CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`210563Orig1s000
`210563Orig2s000
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`

`

`Clinical Pharmacology Review
`
`NDA 210563 (SDN 001, eCTD 001)
`
`Original submission
`
`09/12/2017
`
`02/28/2018
`
`IMBRUVICA®
`
`Ibrutinib
`
`Tablets 140 mg, 280 mg, 420 mg and 560 mg
`
`Oral
`
`Pharmacyclics LLC
`
`NDA
`Type/Category
`Submission Date
`PDUFA
`Brand Name
`Generic name
`Formulation and Strength
`Route of Administration
`Applicant
`Approved Indications
`
`
`
`
`
`
`
`Treatment of patients with:
` Mantle cell lymphoma (MCL) who have received at least one
`prior therapy;
`Chronic lymphocytic leukemia (CLL)/Small lymphocytic
`lymphoma (SLL);
`CLL/SLL with 17p deletion;
` Waldenström’s macroglobulinemia (WM);
` Marginal zone lymphoma (MZL) who require systemic therapy
`and have received at least one prior anti-CD20-based therapy.
`Chronic graft versus host disease (cGVHD) after failure of one or
`more lines of systemic therapy
`Approved Dosing Regimen MCL and MZL: 560 mg taken orally once daily
`CLL/SLL, WM and cGVHD: 420 mg taken orally once daily
`Division of Clinical Pharmacology V (DCPV)
`
`OCP Divisions
`OND Division
`OCP Primary Reviewer
`OCP Team Leader
`
`Division of Hematology Products (DHP)
`
`Liang Li, Ph.D.
`
`Olanrewaju Okusanya, Pharm.D.; M.S.
`
`Reference ID: 4206250
`
`1
`
`

`

`Contents
`1.
`EXECUTIVE SUMMARY .................................................................................................................................4
`
`1.1.
`1.2.
`
`RECOMMENDATIONS .........................................................................................................................................4
`POST-MARKETING REQUIREMENTS AND COMMITMENTS..........................................................................................4
`
`2.
`
`SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT ..............................................................................5
`
`PHARMACOLOGY AND CLINICAL PHARMACOKINETICS ...............................................................................................5
`2.1.
`DOSING AND THERAPEUTIC INDIVIDUALIZATION ......................................................................................................5
`2.2.
`2.2.1.
`General dosing ....................................................................................................................................5
`2.2.2.
`Therapeutic individualization ..............................................................................................................5
`2.3.
`OUTSTANDING ISSUES........................................................................................................................................5
`2.4.
`SUMMARY OF LABELING RECOMMENDATIONS ........................................................................................................5
`
`3.
`
`COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW .................................................................................6
`
`OVERVIEW OF THE PRODUCT AND REGULATORY BACKGROUND..................................................................................6
`3.1.
`GENERAL PHARMACOLOGICAL AND PHARMACOKINETIC CHARACTERISTICS ...................................................................6
`3.2.
`CLINICAL PHARMACOLOGY QUESTIONS .................................................................................................................7
`3.3.
`3.3.1.
`Is the to-be-marketed formulation the same as the clinical trial formulation, and if not, are there
`bioequivalence data to support the to-be-marketed formulation? ......................................................................7
`3.3.2.
`Are there clinically relevant food-drug interactions for the to-be-marketed formulation and what is
`the appropriate management strategy? ............................................................................................................12
`
`4.
`
`APPENDICES ...............................................................................................................................................14
`
`SUMMARY OF BIOANALYTICAL METHOD VALIDATION AND PERFORMANCE.................................................................14
`4.1.
`CLINICAL PK AND/OR PD ASSESSMENTS..............................................................................................................14
`4.2.
`4.2.1.
`Trial 1021 ..........................................................................................................................................14
`4.2.2.
`Trial 1022 ..........................................................................................................................................15
`4.2.3.
`Trial 1019 ..........................................................................................................................................16
`
`List of Tables
`
`Table 1: Summary of the Geometric Mean Ratios and 90% Confidence Intervals of the Ibrutinib PK
`Parameters from a Food Effect Trial and Two Pivotal Bioequivalence Trials. ..............................................5
`Table 2: Identity of Study Ibrutinib Formulations.........................................................................................7
`Table 3: Summary of the Statistical Analysis of the Ibrutinib PK Parameters After Single Administration as
`Four 140-mg Oral Capsule of IMBRUVICA® or as one Single 560-mg Oral Tablet Under Fasted Conditions.
`......................................................................................................................................................................8
`Table 4: Summary of the Statistical Analysis of the Ibrutinib PK Parameters After Single Administration as
`a 140-mg Oral Capsule of IMBRUVICA® or as a 140-mg Oral Tablet Under Fasted Conditions....................8
`
`2
`
`Reference ID: 4206250
`
`

`

`Table 5: Summary of the Statistical Analysis of the Pharmacokinetic Parameters of Ibrutinib After Single
`Administration of Ibrutinib as a Single 560-mg Oral Tablet of Under Fasted and Fed Conditions.............13
`Table 6: Summary of Bioanalytical Methods for Ibrutinib..........................................................................14
`Table 7: Pharmacokinetic Results of Ibrutinib After Single Administration of Ibrutinib as Four 140-mg
`Capsules of IMBRUVICA® or as One Single 560-mg Oral Tablet Under Fasted Condition. .........................15
`Table 8: Pharmacokinetic Results of Ibrutinib After Single Administration of Ibrutinib as a 140-mg Capsules
`of IMBRUVICA® or as a 140-mg Oral Tablet Under Fasted Condition. .......................................................16
`Table 9: Pharmacokinetic Results of Ibrutinib After Single Administration of Ibrutinib as a Single 560-mg
`to-be-marketed Tablet Under Fasted and Fed Conditions.........................................................................17
`
`List of Figures
`
`Figure 1: BTK Occupancy of > 90% at Doses ≥ 2.5 mg/kg in Trial 04753. ...................................................10
`Figure 2: Predicted BTK Occupancy at Steady State after Administration of one 560-mg to-be-marketed
`Tablet and Four 140-mg Capsules Once Daily. ...........................................................................................10
`Figure 3: Dose-response Relationship for ORR in Phase 1 Dose Escalation Trial PCYC-04753. ..................11
`Figure 4: Bar Chart (±99% CIs) of Overall Response Rate in Patients with CLL (Trials 1102, 1112, 1115, 1117,
`CLL3001, 04753 in NDA205552) Classified by Ibrutinib Cmax,ss Quartile......................................................11
`Figure 5: Bar Chart (±99% CIs) of Overall Response Rate in Patients with CLL (Trials 1104, MCL2001,
`MCL3001, 04753 in NDA205552) Classified by Ibrutinib Cmax,ss Quartile....................................................12
`Figure 6: Mean Plasma Concentration-Time Profiles of Ibrutinib After Single Administration of Ibrutinib as
`Four 140-mg Capsules of IMBRUVICA® or as one Single 560-mg to-be-marketed Tablet Under Fasted
`Conditions...................................................................................................................................................15
`Figure 7: Mean Plasma Concentration-Time Profiles of Ibrutinib After Single Administration of Ibrutinib as
`a 140-mg Capsules of IMBRUVICA® or as a 140-mg to-be-marketed Tablet Under Fasted Conditions. ....16
`Figure 8: Mean Plasma Concentration-Time Profiles of Ibrutinib After Single Administration of Ibrutinib as
`a Single 560-mg to-be-marketed Tablet Under Fasted and Fed Conditions...............................................17
`
`Reference ID: 4206250
`
`3
`
`

`

`1. EXECUTIVE SUMMARY
`Ibrutinib (IMBRUVICA®) is approved for the treatment of several B-cell malignancies and chronic graft
`versus host disease (cGVHD). In the current submission, the Applicant seeks the approval of a new tablet
`formulation at dose strengths of 140 mg, 280 mg, 420 mg, and 560 mg.
`
`The Applicant submitted the study results of a relative bioavailability (BA) trial, a food effect trial, and two
`pivotal bioequivalence (BE) trials to support the to-be-marketed tablet formulation in 4 different strengths
`of 140 mg, 280 mg, 420 mg, and 560 mg for ibrutinib.
`
`The review primarily focuses on:
`
`1)
`2)
`
` the bioequivalence between ibrutinib to-be-marketed tablets and current available capsules;
` food effect on to-be-marketed tablets.
`
`The AUC of the to-be-marketed tablet was BE to that of the reference capsule at 140 mg and 560 mg dose
`strength. Although the Cmax of the to-be-marketed tablet was 10.2% lower at 140 mg and 27.7% lower at
`560 mg as compared to the reference capsule formulation, such difference in Cmax is not expected to
`translate clinically meaningful impact on the effectiveness of ibrutinib. The food effect was generally
`comparable between tablet and capsule formulations. Overall, no clinically meaningful difference is
`expected between the reference capsule formulation and the to-be-marketed tablet formulation of
`ibrutinib.
`
`1.1.Recommendations
`The Office of Clinical Pharmacology has reviewed the information submitted. The to-be-marketed tablet
`formulation at dose strengths of 140 mg, 280 mg, 420 mg, and 560 mg is considered approvable from a
`clinical pharmacology perspective. Dosing guidelines regarding food timings for ibrutinib tablets should
`follow the same recommendation for the ibrutinib capsules in the current labeling, i.e., there are no
`restrictions for food consumption when taking ibrutinib tablets or capsules.
`
`1.2.Post-Marketing Requirements and Commitments
`There are no post-marketing requirements or commitments.
`
`Signatures:
`
`Liang Li, Ph.D.
`Clinical Pharmacology Reviewer
`Division of Clinical Pharmacology V
`
`Olanrewaju Okusanya, Pharm.D.; M.S.
`Acting Clinical Pharmacology Team Leader
`Division of Clinical Pharmacology V
`
`Reference ID: 4206250
`
`4
`
`

`

`Cc: DHP:
`DCPV:
`
`RPM – K Miller; MO – M Merino; MTL – T Wroblewski
`DDD – B Booth; DD – NA Rahman
`
`2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT
`
`2.1.Pharmacology and Clinical Pharmacokinetics
`Ibrutinib is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK). IMBRUVICA® (ibrutinib) has been
`approved for the treatment of patients with MCL or MZL at a recommended dose of 560 mg once daily
`(QD) and patients with CLL/SLL, WM or cGVHD at a recommended dose of 420 mg QD. For brevity, only
`information related to the current submission is summarized in Table 1.
`
`Table 1: Summary of the Geometric Mean Ratios and 90% Confidence Intervals of the Ibrutinib PK
`Parameters from a Food Effect Trial and Two Pivotal Bioequivalence Trials.
`
` Test vs. Reference formulaton
`
`1 х 560-mg tablet vs.
`4 х 140-mg capsules
`1 х 140-mg tablet vs.
`1 х 140-mg capsule
`1 х 560-mg tablet under fed
`condition vs. fasted condition
`
`Cmax
`72.3%
`(67.6%, 77.3%)
`89.8%
`(84.2%, 95.7%)
`447.8%
`(369.5%, 542.6%)
`
`GMR (90% CI)
`AUClast
`97.9%
`(94.3%, 101.7%)
`107.2%
`(103.8%, 110.8%)
`197.2%
`(172.6%, 225.4%)
`
`AUCinf
`95.7%
`(91.5%, 100.0%)
`106.8%
`(103.4%, 110.4%)
`188.4%
`(164.5%, 215.7%)
`
`2.2.Dosing and Therapeutic Individualization
`
`2.2.1. General dosing
`The recommended ibrutinib dose is 560 mg for the treatment of patients with MCL or MZL, and 420 mg
`for the treatment of patients with CLL/SLL, WM or cGVHD administered orally once daily as a
`monotherapy with or without food. No new dosing recommendations are provided for this new
`formulation.
`
`2.2.2. Therapeutic individualization
`There is no additional data to support therapeutic individualization in this NDA submission.
`
`2.3.Outstanding Issues
`There are no outstanding issues at this time.
`
`2.4.Summary of Labeling Recommendations
`The ibrutinib tablet formulations at four strengths of 140 mg, 280 mg, 420 mg and 560 mg have been
`updated in the labeling.
`
`5
`
`Reference ID: 4206250
`
`

`

`3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW
`
`3.1.Overview of the Product and Regulatory Background
`Ibrutinib received FDA approvals for the following indications:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`11/13/2013: Accelerated approval for the treatment of patients with MCL who have received
`at least one prior therapy;
`02/12/2014: Accelerated approval for the treatment of patients with CLL who have received at
`least one prior therapy;
`07/28/2014: Full approval for the treatment of patients with CLL who have received at least one
`prior therapy, and approval for the treatment of patients with CLL with 17p deletion;
`01/29/2017: Full approval for the treatment of patients with WM;
`03/04/2016: Full approval for the treatment of patients with CLL;
`05/06/2016: Full approval for the treatment of patients with CLL/SLL, and dosing of ibrutinib with
`bendamustine and rituximab in patients with CLL/SLL; full approval for the treatment of patients
`with CLL/SLL with 17p deletion;
`01/18/2017: Accelerated approval for the treatment of patients with MZL who require systemic
`therapy and have received at least one prior anti-CD20-based therapy;
`08/02/2017: Full approval for the treatment of patients with cGVHD.
`
`In this new NDA submission, the Applicant submitted results of the relative BA trial, the food effect trial,
`and two pivotal BE trials to support the to-be-marketed tablet formulation in 4 different strengths of 140
`mg, 280 mg, 420 mg, and 560 mg for ibrutinib:
`
`
`
`
`
`
`
`
`
`Trial 54179060CLL1018 (hereafter referred to as CLL1018): A Single-Dose, Open-Label,
`Randomized, 4-way Crossover Study to Assess the Relative Bioavailability of Four Ibrutinib Tablet
`Formulations in Healthy Adult Subjects Compared to the Imbruvica Capsule
`Trial 54179060CLL1019 (hereafter referred to as CLL1019): Open-Label, Randomized, 2-way-
`Crossover Study to Determine the Effect of Food on the Pharmacokinetics of Ibrutinib
`Administered as 560-mg Tablet
`Trial 54179060CLL1021 (hereafter referred to as CLL1021): A Single-Dose, Open-Label,
`Randomized, Replicate Crossover Study in Healthy Adult Subjects to Assess the Bioequivalence of
`an Ibrutinib 560-mg Tablet Compared to Four IMBRUVICA 140 mg Capsules
`Trial 54179060CLL1022 (hereafter referred to as CLL1022): A Single-Dose, Open-Label,
`Randomized, Replicate Crossover Study in Healthy Adult Subjects to Assess the Bioequivalence of
`an Ibrutinib 140-mg Tablet Compared to the IMBRUVICA 140-mg Capsule
`
`3.2.General Pharmacological and Pharmacokinetic Characteristics
`Please refer to the IMBRUVICA® labeling and the clinical pharmacology review in the original (DARRTS ID:
`3400137) and supplement (DARRTS ID: 3529464, 3688592, 3887396, 3887396, 3948695, 4028014 and
`4123064) NDA 205552 submissions regarding the detailed PK characteristics of ibrutinib.
`
`6
`
`Reference ID: 4206250
`
`

`

`3.3.Clinical Pharmacology Questions
`For brevity, only questions related to the current submission are addressed below. For additional
`information, please refer to the clinical pharmacology reviews for the original and supplement
`NDA205552 submissions.
`
`3.3.1. Is the to-be-marketed formulation the same as the clinical trial formulation, and if not,
`are there bioequivalence data to support the to-be-marketed formulation?
`
`BE assessment
`The to-be-marketed formulation will be a new film-coated immediate-release tablet dosage form of
`ibrutinib in four strengths (140 mg, 280 mg, 420 mg and 560 mg) manufactured jointly by Catalent CTS,
`LLC and AbbVie Inc. The manufacturing process for the to-be-marketed formulation was developed at
`, and transferred to the commercial manufacturing site Catalent,
`Kansas City, MO and later from Catalent to the second commercial site AbbVie, North Chicago, IL.
`Formulations from Catalent were used in the two BE trials. The Applicant claimed that process
`development studies performed at Catalent and AbbVie have demonstrated that the manufacturing
`process is suitable for the manufacture of commercial batches using the established manufacturing
`process parameters.
`
`
`In the relative BA Trial CLL1018, four different experimental 560-mg tablet formulations
` were selected for
`evaluation against the commercial 140-mg capsule in healthy subjects under fasted conditions at a single
`dose of 560 mg (Table 2). Results from the trial demonstrated that exposures for Formulation D were
`closest to the reference capsule formulation as evidenced by a GMR (90% CI) of the test to the reference
`of 91.8% (74.6%, 112.8%) for Cmax, 106.6% (94.4%, 120.5%) for AUClast, and 110.2% (94.9%, 128.0%) for
`AUC0-inf. As such, Formulation D was selected for evaluation in the food effect trial and two pivotal BE trials
`in healthy subjects.
`
`Table 2: Identity of Study Ibrutinib Formulations.
`
`Source: Table 1 from Clinical Study Report 54179060CLL1018.
`
`Two formal BE trials CLL1021 and CLL1022 were performed to compare the PK of the to-be-marketed
`tablet to the reference capsule at the lowest strength of 140 mg and the highest strength of 560 mg in
`healthy subjects under fasted conditions.
`
`7
`
`Reference ID: 4206250
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`In Trial CLL1021, the GMR (90% CI) of one 560-mg to-be-marketed tablet (test) vs. four 140-mg ibrutinib
`capsules (reference) was 97.9% (94.3% - 102%) for AUClast and 95.7% (91.5% - 100%) for AUC0-inf (Table 3).
`The 90% CIs of the GMR for both AUClast and AUCinf fell completely within the 80.0% to 125.0% BE limits.
`However, the GMR (90% CI) between two treatments for Cmax was 72.3% (67.6% - 77.3%), with the 90% CI
`of the GMR falling well below the 80.0% BE lower boundary limit.
`
`Table 3: Summary of the Statistical Analysis of the Ibrutinib PK Parameters After Single Administration
`as Four 140-mg Oral Capsule of IMBRUVICA® or as one Single 560-mg Oral Tablet Under Fasted
`Conditions.
`
`Source: Applicant’s Table 4 from Clinical Study Report 54179060CLL1021.
`
`In Trial CLL1022, the GMR (90% CI) of 140-mg to-be-marketed tablet (test) vs. 140-mg ibrutinib capsule
`(reference) was 89.8% (84.2% - 95.6%) for Cmax, 107.2% (103.8% - 110.8%) for AUClast and 106.8% (103.4%
`- 110.4%) for AUC0-inf (Table 4). The 90% CIs of the GMR fell completely within the 80.0% to 125.0% BE
`limits.
`
`Table 4: Summary of the Statistical Analysis of the Ibrutinib PK Parameters After Single Administration
`as a 140-mg Oral Capsule of IMBRUVICA® or as a 140-mg Oral Tablet Under Fasted Conditions.
`
`Reference ID: 4206250
`
`8
`
`

`

`Source: Applicant’s Table 4 from Clinical Study Report 54179060CLL1022.
`
`In both Trial CLL1021 and CLL1022, ibrutinib 140-mg and 560-mg tablets were associated with an
`acceptable safety profile after single dose administration in healthy subjects. There were no deaths or
`serious adverse events reported in both trials. The observed safety findings in the trials were consistent
`with the known safety profile of ibrutinib under NDA 205552 and no new or unanticipated safety concerns
`were identified.
`
`Clinical Relevance of Cmax
`Although a mean 27.7% lower Cmax was observed for the 560-mg tablet compared to four 140 mg capsules
`in Trial CLL1021, this difference in Cmax is not expected to translate clinically meaningful impact on the
`effectiveness of ibrutinib because of the following reasons:
`
` Maximum BTK occupancy achieved at doses 2.5 mg/kg and above
`
`The dose-response relationship for BTK occupancy (Figure 1) in the Phase 1 dose escalation Trial PCYC-
`04753 showed that maximum BTK occupancy was achieved at doses of ≥ 2.5 mg/kg (≥ 175 mg for patients
`with an average weight of 70 kg). In addition, as shown in Figure 2, the predicted steady-state BTK
`receptor occupancy versus time profiles for the 560-mg to-be-marketed tablet overlapped with that for
`the 560 mg (4 x 140-mg) capsule, with nearly identical BTK receptor occupancy of 96% for the tablet
`formulation and 97% for the capsule formulation at the peak concentrations.
`
`Reference ID: 4206250
`
`9
`
`

`

`Figure 1: BTK Occupancy of > 90% at Doses ≥ 2.5 mg/kg in Trial 04753.
`
`Source: Applicant’s Figure 10 from Clinical Study Report PCYC-04753.
`
`Figure 2: Predicted BTK Occupancy at Steady State after Administration of one 560-mg to-be-marketed
`Tablet and Four 140-mg Capsules Once Daily.
`
`Source: Applicant’s Figure 2 from Summary of Clinical Pharmacology Studies.
`
`Flat dose- and exposure-response relationship for clinical response at doses 2.5 mg/kg and
`above
`
`
`
`The flat dose-response relationship for clinical primary efficacy endpoint, overall response rate (ORR), was
`achieved at doses of ≥ 2.5 mg/kg (≥ 175 mg for patients with an average weight of 70 kg) in the Phase 1
`dose escalation Trial PCYC-04753 (Figure 3). The exposure-response relationships between ibrutinib Cmax
`and ORR were also found flat across 4 quartiles ranging from lowest to highest Cmax in patients with CLL at
`the recommended dose of 420 mg once daily (Figure 4) and in patients with MCL at the recommended
`
`10
`
`Reference ID: 4206250
`
`

`

`dose of 560 mg once daily (Figure 5). This suggests that small differences in Cmax between the two
`formulations are not expected to have a significant impact on efficacy.
`
`Figure 3: Dose-response Relationship for ORR in Phase 1 Dose Escalation Trial PCYC-04753.
`
`Source: Reviewer’s Figure 4 from Clinical Pharmacology Review for Original NDA 205552 (Reference ID: 3400137).
`
`Figure 4: Bar Chart (±99% CIs) of Overall Response Rate in Patients with CLL (Trials 1102, 1112, 1115,
`1117, CLL3001, 04753 in NDA205552) Classified by Ibrutinib Cmax,ss Quartile.
`
`Source: Applicant’s Figure 4 from Summary of Clinical Pharmacology Studies.
`
`Reference ID: 4206250
`
`11
`
`

`

`Figure 5: Bar Chart (±99% CIs) of Overall Response Rate in Patients with CLL (Trials 1104, MCL2001,
`MCL3001, 04753 in NDA205552) Classified by Ibrutinib Cmax,ss Quartile.
`
`Source: Applicant’s Figure 5 from Summary of Clinical Pharmacology Studies.
`
`Comparable Cmax for 560-mg tablet and four 140-mg capsules under fed conditions
`
`
`
`Although ibrutinib is recommended taken regardless of food, it is unlikely administered repeatedly under
`fully fasted conditions (fasting overnight and until 4 hours after ibrutinib administration) in a real clinical
`setting. The food effect Trial, CLL1019, demonstrated that the effect of food was more pronounced on
`Cmax for the tablet with the GMR of fed vs. fasted of 4.5 compared to the capsule with a GMR of 3.1
`(Section 3.3.2). These differences in food effect between the tablet and capsule formulaton translate to
`a 2% difference in Cmax under fed conditions between the 2 formulations based on the cross-study
`comparision of the food effect GMRs for Cmax for tablet (Trial CLL1019) and for capsule (Trial CLL1001
`under NDA 205552). As such, the difference in Cmax observed between the tablet and capsule formulations
`when ibrutinib is given fasted is not expected when given with food.
`
`Comparable Ctrough for 560-mg tablet vs. four 140-mg capsules
`
`
`
`The GMR (90% CI) of trough concentrations (Ctrough) for 560-mg tablet vs four 140-mg capsules after single
`dose administration in Trial CLL1021 was estimated to be 108.8% (101.7%, 116.2%). This indicates that
`the tablet formulation would produce comparable ibrutinib trough concentrations as the capsule
`formulation, and hence is expected to maintain a similar minimum BTK occupancy compared to the
`capsule formulation.
`
`3.3.2. Are there clinically relevant food-drug interactions for the to-be-marketed formulation
`and what is the appropriate management strategy?
`
`Yes. high-fat, high-caloric breakfast had statistically significant interaction with the to-be-marketed 560-
`mg tablet based on the assessment in Trial CLL1019. As shown in Table 5, administration of a single dose
`12
`
`Reference ID: 4206250
`
`

`

`of 560-mg tablet with a high-fat, high-caloric meal resulted in 4.5-fold higher in Cmax, 1.9-fold to 2.0-fold
`higher in AUC compared to administration under fasted condition. This fold change in exposure is
`generally consistent with the 2-fold to 4-fold higher Cmax and 2-fold higher AUC observed with food with
`the capsule formulation in Trial CLL1001 under NDA 205552.
`
`Table 5: Summary of the Statistical Analysis of the Pharmacokinetic Parameters of Ibrutinib After Single
`Administration of Ibrutinib as a Single 560-mg Oral Tablet of Under Fasted and Fed Conditions.
`
`Source: Applicant’s Table 6 from Clinical Study Report CLL1019.
`
`The safety results from Trial CLL1019 confirmed that ibrutinib 560-mg tablet under fed condition had an
`acceptable tolerability profile in healthy subjects. No new or unanticipated safety signals were identified.
`Therefore, dosing guidelines regarding food timings for ibrutinib tablet formulations should follow the
`same recommendation for the capsule formulation in the current labeling, i.e., there are no restrictions
`for food consumption when taking ibrutinib tablets or capsules.
`
`
`
`Reference ID: 4206250
`
`13
`
`

`

`4. APPENDICES
`
`4.1.Summary of Bioanalytical Method Validation and Performance
`Plasma samples were analyzed for concentrations of ibrutinib via a validated liquid chromatography-
`tandem mass spectrometry method
` which was the same bioanalytical
`method used in prior original and supplement NDA 205552 submissions. The bioanalytical method was
`adequately validated with a calibration range of 0.5 ng/mL to 250 ng/mL for both ibrutinib and PCI-45227
`(dihydrodiol metabolite), and was demonstrated long-term storage stability for samples in the current
`trial. Table 6 is a summary of bioanalytical report and corresponding bioanalytical method performance
`for Trial CLL1018, CLL1019, CLL1021 and CLL1022.
`
`Table 6: Summary of Bioanalytical Methods for Ibrutinib.
`
`Matrix
`Plasma
`
`Trial No.
`54179060CLL1018
`54179060CLL1019
`54179060CLL1021
`54179060CLL1022
`
`Bioanalytical Report Bioanalytical method performance
`JNJ-R5932
`Method BTM-2201-R0
`Lower limit of quantification: 0.5 ng/mL
`Calibrated Range: 0.5 to 250 ng/mL
`Intra-assay Precision (%CV): 4.1% to 5.8%
`Intra-assay Accuracy (% Diff): -11.2% to -0.9%
`Bench Top Stability: 6 hours at RT
`Long-term Stability: 328 days at -20 °C and -
`70 °C
`Free thaw stability: 3 freeze (-70 °C)/thaw (ice
`water bath or room temperature) cycles
`
`4.2.Clinical PK and/or PD Assessments
`
`The current submission provided PK data of ibrutinib in healthy subjects after single administration of
`ibrutinib as four 140-mg capsules or as one single 560-mg to-be-marketed tablet under fasted condition
`in Trial 1021, as a 140-mg capsules or as a 140-mg to-be-marketed tablet under fasted condition in Trial
`1022, and as a single 560-mg to-be-marketed tablet under fasted and fed conditions.
`
`4.2.1. Trial 1021
`The mean plasma concentration-time profiles of ibrutinib for both treatments in Trial 1021 are presented
`in Figure 6, and the summary list of key PK parameters is presented in Table 7. Compared to the
`IMBRUVICA® capsules (reference), oral administration of the 560-mg to-be-marketed tablet (test)
`resulted in lower peak plasma concentrations. Mean Cmax values were 38.3 ng/mL for the test formulation
`and 51.9 ng/mL for the reference formulation. Mean AUClast, AUCinf, apparent terminal half-life (t1/2), and
`median tmax values were comparable for both treatments.
`
`14
`
`Reference ID: 4206250
`
`(b) (4)
`
`(b) (4)
`
`

`

`Figure 6: Mean Plasma Concentration-Time Profiles of Ibrutinib After Single Administration of Ibrutinib
`as Four 140-mg Capsules of IMBRUVICA® or as one Single 560-mg to-be-marketed Tablet Under Fasted
`Conditions.
`
`Source: Applicant’s Figure 2 from Clinical Study Report CLL1021.
`
`Table 7: Pharmacokinetic Results of Ibrutinib After Single Administration of Ibrutinib as Four 140-mg
`Capsules of IMBRUVICA® or as One Single 560-mg Oral Tablet Under Fasted Condition.
`
`Source: Applicant’s Table 3 from Clinical Study Report CLL1021.
`
`4.2.2. Trial 1022
`The mean plasma concentration-time profiles of ibrutinib for both treatments in Trial 1022 are presented
`in Figure 7. The ibrutinib plasma concentrations declined in parallel for both treatments. The summary
`list of key PK parameters is presented in Table 8. Oral administration of the 140-mg to-be-marketed tablet
`(test) resulted in comparable mean Cmax, AUClast, AUCinf, apparent terminal half-life (t1/2), and median tmax
`values compared to the IMBRUVICA 140-mg capsule (reference).
`
`15
`
`Reference ID: 4206250
`
`

`

`Figure 7: Mean Plasma Concentration-Time Profiles of Ibrutinib After Single Administration of Ibrutinib
`as a 140-mg Capsules of IMBRUVICA® or as a 140-mg to-be-marketed Tablet Under Fasted Conditions.
`
`Source: Applicant’s Figure 2 from Clinical Study Report CLL1022.
`
`Table 8: Pharmacokinetic Results of Ibrutinib After Single Administration of Ibrutinib as a 140-mg
`Capsules of IMBRUVICA® or as a 140-mg Oral Tablet Under Fasted Condition.
`
`Source: Applicant’s Table 3 from Clinical Study Report CLL1022.
`
`4.2.3. Trial 1019
`The mean plasma concentration-time profiles of ibrutinib for both treatments in Trial 1019 are presented
`in Figure 8. The mean PK profiles showed that the peak plasma concentration occurred later but was
`higher under fed compared to fasted condition, with maximum peak levels achieved at 4 and 1 hour,
`respectively. The summary list of key PK parameters is presented in Table 9. Compared to a single 560-
`mg to-be-marketed tablet under fasted condition, oral administration under fed conditions resulted in
`higher peak plasma concentrations (183 ng/mL vs. 49.0 ng/mL), longer median tmax (4 hr vs. 1.3 hr), higher
`16
`
`Reference ID: 4206250
`
`

`

`AUClast (743 ng∙h/mL vs. 426 ng∙h/mL), higher AUCinf (750 ng∙h/mL vs. 460 ng∙h/mL), and slightly shorter
`mean t1/2 (6.4 hr vs. 8.4 hr).
`
`Figure 8: Mean Plasma Concentration-Time Profiles of Ibrutinib After Single Administration of Ibrutinib
`as a Single 560-mg to-be-marketed Tablet Under Fasted and Fed Conditions.
`
`Source: Applicant’s Figure 1 from Clinical Study Report CLL1019.
`
`Table 9: Pharmacokinetic Results of Ibrutinib After Single Administration of Ibrutinib as a Single 560-mg
`to-be-marketed Tablet Under Fasted and Fed Conditions.
`
`Source: Applicant’s Table 5 from Clinical Study Report CLL1019.
`
`Reference ID: 4206250
`
`17
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LIANG LI
`01/12/2018
`
`OLANREWAJU OKUSANYA
`01/16/2018
`
`Reference ID: 4206250
`
`