Summary

• In adults, plasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding component.¹
• In children (6 months to 9 years of age), in vitro plasma protein binding of rivaroxaban is approximately 90%.¹
• The terminal elimination half-life (t_1/2) of rivaroxaban is 5 to 9 hours in healthy adult subjects aged 20 to 45 years and 11 to 13 hours in elderly subjects aged 60 to 76 years.¹
• In pediatric patients, mean half-life values of rivaroxaban were 4.2 hours in adolescents, 3 hours in children 2 to 12 years of age, 1.9 hours in children 0.5 to <2 years of age, and 1.6 hours in children <0.5 years of age.¹
• In a phase 1, single-center, nonrandomized, open-label, multiple-dose, parallel-design study that compared the pharmacokinetics (PK) of rivaroxaban in patients who had undergone Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) with the PK observed in subjects with a body mass index (BMI) of ≥40 kg/m² (class III obesity group) and a group of healthy volunteers (control group), mean area under the concentration-time curve under 24 hours (AUC_0-24) and maximum plasma concentration (C_max) were lower in the surgical groups than in the control group after the first dose. None of the surgical groups met steady state bioequivalence criteria for either AUC or C_max; whereas, the group with class III obesity met bioequivalence criteria compared to controls at steady state.²
• Rivaroxaban demonstrated predictable, dose-dependent PK and pharmacodynamics (PD) in healthy patients, patients with moderate to severe heart failure, patients with mild or moderate renal impairment, patients with nonvalvular atrial fibrillation (AF), patients undergoing major orthopedic surgery, and patients with acute coronary syndrome (ACS) in single-dose, multiple-dose, and PK modeling studies.^3-12
• A crushed rivaroxaban 20 mg tablet showed similar relative bioavailability when administered orally or via nasogastric (NG) tube compared to that of a whole rivaroxaban 20 mg tablet administered orally.¹³
• The PK and PD of rivaroxaban was found to be consistent with that observed in the adult population.¹⁴ Also, among the pediatric population, the bodyweight-adjusted rivaroxaban regimens with either tablets or suspension are validated and can provide an alternative treatment option for venous thromboembolism (VTE) in children.¹⁵
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^16-35

PRODUCT LABELING

Adult Population

Pharmacokinetics

The absolute bioavailability of rivaroxaban is dose dependent. For the 2.5 mg and 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. Rivaroxaban 2.5 mg and 10 mg tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of rivaroxaban with food increases the bioavailability of the 20 mg dose (AUC and C_max increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg tablets should be taken with food. The C_max of rivaroxaban appear 2 to 4 hours after tablet intake.

Plasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding component.

The terminal t_1/2 of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years and 11 to 13 hours in elderly subjects aged 60 to 76 years.

Pediatric Population

Pharmacodynamics

In children treated with rivaroxaban, the correlation between anti-factor Xa to plasma concentrations is linear with a slope close to 1.¹

Pharmacokinetics

The rate and extent of absorption were similar between the tablet and suspension. After repeated administration of rivaroxaban for the treatment of VTE, the C_max of rivaroxaban in plasma was observed at median times of 1.5 to 2.2 hours in subjects who ranged from birth to less than 18 years of age.¹

In children who were 6 months to 9 years of age, in vitro plasma protein binding of rivaroxaban is approximately 90%.¹

The half-life of rivaroxaban in plasma of pediatric patients treated for VTE decreased with decreasing age. Mean half-life values were 4.2 hours in adolescents, 3 hours in children 2 to 12 years of age, 1.9 hours in children 0.5 to <2 years of age, and 1.6 hours in children <0.5 years of age.¹

An exploratory analysis in pediatric patients treated for VTE did not reveal relevant differences in rivaroxaban exposure based on gender or race.¹

clinical data

Adult Population

Single- and Multiple-Dose PK and PD

ABSORB² (Rivaroxaban Pharmacokinetics and Pharmacodynamics After Bariatric Surgery and in Morbid Obesity) was a phase 1, single-center, nonrandomized, open-label, multiple-dose, parallel-design study that compared the PK of rivaroxaban 20 mg daily for 8 days in patients who had undergone RYGB or SG with the PK observed in individuals with a body mass index (BMI) of ≥40 kg/m² (class III obesity group) and a group of healthy volunteers (control group).

• The primary endpoint was the rivaroxaban plasma concentration profile on day 1 and at steady state on day 8; this was measured to determine C_max, time required to reach C_max (T_max), and AUC.
• A total of 64 individuals were included in the PK analysis:
  • Class III obesity group: n=16; mean age, 38.7 years; 75.0% were female.
  • RYGB group: n=16; mean age, 48.1 years; 87.5% were female.
  • SG group: n=16; mean age, 44.4 years; 68.8% were female.
  • Control group (subjects without a history of surgery but with similar age and BMI as of the patients in the surgical groups): n=16; mean age, 45.7 years; 75.0% were female.
• After the first dose:
  • The mean AUC_0-24 for the surgical groups (RYGB, 1806.8 ng.h/mL; SG, 1648.9 ng.h/mL) was lower than that for the control group (1893.5 ng.h/mL).
  • Mean C_max was lower in the RYGB group (214.9 ng/mL) than in the other groups (class III obesity, 260.5 ng/mL; SG, 252.5 ng/mL; and control group, 264.1 ng/mL). However, this difference was less pronounced once steady state was reached (RYGB, 256.9 ng/mL; class III obesity, 292.7 ng/mL; SG, 265.8 ng/mL; and controls, 288.8 ng/mL).
• At steady state, the AUC values remained lower in surgical groups (RYGB, 2129.9 ng.h/mL; SG, 1946.4 ng.h/mL) than in the control group (2224.8 ng.h/mL).
• On day 8, compared with the control group, none of the surgical groups met the steady-state bioequivalence criteria for AUC (RYGB: ratio of the geometric mean [GMR], 93.6% [90% confidence interval [CI]: 78.0-122.2]; SG: GMR, 86.3% [90% CI: 71.4-104.2]) or C_max (RYGB: GMR, 87.3% [90% CI: 72.6-104.9]; SG: GMR, 93.2% [90% CI: 77.6-112.1]). However, compared with the control group, the class III obesity group met the steady-state bioequivalence criteria for AUC (GMR, 102.4% [90% CI: 85.4-122.7]) and C_max (GMR, 96.8% [90% CI: 80.6-116.4]).

Moore et al (2014)³⁶ investigated the PK and PD of rivaroxaban across each renal function group, with rivaroxaban 5 mg in subjects with mild or moderate renal impairment, and 10 mg in all subject groups, with and without concomitant steady-state erythromycin 500 mg 3 times daily (TID) for 6 days. The route of administration for erythromycin was not noted.

• Rivaroxaban 10 mg with erythromycin administered together to subjects with normal renal function increased rivaroxaban C_max by 40% and the AUC from zero to infinity (AUC_inf) value by 39%.
• Rivaroxaban 10 mg with erythromycin administered together in subjects with mild or moderate renal impairment increased rivaroxaban C_max by 56% and 64%, and AUC_inf by 76% and 99%, respectively, relative to subjects with normal renal function.
• Rivaroxaban 10 mg administered to subjects with mild or moderate renal impairment increased rivaroxaban C_max by 23% and 36%, and AUC_inf by 15% and 17%, respectively, relative to subjects with normal renal function.

Kubitza et al (2013)³ conducted a randomized, single-blind, placebo-controlled, parallel-group, single-dose study (N=34), in which healthy subjects were enrolled into 4 groups: young males or females (aged 18 to 45 years) and elderly males or females (aged >75 years) to evaluate the impact of age and gender on the PK and PD of rivaroxaban 10 mg in a 2:1 ratio.

• In all 4 groups, the C_max was similar, and the time to C_max and t_1/2 were not significantly affected by age or gender. AUC values were approximately 41% higher in elderly subjects compared with young subjects (P=0.0013; 90% CI: 1.20-1.66), but AUC was not significantly influenced by gender. The total clearance and renal clearance were inversely correlated with age.
• Factor Xa (FXa) was inhibited by rivaroxaban and maximum effect (E_max) occurred 2-4 hours after rivaroxaban administration. Inhibition of FXa activity was in the range of 45-58%.
• Gender did not have a significant influence on inhibition of FXa activity.
• In the elderly group, the E_max was increased (least-squares means [LSM] ratio 1.11; 90% CI: 1.02-1.20; P<0.05), as well as AUC from first to last reading (AUC_0-tn; LSM ratio 1.58; 90% CI: 1.32-1.89; P<0.05) compared to the younger subjects. Twenty-four hours after rivaroxaban administration, FXa activity returned to 10% of the baseline value in most groups.
• Following rivaroxaban administration, prolongation of prothrombin time (PT) was observed in all study groups. E_max occurred 2-4 hours after rivaroxaban was administered and ranged from 1.63 to 1.68 times the baseline value.
• Compared with males, the AUC_0-tn was significantly lower in females.
• The elderly group had an increased AUC_0-tn of PT prolongation as compared with the younger group (LSM ratio: 1.46; 90% CI: 1.29-1.66; P<0.05).
• Twenty-four hours after rivaroxaban administration, AUC_0-tn values for prolongation of PT were close to baseline values. There was an inverse correlation between AUC_0-tn values for inhibition of FXa activity and prolongation of PT with creatinine clearance (CrCl). There was a weaker correlation between CrCl and E_max associated with inhibition of FXa activity and prolongation of PT.

Gheorghiade et al (2010)⁶ conducted a phase 1b, randomized (ratio 2:1), multicenter, single- and multiple-dose study (N=26), in which 2 cohorts of patients with moderate to severe heart failure (cohort 1, acute decompensated heart failure; cohort 2, symptomatic chronic heart failure with left ventricular ejection fraction <40%) received rivaroxaban 10 mg once daily (cohort 1, n=6; cohort 2, n=12), subcutaneous enoxaparin 40 mg once daily (cohort 1, n=2; open label), or matching doses of oral placebo (cohort 2, n=6; double blind).

• Rapid absorption of rivaroxaban was observed, with time to C_max ranging from 1-4 hours across cohorts. No major differences in plasma concentration profiles were observed between cohorts on day 1, after a single dose; however, rivaroxaban plasma exposure was 21% (C_max) to 23% (AUC over 24 hours [AUC_24h]) higher in cohort 1 than cohort 2.
• At steady state on day 6, rivaroxaban exposure was 10% (AUC_24h) to 16% (C_max) higher in cohort 1 than in cohort 2. The PT-versus-time profiles of rivaroxaban for both cohorts were similar to the plasma concentration-time curve. There were no significant differences in baseline PT between treatment arms in either cohort.
• Mean relative changes from baseline to day 6 in PT (2-, 3-, and 4-hours post-dose) ranged from 1.54 to 1.58 seconds for cohort 1 and 1.47 to 1.51 seconds for the rivaroxaban arm in cohort 2 and 1.01 to 1.07 seconds for the placebo arm of cohort 2.
• A significant difference between rivaroxaban (decrease of 2.7 ng/mL) and placebo (increase of 11.6 ng/mL) was observed in change from baseline to day 7 in prothrombin fragment 1.2 for cohort 2 (absolute difference, 14.3 ng/mL; P=0.0009). A significant difference between rivaroxaban (3.3-second median increase) and placebo (0.4-second median decrease) was observed in change from baseline to day 7 in prothrombinase-induced clotting time for cohort 2 (shift in median, 3.55 seconds; P=0.007). No significant differences were observed in the rate of D-dimer and thrombin-antithrombin complex levels, although there was a numerical decrease from baseline in the rate of D-dimer formation and a numerical increase in the rate of thrombin-antithrombin complex formation in cohort 2.
• Accumulation over 6 days of multiple dosing was minimal. Overall, the mean t_1/2 ranged from 7-9 hours. There were no discontinuations due to adverse events.

Kubitza et al (2005)⁴ conducted a randomized, single-blind, placebo-controlled, single-dose study (N=103), in which healthy subjects received rivaroxaban at doses ranging from 1.25 to 80 mg (tablets) or 5 mg oral solution. All doses were safe and well tolerated; risk of bleeding was not increased.

• Relative bioavailability of the oral solution was approximately 80%. Plasma concentrations and PD effects (inhibition of FXa activity, PT, activated partial thromboplastin time [aPTT], HepTest) were dose dependent.
• After administration of tablets, peak plasma concentration was reached after 2 hours. Maximum FXa inhibition occurred 1-4 hours after administration of tablets and ranged from 20% to 61% with doses of 5 to 80 mg. The t_1/2 of the biologic effect with tablets was 6 to 7 hours. PT prolongation followed a similar profile to FXa inhibition.
• Proportion of the administered dose excreted in urine as unchanged drug ranged from about 40% (1.25 mg dose) to about 10% (60- to 80-mg dose). FXa activity was selectively inhibited; direct action on thrombin (factor 2a) and antithrombin was not observed. FXa inhibition and prolongation of PT both correlated strongly with plasma concentrations of rivaroxaban (r=0.949 and 0.935, respectively).

Kubitza et al (2005)⁵ conducted a randomized, single-blind, placebo-controlled, multiple-dose study (N=64), in healthy subjects who received rivaroxaban 5 mg (once daily, twice daily [BID], or TID), 10 mg BID, 20 mg BID, or 30 mg BID on days 0 and 3 to 7.

• No clinically relevant changes in bleeding time or other safety variables were observed.
• Maximum FXa inhibition occurred at approximately 3 hours and was maintained for at least 12 hours at all doses. PT, aPTT, and HepTest were prolonged to a similar extent to FXa inhibition at all doses.
• Dose-proportional PK (AUC during a dosing interval divided by dose per kg body weight [AUC_t, norm] and C_max divided by dose per kg body weight (C_max, norm) were observed at steady state (day 7).
• C_max values were reached at 3 to 4 hours for all doses and all regimens. t_1/2 of rivaroxaban was 5.7-9.2 hours at steady state. No relevant accumulation occurred at any dose.
• Plasma concentrations of rivaroxaban were linked to FXa inhibition using an E_max model and to PT by a direct linear relationship (r=0.950 and 0.958, respectively).

PK Modeling Studies

Girgis et al (2014)⁷ reported findings from prespecified PK/PD modeling analyses, based on matched PK and PD data obtained from a subset of patients enrolled in the ROCKET AF trial with nonvalvular AF randomized to receive rivaroxaban 20 mg once daily (normal/mildly impaired renal function; N=161) or 15 mg once daily (moderate renal impairment; CrCl 30-49 mL/min; N=25).

• Population-simulated ratios (moderate renal impairment: mild renal impairment or normal renal function) of the means of C_max and AUC_0-24h fell within a prespecified statistic test range of 0.70-1.43.
• FXa activity was negatively correlated with increasing plasma rivaroxaban concentration. Age had a moderate effect on baseline parameter of the FXa activity model; FXa activity values varied approximately 30% for the age range included in the study population.
• There was a near-linear relationship between rivaroxaban concentration and PT and prothrombinase-induced clotting time values. Inhibitory effects were observed through 24 hours post-dose.
• An effect of renal function was detected in the PT and prothrombinase-induced clotting time models, with a moderate influence on base and exponent parameters.

Xu et al (2012)¹² evaluated population PK and PD using a PK model with samples from 2290 patients from the ATLAS ACS-TIMI 46 trial who received rivaroxaban total daily dose of 5, 10, or 20 mg.³⁷

• The primary PD endpoint was PT, and the relationship between PK and PT.
• The PK of rivaroxaban in this patient population was adequately described by an oral 1-compartment model with first-order absorption and elimination.
• Population estimates for absorption rate, apparent clearance, and volume of distribution were 1.24 h^-1 (interindividual variability: 139%), 6.48 L/h (31%), and 57.9 L (10%), respectively. Covariate estimates were consistent with those observed in patients with VTE, deep vein thrombosis, and AF.
• PT correlated with rivaroxaban concentrations in an almost linear fashion, with little inter-individual variability. It was concluded the PK and PD of rivaroxaban are predictable in patients with ACS.

Mueck et al (2008)¹¹ conducted a PK/PD study utilizing data from 2 phase 2b dose-finding studies (ODIXa-KNEE and ODIXa-HIP) of rivaroxaban for VTE prevention.

• Patients received rivaroxaban 2.5, 5, 10, 20 or 30 mg BID or subcutaneous enoxaparin 40 mg once-daily (ODIXa-HIP) or 30 mg BID (ODIXa-KNEE).
• Nonlinear, mixed-effect population modeling was used to analyze data from 517 in the hip study and 492 in the knee study. A subset of 36 patients from the hip study underwent full PK/PD profiling. Population PK of rivaroxaban was well described by an oral, 1-compartment model.
• Absorption and clearance showed high interindividual variability on postoperative day 1. Clearance was 26% lower in the knee study, resulting in approximately 30% higher rivaroxaban exposure. Population PK values demonstrated that plasma concentrations of rivaroxaban increased dose dependently. Rivaroxaban showed rapid absorption, with C_max reached at 1-2 hours.
• Several covariates were shown to affect the PK of rivaroxaban: clearance was affected by age (ODIXa-HIP), hematocrit (on first postoperative day, in knee study), gender (ODIXa-KNEE), and renal function (in both studies). Volume of distribution was affected by body weight in both studies. Modeling of rivaroxaban exposure under extreme case scenarios (eg, age, weight, renal function) suggested that dose adjustment may not be necessary in such patients.
• Surgery was shown to affect FXa activity and PT, likely due to bleeding during surgery and intravenous fluid administration. FXa activity correlated with plasma concentrations of rivaroxaban.
• Covariates that influenced the effect of rivaroxaban on FXa activity were age, gender, body weight, hematocrit, serum albumin and CrCl; however, the effect of these covariates was small and not clinically meaningful.
• PT also correlated linearly with rivaroxaban plasma concentrations. However, in the knee study, the correlation deviated slightly from linearity at rivaroxaban concentrations that would be higher than the average concentration range of effective rivaroxaban doses.
• Serum albumin levels and CrCl influenced PT slightly, possibly due to altered sensitivity of patients in their postsurgical condition.
• Rivaroxaban will not require routine anticoagulation monitoring, due to its predictable PK/PD profile; however, if necessary, rivaroxaban exposure can be assessed using the PT. The international normalized ratio is not an appropriate PD measurement, as this test was developed for coagulation monitoring of vitamin K antagonists, and the international sensitivity index value used in the calculation indicates the overall sensitivity of the PT reagent to reductions in vitamin K dependent clotting factors.
• In conclusion, rivaroxaban demonstrated predictable, dose-dependent PK/PD effects in patients undergoing major orthopedic surgery.

Mueck et al (2007)⁸ conducted a phase 1, multiple-ascending-dose study using nonlinear, mixed-effect modeling to analyze rivaroxaban plasma concentration and PD data (FXa activity and clotting tests) in healthy subjects who received rivaroxaban 5 mg once daily, BID or TID or 10, 20 or 30 mg BID.

• The population PK of rivaroxaban was described by an oral, 2-compartment model with first-order absorption and central compartment elimination.
• Population mean estimates for apparent oral clearance and volume of distribution for the central compartment were 9.2 L/hr and 55 L, respectively, with moderate inter-individual variability (17.4% and 30.7%, respectively). Total volume of distribution at steady state was ~70 L. Residual (unexplained) variability was 25%.
• FXa activity correlated with rivaroxaban plasma concentrations following an inhibitory E_max model. PT and rivaroxaban plasma concentrations correlated with a linear model with a slope of 4.6/100 s/µg/L. Inter-individual variability was low for the correlation with PT. It was concluded that rivaroxaban has predictable, dose-proportional PK and PD and that the PT test might be useful to assess rivaroxaban exposure in patients, if required.

Ericksson et al (2007)⁹ compared the PK/PD of rivaroxaban once daily vs BID by utilizing data from 2 phase 2b dose-finding studies of rivaroxaban for VTE prevention after elective total hip replacement surgery (ODIXa-HIP2³⁸ and ODIXa-OD-HIP³⁹).

• Nonlinear, mixed-effect population modeling was used to analyze C_max and minimum plasma concentrations (C_trough) and PT in 758 patients who received rivaroxaban (total daily doses 5,10, and 20 mg). PK was well described by an oral, 1-compartment model.
• Age and renal function influenced clearance, and body weight influenced volume of distribution, but these effects were moderate and within the variability of the study population.
• In both studies, C_max and C_trough at steady state increased dose dependently. C_max values were higher and C_trough values were lower in the once-daily study versus the BID study; however, the 90% CIs overlapped. These findings suggest that once-daily dosing should not lead to greater risk of bleeding (at C_max) or VTE (at C_trough) than BID dosing.
• In the PD analysis, PT correlated linearly with plasma concentrations of rivaroxaban. It was concluded that the PK and PD of rivaroxaban are predictable in patients undergoing total hip replacement after once daily or BID dosing.⁹

Turpie et al (2006)¹⁰ conducted a PK/PD study utilizing data from 2 phase 2b dose-finding studies of rivaroxaban for VTE prevention (ODIXa-KNEE⁴⁰and ODIXa-HIP2³⁸).

• Nonlinear, mixed-effect population modeling was used to analyze data from 1009 patients; population PK was described by an oral, 1-compartment model.
• Variability was low to moderate overall; however, absorption and clearance showed high interindividual variability on the first postoperative day.
• Covariate analysis indicated that volume of distribution of rivaroxaban was influenced by body weight; clearance was influenced by study day (postop day 1 or steady state), age, renal function, and gender. Modeling of rivaroxaban exposure under extreme case scenarios (age, weight, renal function) suggested dose adjustment may not be necessary in patients receiving rivaroxaban for prophylaxis following total hip and knee replacement surgery.
• Rivaroxaban showed a rapid onset of action, with maximum FXa inhibition at 1-2 hours after dosing. FXa activity and PT correlated with plasma concentrations of rivaroxaban.¹⁰

Bioavailability of Crushed Rivaroxaban Tablet

Moore et al (2014)¹³ investigated stability and NG-tube adsorption characteristics and relative bioavailability of rivaroxaban in a phase 1, single-center, open-label, randomized, 3-period, 3-treatment crossover study.

• In 55 healthy adults, the relative bioavailability of rivaroxaban 20 mg administered orally as a whole tablet (Whole-Oral), crushed tablet in 70 mL applesauce suspension (Crushed-Oral), or crushed tablet in 50 mL water suspension via NG tube (Crushed-NG) were determined.
• There were no significant changes in mean percentages of nondegraded rivaroxaban recovered over 4 hours for crushed tablet suspensions in water, applesauce, and juice (50 mL orange or cranberry juice) (≥98.5% recovery across all suspensions and time points) or after NG tube exposure (recovery: 99.1% for silicone and 98.9% for polyvinyl chloride NG tubes).
• 98% of subjects who received the Crushed-NG displayed a double concentration-time peak.
  • The first peak occurred ~45 minutes after dosing. The second peak occurred 4-6 hours after dosing and was consistent with the time of peak plasma concentrations seen with Reference and Crushed-Oral dose administrations.
• Relative bioavailability was similar between Crushed-Oral and Reference dosing (C_max and AUC values were within 80%-125% bioequivalence limits).
• Relative bioavailability was also similar between the Crushed-NG and Reference dosing (AUC values were within bioequivalence limits; C_max [90% CI: 78.5%-85.8%] was slightly below the 80% lower bioequivalence limit).

Pediatric Population

Single- and Multiple-Dose PK/PD

Zhu et al (2021)¹⁴ presented the PK, PD and exposure results of rivaroxaban from the phase 3 UNIVERSE study in pediatric patients. The UNIVERSE study was a multicenter, 2-part, open-label, prospective, active-controlled study that evaluated the PK and PD profiles, safety, and efficacy of rivaroxaban for thromboprophylaxis in pediatric patients aged 2-8 years with single-ventricle physiology who had undergone the Fontan procedure within 4 months prior to enrollment.

Methods

• Part A was the 12-month, nonrandomized, open-label part of the study that assessed the PK and PD profiles following administration of rivaroxaban.
• Part B was the randomized, open-label, active-controlled part of the study that evaluated the safety and efficacy of rivaroxaban vs aspirin (usual standard of care) for thromboprophylaxis for 12 months. The PK and PD parameters were also assessed in patients randomized to XARELTO.
• Rivaroxaban 0.1% (1 mg/mL) oral suspension was administered BID by body weight.
• PK/PD assessments were performed on the first day of dosing and at months 3 and 12.

Results

• Of the 12 patients enrolled in part A, 10 completed the PK and PD assessments for 12 months. However, all 12 patients had PK samples taken after administration and were included in the part A PK assessment.
  • The geometric mean AUC from time 0 to 24 hours for steady-state exposure (AUC_ss,24h) of rivaroxaban with the body weight-based dose regimen was 1698 μg·hours/L (90% CI, 1336-2157). See Table: Exposure Metrics of Rivaroxaban in the UNIVERSE Study.
• Part B included 100 patients (rivaroxaban, n=66; aspirin, n=34). Of the 66 patients randomized to rivaroxaban, 2 did not receive any drug.
  • The apparent clearance of the central compartment (CL/F) and the apparent central volume of distribution (Vc/F) were estimated to be 1.01 L/hour and 1.20 L/hour, respectively.

Young et al (2020)¹⁵ reported results of the PK analyses of the bodyweight-adjusted rivaroxaban regimens used in the EINSTEIN-Junior (Jr) study. EINSTEIN-Jr was a randomized, open-label, multicenter study that compared the efficacy and safety of rivaroxaban with standard anticoagulants for the treatment of VTE and evaluated the PK of rivaroxaban in pediatric patients aged ≤17 years.

Methods

• Pediatric patients aged 0-17 years with objectively confirmed VTE who had completed ≥5 days of initial heparin therapy were eligible.
• Rivaroxaban was administered as a body weight-adjusted 20 mg-equivalent dose once daily in patients with a body weight of ≥30 kg, BID in patients with a body weight of ≥12 to <30 kg, or TID in patients with a body weight of <12 kg as either immediate release film-coated tablets (strengths of 5, 10, 15, or 20 mg) or an oral suspension (1 mg/mL).
• Blood samples for PK assessments were taken on days 2, 30, 60, and 90.
• A comprehensive pediatric population PK model was used to evaluate AUC_ss,24h, C_max at steady state (C_max,ss), and concentration at the end of the dosing interval at steady state (C_trough,ss).

Results

• Of the 335 children randomized to rivaroxaban, 316 (94.3%) were evaluable for PK analysis (tablet, n=121 [38.3%]; suspension, n=195 [61.7%]).
• Geometric mean values for the t_1/2 of rivaroxaban decreased with decreasing age, from 4.2 hours in children aged ≥12 years to approximately 3 hours in children aged 211 years and 1.9 and 1.6 hours in children aged 0.5-1 year and <0.5 years, respectively.
• Relative oral bioavailability decreased with increasing dose per bodyweight.
• Individual values for AUC_ss,24h, C_max,ss, and C_trough,ss were within the adult reference range and were comparable for the tablet and suspension formulation. See Table: Exposures Observed in Children With Once Daily Rivaroxaban Tablets or Oral Suspension.
• Rivaroxaban clearance was not influenced by the strength of cytochrome P 3A4 (CYP3A4) or P-glycoprotein inhibitors, and CYP3A4 inducers.
• There was no clustering observed for any of the PK parameters with efficacy, bleeding, or adverse-event outcomes.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 28 October 2024.