CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`215859Orig1s000
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`NON-CLINICAL REVIEW(S)
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
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`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`
`NDA 215859
`1
`June 22, 2021
`June 22, 2021
`Xarelto (Rivaroxaban) Oral Suspension
`• Venous thromboembolism (VTE) and the
`reduction in the risk of recurrent VTE in
`children from birth to < 18 years of age,
`• Thromboprophylaxis in pediatric patients 2
`years of age and older with congenital heart
`disease (CHD) after the Fontan procedure
`Janssen Pharmaceuticals Inc.
`Division of Non-Malignant Hematology
`Bo Yeon Lee, Ph.D.
`Pedro Del Valle, Ph.D., FATS
`Todd Bourcier, Ph.D.
`DPT-CHEN
`Ann Farrell, MD
`DNH
`Carleveva Thompson, MS
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 215859 are owned by Janssen Pharmaceuticals Inc. or
`are data for which Janssen Pharmaceuticals Inc. has obtained a written right of
`reference.
`
`Applicant:
`Review Division:
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`
`Reference ID: 4888706
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`1
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`
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`Any information or data necessary for approval of NDA 215859 that Janssen
`Pharmaceuticals Inc. does not own or have a written right to reference constitutes one
`of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries
`of a previously approved application is for descriptive purposes only and is not relied
`upon for approval of NDA 215859.
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`Reference ID: 4888706
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`NDA 215859
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`
`
`Bo Yeon Lee, Ph.D.
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`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 4
`1.1
`INTRODUCTION .................................................................................................... 4
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 4
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS ................................................ 5
`5.1
`PK/ADME .......................................................................................................... 5
`OVERALL NONCLINICAL ASSESSMENT .................................................................. 10
`
`REFERENCES .............................................................................................................. 13
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`Reference ID: 4888706
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`NDA 215859
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`
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`Bo Yeon Lee, Ph.D.
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`Executive Summary
`1
`Introduction
`1.1
`Rivaroxaban (JNJ-39039039, BAY 59-7939, Xarelto®) is a selective inhibitor of the
`serine protease coagulation Factor Xa (FXa) being developed for the prevention and
`treatment of thrombo-embolic events. (Reference NDAs 022406 and 202439)
`
`Currently, Xarelto is approved in adult patients for the following indications; 1) to reduce
`risk of stroke and systemic embolism in nonvalvular atrial fibrillation, 2) for treatment of
`deep vein thrombosis (DVT), 3) for treatment of pulmonary embolism (PE), 4) for
`reduction in the risk of recurrence of DVT or PE, 5) for the prophylaxis of DVT, which
`may lead to PE in patients undergoing knee or hip replacement surgery, 6) for
`prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients, 7) to
`reduce the risk of major cardiovascular events in patients with chronic coronary artery
`disease (CAD) or peripheral artery disease (PAD) (Xarelto USPI, revised 03/2020).
`
`The Sponsor submitted this NDA 245859 for 2 indications in pediatric population: 1)
`venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE in
`children from birth to < 18 years of age, and 2) thromboprophylaxis in pediatric patients
`2 years of age and older with congenital heart disease (CHD) after the Fontan
`procedure
`
`In support of the clinical development in pediatric population, the Sponsor conducted
`additional pharmacokinetics studies including protein binding using plasma from
`pediatric healthy volunteers and substrate characteristics towards fetal CYP3A7. There
`are no new pharmacology or toxicology studies submitted. There are no outstanding
`issues from a Pharmacology/Toxicology perspective that would prevent the approval of
`rivaroxaban for the proposed indications.
`
`1.2 Brief Discussion of Nonclinical Findings
`Xarelto® is an approved drug in adult populations and the Sponsor has submitted this
`NDA to support the clinical development and market authorization of rivaroxaban in
`pediatric populations.
`
`The nonclinical program reviewed under reference NDAs 202439 and 022406
`concluded that rivaroxaban was approvable for the indications listed above in adult
`patient population. The reference NDAs include nonclinical studies in juvenile,
`adolescent and adult rats, and the overall nonclinical assessment remains unchanged.
`In addition, the Sponsor submitted additional PK studies of pediatric protein binding and
`of substrate characteristics towards a fetal CYP isoform, which showed that the
`unbound fraction in pediatric plasma was higher than in adult plasma and that
`rivaroxaban is a poor substrate for the fetal isoform CYP3A7.
`
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`Reference ID: 4888706
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`NDA 215859
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`Bo YeonLee, Ph.D.
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`Therefore, there are no safety concerns from the nonclinical perspective and
`rivaroxabanis approvable to be usedin pediatric populations for the proposed
`indications based on the nonclinical assessment of the new PK studies and reviews by
`nonclinical reviewers of reference NDAs.
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`5
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`Pharmacokinetics/ADME/Toxicokinetics
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`5.1
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`PK/ADME
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`Study Title: Rivaroxaban: Supplementary Investigations on Binding to Plasma
`Proteins in Pediatric Human Plasma of Rivaroxaban In Vitro (Study PH-41585)
`Non-GLP compliant
`
`The Sponsor assessedprotein binding of Rivaroxabanin pediatric human plasma (< 2
`years old children, 2-6 years old children, and > 6 years old children) using radiolabeled
`['4C]BAY 59-7939 (rivaroxaban), and the unboundfractions of ['*C]BAY 59-7939 was
`determined.
`
`Plasma samples were pooled to test from < 2 years old children, 2-6 years old children,
`> 6 years old children, and healthy adult volunteers (represents a control in this study).
`(see, Table 1) Protein binding of rivaroxaban to human plasma samples was analyzed
`by the equilibrium dialysis method.
`
`The protein binding assay showedthat the binding of rivaroxaban ranged between 95.4
`yg/L - 99.9 ug/L. The unboundfractions were determined as 11.1%, 11.2%, and 9.23%
`in < 2 years old children, 2-6 years old children, and > 6 years old children, respectively.
`(see, Table 2) The unboundfraction of rivaroxaban washigherin pediatric plasma than
`in adult plasma, and unboundfraction in plasma from man (control) was 6.82% whichis
`comparableto the reported data 5.07% from reference NDA 022406.(see, Table 3)
`
`Table 1. List of Plasma Samples from Pediatric Population
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`(Excerpted from submission)
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`Species
`___Age
`_ Gender _
`Race
`Ethnicity
`Pediatric human
`8 months
`M
`Caucasian
`European
`1 year
`F
`African
`African American
`6 months
`F
`African
`African American
`5 years
`F
`African
`African American
`3 years
`M
`African
`African American
`2 years
`F
`African
`African American
`9 years
`F
`Caucasian
`8 years
`F
`Caucasian
`N/A
`
`7 years
`F
`Caucasian
`N/A
`Man
`N/A
`male
`Caucasian
`k
`N/A
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`ci
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`Supplier
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`ae
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`lola
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`Reference ID: 4888706
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`NDA 215859
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`Bo YeonLee, Ph.D.
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`Table 2. Rivaroxaban Binding to Pediatric Human Plasma Proteins.
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`(Excerpted from submission)
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`Species
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`Concentration for protein binding
`assay
`[%]
`[%]
`[ug/L]
`3.19
`Ti
`99.9
`Human, <2 years and younger
`6.88
`11.2
`95.4
`Human, 2 - 6 years old
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`
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`99.9 9.23Human, >6 years and older 4.04
`CV = coefficient of variation
`a = arithmetic mean unboundfraction from three independent experiments at the respective
`concentration
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`fu?
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`CV
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`Table 3. Binding of [14C]BAY 59-7939 to Plasma Proteins in Healthy Adult
`Volunteers
`
`)
`
`p
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`***_07
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`pf
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`*** = mean human male and female, conc. 0.1 - 3 ug/mL
`*** = mean human male and female, conc. 10 - 300 g/mL
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`Study Title: Rivaroxaban: In Vitro Intrinsic Clearances with Recombinant Human
`CYP Isoforms (Study PH-41153)
`
`Rivaroxaban wasshownto be substrate for CYP2J2, CYP3A4 and 3A95in adults
`(reference NDA 022406, eCTD4.2.2.4, PH-32627), andis eliminated via 3 pathwaysin
`adults: ~43.5% of the dose is excreted by transporter-mediated as unchanged drug via
`urine and feces, ~14% of the doseis by hydrolytic cleavage of the amide bondsyielding
`M-4 and M-7, and 32% of the doseis eliminated via oxidative pathways. CYP2J2 and
`CYP3A4/3A5-mediated oxidation yield M-2, M-3, M-8, and M-9 (by CYP3A4) and M-2
`(by CYP2J2). (see Figure 1).
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`NDA 215859
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`Figure 1. Proposed Primary Oxidative Metabolites of Rivaroxaban from In Vitro
`Studies
`
`Bo Yeon Lee, Ph.D.
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`
`
`(Excerpted from submission)
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`
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`* Bold arrows are the main metabolic in vivo pathway
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`
`
`The activity of CYP3A4 may differ between pediatric populations and adults due to
`changes of CYP3A activity during human development. CYP3A4 activity is negligible at
`birth and increase to ~40% of adult activity within the 2-12 month of age and reach
`~120% of adult activity at an age of 12 months, then the activity goes down to adult
`levels. Also, inverse activities of the fetal isoform CYP3A7 with peak activity at birth and
`decreasing to negligible levels around 12 months of age is reported (de Wildt et al.,
`1993, Lacroix et al., 1997, Zane et al., 2017)
`
`The Sponsor conducted an in vitro study to evaluate 1) the metabolic stability of
`rivaroxaban at a physiologically relevant concentration (0.1 µM) towards CYP2J2, 3A4,
`3A5 and 3A7 and 2) a potential contribution of CYP3A7 (isoform of CYP3A4) to the
`biotransformation of rivaroxaban in the pediatric population.
`
`Clearance of rivaroxaban and the level of the hydroxylated form of rivaroxaban (OH-
`rivaroxaban) were measured as indicators of enzymatic activity of CYP2J2, 3A4, 3A5
`and 3A7 when incubated with rivaroxaban for up to 60 min. (see Table 4, Figure 2A&B).
`The Sponsor commented that the metabolite formation is only a qualitative measure of
`enzymatic activity in this study. (Figure 2).
`
`The hydroxylated metabolites were formed by all 4 CYP enzymes (see Table 4, Figure
`2B). Intrinsic clearance of rivaroxaban was highest with CYP2J2 (2.49 µL/min/pmol) and
`then CYP3A4 (0.38 µL/min/pmol), while CYP3A5 and CYP3A7 were 8-fold lower (<
`0.05 µL/min/pmol). (see Table 4).
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`NDA 215859
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`Results show evidence that rivaroxaban is a poor substrate for the CYP3A7, fetal
`isoform of CYP3A4, and it is unlikely that CYP3A7 will contribute to hepatic clearance of
`rivaroxaban in the pediatric population.
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`Bo Yeon Lee, Ph.D.
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`
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`Table 4. Clearance and Metabolite Formation of 0.1 µM Rivaroxaban with CYP2J2,
`3A4, 3A5, and 3A7
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`(Excerpted from submission)
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`Reference ID: 4888706
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`NDA 215859
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`Figure 2. Clearance (Figure 2A) and Metabolite Formation (Figure 2B) of 0.1 µM
`Rivaroxaban with CYP2J2, 3A4, 3A5, and 3A7
`(Excerpted from submission)
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`Bo Yeon Lee, Ph.D.
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`
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`Reference ID: 4888706
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`Bo Yeon Lee, Ph.D.
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`NDA 215859
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`Overall Nonclinical Assessment
`The nonclinical package of reference NDA 202439 included juvenile studies conducted
`in rats of PND 4-26 (pilot study) and PND 10-105 (pivotal study), corresponding to the
`human age ranges of neonate to toddler and infant to adolescent, respectively.
`
`Nonclinical assessment of juvenile studies of reference NDA 202439 by Dr. Harlow
`pointed out 2 things to note:
`1) exposure to rivaroxaban was 6- to 10-fold higher in the younger rats,
`particularly between PND 10 and 15 compared to exposure in ≥31 days old rats,
`which could be due to a combination of immature renal development in the rat
`(Zoetis and Hurtt, 2003) and decreased expression of CYP P450 3A4 (Asaoka et
`al. 2009, DeZwart et al. 2004).
`2) expected prolonged thromboplastin time from pharmacological effect of
`rivaroxaban was not observed in coagulation test, which is suspected that the
`blood samples were collected prior to administration of rivaroxaban.
`
`Dr. Harlow concluded that data from the coagulation test is inconclusive and the effect
`of rivaroxaban on coagulation was not fully evaluated. She also commented that any
`pediatric studies in humans will need to be carefully designed to determine the
`appropriate levels of rivaroxaban for a therapeutic effect in neonates and infants
`undergoing rapid changes in their hemostatic, renal and metabolic systems, considering
`the levels of Factor X in the neonate at birth are about 37-40% of the adult human level
`(Andrew et al. 1987, Hassan et al. 1990).
`
`In this NDA, the Sponsor provided a nonclinical risk assessment of 2 new PK studies to
`support clinical development and market authorization in proposed pediatric indications
`and summary of overall nonclinical program of reference NDAs 202439 and 022406.
`
`The Sponsor estimated safety margins for the pediatric indications in this NDA (see,
`Table 5) based on pediatric exposures obtained with population PK modeling with
`bodyweight-adjusted dosing scheme in pediatric populations, resulting in rivaroxaban
`exposure similar to that observed in adult patients with deep vein thrombosis (DVT)
`(eCTD 2.7.2. Summary of Clinical Pharmacology Studies- Einstein Jr). Systemic
`exposure (Cmax and AUC) in juvenile rats and the estimated safety margin was also
`provided by the sponsor. (see, Table 6). There was discrepancy in exposure data of 13-
`week pilot (gavage) toxicity study in juvenile rats shown in Table 6 compared to the
`study report PH-36598. Note the corrected data and calculated margin of exposure by
`the reviewer (see, Table 7)
`
`The systemic exposure from 14-week repeat dose toxicology study in juvenile rats (NDA
`202439, eCTD 4.2.3.5.4, PH-36347) was ~5-fold lower compared to that of 3-week pilot
`toxicity study in juvenile rats (NDA 202439, eCTD 4.2.3.5.4, PH-36153). The Sponsor
`conducted additional 13-week repeat dose toxicology study in juvenile rats (NDA
`202439, eCTD 4.2.3.5.4, PH-36598) and explains that the lower systemic exposure was
`due to vehicle difference (0.5 % Tylose® vs. Solutol HS15®/ethanol/water); When
`emulsifying vehicle (Solutol HS15®/ethanol/water) which mimics the absorption-
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`Reference ID: 4888706
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`Bo Yeon Lee, Ph.D.
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`NDA 215859
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`enhancing effects of milk was used, the systemic exposure was not lower but
`comparable to other juvenile studies.
`
`Overall nonclinical assessment including the review of reference NDAs and newly
`submitted PK study reports finds no safety concerns from the perspective of
`Pharmacology & Toxicology for approvability of rivaroxaban in pediatric population for
`the two proposed indications.
`
`
`Table 5. Systemic Exposure and Margins of Exposure Compared to Pediatric
`Exposure
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`(Excerpted from submission)
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`Reference ID: 4888706
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`NDA 215859
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`Table 6. Systemic Exposure in Juvenile Rats and Margins of Exposure Compared
`to Pediatric Exposure
`
`Bo Yeon Lee, Ph.D.
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`(Excerpted from submission)
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`NDA 215859
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`Bo YeonLee, Ph.D.
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`Table 7. Corrected Data of Systemic Exposure and Margin of Exposure from 13-
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`Daily
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`Total Exposure
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`Unbound Exposure
`
`g*h/L
`
`g/L
`
`g*h/L
`
`weekrmStudyinJuvenileRats(PH-36598)
` 6] [ste0[134|10300[77aors[1s|22a|09|
`
`
`== 1700 21.59|0.8|186.6914700
`
`sn|[a[me|ahT=[ocLm|a[
`
`(mg/kg)
`
`g/L
`
`Taare[a6|22200|03|2003|11|zeros|11
`seo|161|30500|166|4026|18|sores|19
`
`F
`sro|244[01500|258|7328|28|e105|20|
`MoE = margins of exposure (when compared to the humanplasmalevels)
`furat = 1.27 %, fuhuman pediatric = 11.2 % (M4.2.2.3/PH 41585 version 2)
`Pediatric reference exposures are the highest steady state Cmax (236.66 pg/L, age group 12 to < 18 years) and AUC
`(2380.96 pg*h/L, age group 2 to < 6 years) obtained by population PK modeling (M2.7.2/Einstein Jr/Table 3-2)
`
`References
`
`e Andrew M, PaesB, Milner R, Johnston M, Mitchell L, Tollefsen D, Powers P.
`1987. Developmentof the human coagulation system in the full-term infant.
`Blood.; 70: 165-172
`e Asaoka Y, Sakai H, Sasaki J, Goryo M, Yanai T, Masegi T, Okada K. 2010.
`Changesin the gene expression and enzymeactivity of hepatic cytochrome
`P450in juvenile Sprague-Dawleyrats. J Vet Med Sci.; 72(4): 471-9.
`e de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A.
`Clinical Pharmacokinetics. 1999;37(6):485-505.
`e de Zwart LL, Haenen HE, Versantvoort CH, Wolterink G, van Engelen JG, Sips
`AJ. 2004. Role of biokinetics in risk assessmentof drugs and chemicals in
`children. Regul Toxicol Pharmacol.; 39(3): 282-309.
`e Hassan HJ, Leonardi A, Chelucci C, Mattia G, Macioce G, Guerriero R, Russo G,
`Mannucci PM, Peschle C. 1990. Blood coagulation factors in human embryonic-
`fetal development: preferential expression of the FVII/tissue factor pathway.
`Blood.; 76(6):1158-64.
`e Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T. Expression of CYP3Ain
`the Human Liver — Evidencethat the Shift between CYP3A7 and CYP3A4
`Occurs Immediately After Birth. European Journal of Biochemistry.
`1997 ;247(2):625-34.
`e Zane NR, Chen Y, Wang MZ, Thakker DR. Cytochrome P450 and
`flavincontaining monooxygenase families: age-dependentdifferencesin
`expression and functional activity. Pediatric Research. 2017;83:527.
`e Zoetis T, Hurtt ME. 2003. Species comparison of anatomical and functional renal
`development. Birth Defects Res B Dev Reprod Toxicol.; 68(2): 111-20.
`
`Reference ID: 4888706
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`BO Y LEE
`11/15/2021 05:04:45 PM
`
`PEDRO L DELVALLE
`11/15/2021 05:17:14 PM
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`Reference ID: 4888706
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`