major bleeding risks were assessed using exposure-response analyses derived from literature. RESULTS: The model accurately described the pharmacokinetics of orally administered dronedarone in healthy subjects and accurately predicted DDIs between dronedarone and four CYP3A4 and P-gp substrates with fold errors <1.5. Dronedarone co-administration led to a 1.29 (90 % confidence interval (CI): 1.14-1.50) to 1.31 (90 % CI: 1.12-1.46)-fold increase in the area under concentration-time curve for rivaroxaban and 1.33 (90 % CI: 1.15-1.68) to 1.46 (90 % CI: 1.24-1.92)-fold increase for apixaban. The PD model indicated that dronedarone co-administration might potentiate the mean major bleeding risk of apixaban with a 1.45 to 1.95-fold increase. However, the mean major bleeding risk of rivaroxaban was increased by <1.5-fold in patients with normal or impaired renal function. CONCLUSIONS: Dronedarone co-administration increased the exposure of rivaroxaban and apixaban and might potentiate major bleeding risks. Reduced apixaban and rivaroxaban dosing regimens are recommended when dronedarone is co-administered to patients with AF.

Leveraging a Previously Published Population Pharmacokinetic Model to Predict Rivaroxaban Exposure in Real-World Patients.

Population pharmacokinetic (PK)/pharmacodynamic models are commonly used to inform drug dosing; however, often real-world patients are not well represented in the clinical trial population. We sought to determine how well dosing recommended in the rivaroxaban drug label results in exposure for real-world patients within a reference area under the concentration-time curve (AUC) range. To accomplish this, we assessed the utility of a prior published rivaroxaban population PK model to predict exposure in real-world patients. We used the model to predict rivaroxaban exposure for 230 real-world patients using 3 methods: (1) using patient phenotype information only, (2) using individual post hoc estimates of clearance from the prior model based on single PK samples of rivaroxaban collected at steady state without refitting of the prior model, and (3) using individual post hoc estimates of clearance from the prior model based on PK samples of rivaroxaban collected at steady state after refitting of the prior model. We compared the results across 3 software packages (NONMEM, Phoenix NLME, and Monolix). We found that while the average patient-assigned dosing per the drug label will likely result in the AUC falling within the reference range, AUC for most individual patients will be outside the reference range. When comparing post hoc estimates, the average pairwise percentage differences were all <10% when comparing the software packages, but individual pairwise estimates varied as much as 50%. This study demonstrates the use of a prior published rivaroxaban population PK model to predict exposure in real-world patients.

Physiologically-Based Pharmacokinetic Modeling-Guided Dose Management of Oral Anticoagulants when Initiating Nirmatrelvir/Ritonavir (Paxlovid) for COVID-19 Treatment.

Patients with coronavirus disease 2019 (COVID-19) with cardiovascular diseases who are at higher risk of progressing to critical illness should be treated with nirmatrelvir/ritonavir (Paxlovid). Ritonavir, the booster in nirmatrelvir/ritonavir, modulates multiple drug metabolizing enzymes and transporters, complicating its use in real-world clinics. We aimed to apply physiologically-based pharmacokinetic (PBPK) modeling to simulate the complex drug-drug interactions (DDIs) of ritonavir with two anticoagulants, rivaroxaban and racemic warfarin, to address this important clinical conundrum. Simulations were implemented within Simcyp Simulator. Compound and population models were adopted from Simcyp and our previous studies. Upon verification and validation of the PBPK model of ritonavir, prospective DDI simulations with the anticoagulants were performed in both the general population (20-65 years) and geriatric subjects (65-85 years) with or without moderate renal impairment. Elevated rivaroxaban concentrations were simulated with nirmatrelvir/ritonavir treatment, where the impact was more profound among geriatric subjects with renal impairment. The overexposure of rivaroxaban was restored to normal range on day 4 post-discontinuation of nirmatrelvir/ritonavir, corroborating with the recovery of enzyme activity. A lower 10 mg daily dose of rivaroxaban could effectively maintain acceptable systemic exposure of rivaroxaban during nirmatrelvir/ritonavir treatment. Treatment of ritonavir marginally declined simulated S-warfarin concentrations, but substantially elevated that of R-warfarin, resulting in a decrease in the international normalized ratio (INR). As INR only recovered 2 weeks post-nirmatrelvir/ritonavir treatment, a longer surveillance INR for warfarin becomes important. Our PBPK-guided simulations evaluated clinically important yet untested DDIs and supports clinical studies to ensure proper anticoagulation management of patients with COVID-19 with chronic coagulative abnormalities when initiating nirmatrelvir/ritonavir therapy.