CENTER FOR DRUG EVALUATION AND '
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-880
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEWg S 2
`
`

`

`Clinical Pharmacology and Biopharmaceutics NDA Review
`
`Brand name: REVLIMID®
`
`Generic name: Lenalidomide
`
`Type of dosage form and strength(s): 5 and 10 mg capsules
`
`for the treatment of patients
`the Applicant’s proposed indication is,
`[ndication(s):
`with transfusion—dependent anemia due to low— or intermediate—l-risk myelodysplastic
`syndromes associated with a deletion Sq cytogenetic abnormality with or without
`additional cytogenetic abnormalities.”
`
`NDA number, type: NDA 21—880, 1P
`
`Applicant name: Celgene Corporation
`
`Submission date (letter date):
`
`15—AUG—2005 N 000 B2
`
`12—AUG—2005 N 000 BM
`
`10-AUG—2005 N 000 BS
`
`5-AUG—2005 N 000 SU
`
`24—JUN—2005 _N 000 BM
`
`l—JUN-2005 N 000 BM
`
`17—MAY—2005 N 000 BC
`
`7—APR-2005 N 000
`
`22—DEC—2004 RRZ 001
`
`OCPB Division name: Division of Pharmaceutical Evaluation I
`
`0ND: Division name: Division of Oncologic Drug Products
`
`OCPB Reviewer name: Gene M. Williams, PhD.
`
`OCPB Team Leader name: Brian P. Booth, PhD.
`
`
`
`Table of Contents
`
`'1
`
`Executive Summary
`
`I. 1
`
`1.2
`
`Recommendations
`
`Phase 4 Commitments
`
`Page
`
`' 3
`
`3 _
`
`

`

`1.3
`
`Summary ofImportant Clinical Pharmacology and
`Biopharmaceutics Findings
`
`Question Based Review
`
`2.1
`
`2.2
`
`2.3
`
`2.4
`
`2.5
`
`2. 6
`
`General Attributes ofthe Drug
`
`General Clinical Pharmacology
`
`Intrinsic Factors
`
`7
`
`Extrinsic Factors
`
`General Biopharmaceutics
`
`Analytical Section
`
`Detailed Labeling Recommendations
`
`Appendices
`
`4. I
`
`4.2
`
`Proposed Package Insert (Original)
`
`Cover Sheet and OCPB Filing/Review Form
`
`Apnea
`On 0.
`
`21
`
`25 '
`
`28
`
`35
`
`37
`
`45
`
`

`

`1. Executive Summary
`
`A single commitment for clinical pharmacology and biopharrnaceutics is recommended.
`
`1. 1. Recommendations
`
`This NDA is acceptable from the clinical pharmacology and biopharrnaceutics
`perspective.
`
`1.2. Identify recommended Phase 4 study commitments if the NDA is judged
`approvable
`
`Approximately 2/3 of lenalidomide is excreted as unchanged drug in urine following
`Revlimid dosing. In multiple myeloma patients with mild renal impairment, exposure
`(plasma AUC) was 56% higher than in multiple myeloma patients with normal renal
`function who received the same dose. Based on these data, we recommend that a study be
`conducted to determine the pharmacokinetics of lenalidomide in subjects with renal
`impairment. The study design should be consistent with the FDA Guidance,
`"Pharmacokinetics in Patients with Renal Impairment."
`
`1.3 Summary of Clinical Pharmacology and Biopharmaceutics Findings (1-3
`pageS)
`
`. Lenalidomide is structurally similar to the teratogenic drug thalidomide.
`
`Following oral administration, maximum lenalidomide plasma concentrations occur from
`0.5 - 4 hours post-dose. (Io-administration with food does not alter the extent of
`absorption. Half—life of lenalidomide elimination is approximately 3 hours and the
`phannacokinetic disposition of lenalidomide is, at doses up to 10X the recommended
`clinical dose of 10 mg, linear. Approximately two—thirds of lenalidomide is eliminated
`unchanged through urinary excretion. The process exceeds the glomerular filtration rate
`and therefore entails an active component. In mutliple myeloma patients with mild renal
`impairment, AUCs were 56% higher than in similar patients with normal renal function.
`
`A search for circulating lenalidomide metabolites in human biomaterials (plasma, urine
`or feces) was not performed.
`
`Results from human in vitro metabolism studies show that lenalidomide is not
`
`metabolized through the cytochrome P450 pathway. Human in vitro metabolism studies
`also show that lenalidomide does not inhibit or induce cytochromes P450.
`
`The pharmacokinetics of lenalidomide in patients with renal impairment or hepatic
`impairment have not been systematically studied. The effects of age on the
`pharmacokinetics of lenalidomide have not been studied. No pharmacokinetic data are
`available in patients below the age of 18 years. The effects of gender on the
`pharmacokinetics of lenalidomide have not been studied. Pharmacokinetic differences
`due to race have not been studied.
`
`

`

`Lenalidomide is a BCS Class 3 (high solubility — low permeability) substance. Based on
`the compositional proportionality of the strengths, the dosing regimen used in clinical
`trials, pharamacokinetic linearity, and comparative dissolution profiles, the Applicant
`requests and will be granted a waiver for an in vivo bioequivalence study comparing the
`5 mg capsule strength studied in efficacy and safety studies and the 10 mg strength which
`will be marketed, in addition to the 5 mg strength.
`
`2. Question-Based Review
`
`2.1. General attributes ofthe drug
`
`What pertinent regulatory background or history contributes to the current
`assessment of the clinical pharmacology and biopharrnaceutics of this drug?
`
`REVLIMID® for the treatment of transfusion dependent MDS'(the current indication) has
`been granted Orphan Drug status.
`
`2.1.1. What are the highlights of the chemistry and physical-chemical properties
`of the drug substance and the formulation of the drug product as they relate
`to clinical pharmacology and biopharrnaceutics review?
`
`The active ingredient in the drug product is lenalidomide (CC-5013, CDC—501). lts
`International Union of Pure and Applied Chemistry (IUPAC) name is 3—(4’—amino—l —
`oxo—l,3-dihydro—2H—isoindol—2—yl)piperidine—2,6-dione. a structural representation is
`shown below as FDA Figure 1A. To allow comparisons; a structural representation of
`thalidomide is included as FDA Figure 1B.
`
`FDA Figure l.
`
`A. Lenalidomide -- Applicant’s Section 1.2 from p. 1 of the Quality Overall
`Summary (Section 2.3.8)
`
`H
`N
`
`,
`
`_
`
`O
`
`office
`
`NH:
`
`'
`
`,
`
`B. Thalidomide — Package insert for THALOMID®
`
`0
`
`0
`
`N ‘
`
`H
`N
`
`,
`
`.
`
`O
`
`_
`
`0
`
`Note: - = asymmetric carbon atom
`
`

`

`The molecular formula for lenalidomide is C13H13N303 and the molecular weight is
`. 259.25 grams per mole. Lenalidomide has an asymmetric carbon atom and can therefore
`exist as the optically active forms S(—) and R(+). The drug substance is produced as a
`
`racemic mixture with a net optical rotation of zero. '
`
`
`A Lenalidomide is generally more soluble in organic than
`aqueous solvents, but exhibits the greatest solubility in 0.1N HCl buffer with an
`equilibrium solubility of 18 mg/mL- Solubility was significantly lower in less acidic
`buffers, ranging from about 0.4 to 0.5 mg/mL.
`
`The dosage form is an opaque hard gelatin capsule; the 5 mg strength is a size 2 capsule
`and the 10 mg strength is a size 0 capsule. The inactive ingredients of lenalidomide
`capsules are anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and
`magnesium stearate.
`
`2.1.2. What are the proposed mechanism(s) of action and therapeutic
`indication(s)?
`
`The proposed effects of lenalidomide on biological processes are summarized below. The
`relationship between lenalidomide’s effects on biological processes and its therapeutic
`effect is unknown.
`
`Lenalidomide inhibits the secretion of pro—inflammatory cytokines including tumor
`necrosis factor a (TNF-a), interleukin 1B (IL-lfi), and IL—6 and IL—12 from lipoprotein
`polysaccharide stimulated (LPS—stimulated) peripheral blood mononuclear cells
`(PBMCs). Lenalidomide increases production of the anti—inflammatory cytokine IL— I 0
`from LPS—stimulated PBMC, and consequently inhibits the expression but not the
`enzymatic activity of cyclooxygenase-2 (COX-2).
`
`Lenalidomide induces T—cell proliferation and IL-2 and IFN—y production, and augments
`cytotOxic activity of natural killer cells.
`
`Lenalidomide inhibits the proliferation of various hematopoietic tumor cell lines, in
`particular those with cytogenetic defects of chromosome 5. Anti—proliferative effects
`have been observed in MM.IS multiple myeloma7 and Farage non—Hodgkin’s lymphoma
`cell lines in vitro. Lenalidomide inhibits the VEGF-induced clonogenic response and
`signaling through Akt in KG—l chromosome 5— acute myeloid leukemia cells. In
`Namalwa chromosome 5- Burkitt’s lymphoma cells, lenalidomide inhibits cell cycle
`progression and blocks signaling through Gab-l and Akt.
`
`Lenalidomide induces fetal hemoglobin expression upon CD34+ hematopoietic stem cell
`differentiation in a model of erythroid progenitor differentiation.
`
`Lenalidomide inhibits angiogenesis by blocking the formation of microvessels and
`endothelial cell tubes as well as the migration of endothelial cells in in vitro angiogenesis
`
`

`

`models. Lenalidomide also inhibits production of the pro-angiogenic factor VEGF
`production by PC-3 prostate tumor cells.
`
`The proposed package insert gives the following indication. “REVLlMlD® is indicated
`for the treatment of patients with transfusion—dependent anemia due to low- or
`intermediate—l-risk myelodysplastic syndromes associated with a deletion Sq cytogenetic
`abnormality with or without additional cytogenetic abnormalities.”
`
`2.1.3. What are the proposed dosage(s) and route(s) of administration?
`
`The recommended starting dose of REVLIMID® is 10 mg once daily. A scheme for
`titrating dose in patients who experience certain hematologic toxicities is included in the
`package insert and is reproduced below (indent, font change).
`
`Dose Adjustments During Treatment:
`Patients who are dosed initially at 10 mg and who experience thrombocytopenia that
`develops within the first 4 weeks of starting REVLlMlD® therapy should have their
`dosage adjusted as follows:
`'
`
`.
`
`. . For patients with a baseline platelet count 2100,000/uL, hold REVLlMlD®
`when the platelet count falls to <50,000/uL. REVLlMlD® treatment may be
`resumed at 5 mg/day when the platelet count recovers to 250,000/uL.
`For patients with a baseline platelet count <100,000/uL, hold REVLlMlD®
`when the platelet count falls by 50% of the baseline value. REVLlMlD®
`treatment may be resumed at 5 mg/day when the platelet count recovers to
`250,000/uL for patients whose baseline platelet count was 260,000/uL and
`to 230,000/uL for patients whose baseline platelet count was <60,000/uL.
`
`Patients who are dosed initially at 10 mg and who experience neutropenia that develops
`within the first 4 weeks of starting REVLlMlD® therapy should have their dosage
`adjusted as follows:
`-
`For patients with a baseline ANC 21,000/uL, hold REVLlMlD® when the
`ANC falls to <750/uL. REVLlMlD® treatment may be resumed at 5 mg/day
`when the ANC recovers t0 21,000/uL.
`
`For patients with a baseline ANC <1 ,OOOIuL, hold REVLlMlD® when the ANC falls to
`<500/uL. REVLlMlD® treatment may be resumed at 5 mg/day when the ANC recovers to
`ZSOO/uL
`'
`
`Patients who experience thrombocytopenia after the first 4 weeks of REVLlMlD® therapy
`should have their dosage adjusted as follows:
`0
`If platelet count is < 30,000/uL or platelet count is < 50,000/uL and the
`patient requires platelet transfusions, hold REVLlMlD®. Resume treatment
`at 5 mg/day when platelet count is Z 30,000/uL (without hemostatic failure).
`
`Patients who experience neutropenia after the first 4 weeks of therapy should have their
`dosage adjusted as follows:
`7
`.
`If ANC is < 500/uL for 2 7 days or ANC is < 500/uL associated with fever
`(temperature 2 38.5 ‘fC), hold REVLlMlD®. Resume treatment at 5 mg/day when
`ANC 2 500/pL.
`
`

`

`2.2. General clinical pharmacology '
`
`2.2.1 What are the design features of the clinical pharmacology and clinical
`studies used to support closing or claims?
`
`Support for the efficacy of lenalidomide for the desired indication comes from 2 studies,
`Study MDS-501-001 (MDS—001) and Study CC-5013-MDS—003 (MDS—003). The
`primary study is MDS—003.
`
`MDS—001 was a Phase 1/2, open—label, single-am, 2—stage, dose-finding study of the
`safety and efficacy of lenalidomide for the treatment of subjects with MDS. Based on the
`prior determination that 25 mg/day was the maximum tolerated dose (Study CDC—501—
`001), the initial starting dose of lenalidomide1n this study was 25 mg daily, and the first
`13 subjects who were enrolled1n the study were treated with this dose. Although
`erythroid responses were achieved within 16 weeks, a high incidence of neutropenia and
`thrombocytopenia was observed within the first 4 to 8 weeks of treatment- As a result of
`these findings, the protocol was amended to study 2 lower—dose regimens in sequential
`order: 1) a “continuous regimen” in which 10 mg of lenalidomide was administered daily
`without a planned rest, and 2) a “syncopated” regimen in which 10 mg of lenalidomide
`was administered on Days 1 through 21 of repeated 28-day cycles. Twelve subjects were
`treated with the 10——mg continuous regimen, and, although erythroid responses were
`observed, the median time to dose—limiting neutropenia or thrombocytopenia was found
`to be 13 weeks. Based on these safety findings, enrollment into the 10-~mg syncopated
`regimen was initiated. After 3 erythroid responses were observed among the first 5
`subjects who were treated with the 10——mg syncopated dosing regimen, an additional 15
`subjects were enrolled1n that group to gain fiuther clinical experience with the
`syncopated regimen
`
`Study MDS—003 was a Phase 2, multicenter, open- label, single——arm study of the efficacy
`and safety of lenalidomide when administered at a dose of 10 mg daily either as a
`“syncopated” (i. e. ,administration of 10 mg/day of lenalidomide on Days 1 2-1 of repeated
`28—day cycles) or “continuous” (administration of 10 mg/day of lenalidomide without a
`planned rest) regimen to subjects with an IPSS diagnosis of low— or intermediate—l-risk
`MDS and an associated del 5 (q31—33) cytogenetic abnormality (as an isolated finding or
`associated with other cytogenetic abnormalities) and RBC—transfusion—dependent anemia.
`Based on preliminary data from the pilot study (Study MDS—001), the first 45 enrolled
`subjects were treated with the 10-mg syncopated dosing regimen. However, after
`additional information from the pilot study suggested that the onset of response was more
`‘rapid with the 10-mg continuous dosing regimen than with the 10—mg syncopated
`regimen, without additional safety concerns, the 10-mg continuous dosing regimen was
`adopted, and 103 subjects were enrolled in the study and treated with the continuous
`dosing regimen.
`
`Neither Study MDS—001 nor Study MDS—003 was designed or powered to prospectively
`compare the efficacy of the lenalidomide regimens. A comparison of the outcomes
`
`

`

`
`
`
`
`AdooeiQISSOd1598
`
`.
`
`associated with the “syncopated” and “continuous” regimens in Study MDS—003 is
`shown in the Applicant’s Table 13 which is reproduced below as FDA Table 1.
`
`FDA Table l. Applicant’s Table 13 from p. 28 of the Summary of Clinical Efficacy
`(Section 2.7.3)
`
`Table 13.
`
`Summary of Efficacy Variables by Initial Lenalidemide Regimen and
`Overall in Study MDS—003 ()I'IITT Population)
`
`Efficacy Parameter’
`1.0 Cont
`0v re 1
`65.1% [41.5633RBC—transfusion Independenee= 51.6% (16,1313
`
`Hedian Change From Baseline in Hemoglobin
`5.5
`5.4
`at Maximum value Dunn: Ree onse Period
`":50: Reduction in Pretreatment RBC
`~
`-
`Transfusion Requrrenents
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`Betta Source: Stu-'35" MDS-003, Table 14‘2.1.3 Table 14.2.4.3... 14.2.1.6, and
`Table .1425. 35
`the 1.5 September 200:1 data cutoff date.
`‘ Reeulte rep-regent data anailable as of
`The absence of an": RBC transfusion during any consecutive rolling 55 days in the
`evaluation period and an increase in hemoglobin of at least 1 gg‘dL frcm the minimum
`during the 55 days prior to the maximum during the. transfusion—independent period,
`excluding the first 30 days after the last transfusion before the transfusion-free
`period.
`'
`those
`Based in subjects who were evaluable for cytogenetic response at baseline ti.e.,
`who had at least 20 analyzable metaphaeee at baseline when using conventional cytogenetic
`techniques. Major response — no detectable cytogenetic abnormality if a preexisting
`abnormalityr Has presenz. Minor response - 250%: reduction in the percent of abnormal
`metaphasea.
`
`2.2.2 What is the basis for selecting the response endpoints (i.e., clinical or
`surrogate endpoints) or biomarkers (collectively called pharmacodynamics (PD))
`and how are they measured in clinical pharmacology and clinical studies?
`
`The primary efficacy endpoint in Study MDS-003 is RBC—transfusion independence,
`defined as the absence of any intravenous, RBC transfirsion during any consecutive 56
`days during the treatment period accompanied by at least a l g/dL increase from
`screening/baseline in Hgb. The primary efficacy endpoint of RBC—transfusion
`independence and the secondary efficacy endpoints of the frequency of subjects with a
`250% decrease from baseline in RBC transfusion requirements, platelet response,
`neutrophil response, bone marrow response, cytogenetic response, and duration of
`transfusion independence were assessed based on the criteria set forth by the MDS
`International Working Group (IWG) (Cheson et al, 2000). The change from baseline in
`Hgb concentration (which is not required by IWG criteria for the assessment of
`transfusion independence) was added as an additional criterion for response to further
`quantify and confirm transfusion independence.
`
`

`

`2.2.3 Are the active moieties in the plasma (or other biological fluid)
`appropriately identified and measured to assess pharmacokinetic parameters and
`exposure response relationships?
`
`The performance of the bioanalytical methods will be reviewed in Section 2.6.
`
`The NBA has no data regarding a search for the presence of metabolites in human
`matrices ex vivo. Twenty—one — 43% of an administered dose of 5 - 20 mg was not
`excreted in urine over a 48 hour period (see Section 2.2.5.7). The fate of the un—
`recovered dose (e.g., excretion in feces prior to or subsequent to absorption, excretion in
`urine as metabolites, or extended residence in tissues) is unknown. Thus, unidentified
`metabolites may be present.
`
`Lenalidomide is structurally similar to thalidomide. Administration of thalidomide is
`known to result in circulating thalidomide—derived moieties. The activity of these
`moieties is not known.
`
`2.2.4 Exposure—response
`
`What are the characteristics of the exposure—response relationships
`2.2.4.]
`(dose—response, concentration—response) for eflicacy? If relevant, indicate the
`time to the onset and offset of the desirable pharmacological response or.
`clinical endpoint.
`
`Clinical studies assessing the relationship between exposure and efficacy were not
`performed. The basis of the proposed package insert dosing recommendations is
`presented in Section 2.2.1 ._Pharmacokinetics data were not collected in Study MDS-OO].
`Except for the drug interaction sub—study, pharmacokinetics data were not collected in
`Study MDS—003.
`
`2.2.4.2 What are the characteristics of the exposure-response relationships
`(dose-response, concentration-response) for safety? If relevant, indicate the
`time to the onset and offset of the undesirable pharmacological response or
`clinical endpoint.
`
`Clinical studies assessing the relationship between exposure and safety were not
`performed. The basis of the proposed package insert dosing recommendations is
`presented in Section 2.2.1. Pharmacokinetics data were not collected in Study MDS-OOI.
`Except for the drug interaction sub—study, pharmacokinetics data were not collected in
`Study MDS—003.
`
`Does this drug prolong the QT or QTc interval? (You must ansiver
`2.2.4.3
`this question, unless this is addressed in the question above.)
`
`Neither a thorough QTc study nor a pilot study designed to assess any effects of
`lenalidomide on QT—interval were performed.
`
`

`

`A search for the letters “qt” in the‘Summary of Clinical Safety identifies three
`occurrences, all of which are part of the same sentence. The sentence is part of the
`summary for study 1398/ 180 (A Phase I, single—blind, placebo—controlled, oral dose,
`safety, tolerability, phannacodynamic and pharrnacokinetic study in healthy, male
`subjects), and is reproduced below (indent, font change).
`
`“ECGs were reviewed by an independent cardiologist who reported no conclusive effect of
`lenalidomide (CC-5013) in prolonging QTc and no clinically significant prolongation of QT or
`QTc interval throughout the study.“
`
`Is the dose and dosing regimen selected by the sponsor consistent
`2.2.4.4
`with the known relationship between dose—concentration-response, and are
`there any unresolved dosing or administration issues?
`
`The relationship between dose—concentration and response is largely unknown. The
`currently recommended 10 mg'dose requires frequent dose reductions (approximately
`80% of patients), suggesting that higher doses are not prudent. The efficacy of lower
`doses is unknown. Determination of an optimal dose is an unresolved dosing issue.
`
`2.2.5 What are the PK characteristics of the drug and its major metabolite?
`
`2.2.5.1 What are the single dose and multiple dose PK parameters? (Provide
`tables to refer to in subsequent questions in this section.)
`
`FDA Table 2. (Applicant’s Table 12., following page) summarizes the phannacokinetics
`of lenalidomide. FDA Figures 2. and 3. (Applicant’s Figures 8. and 9., following FDA
`Table 2.) show cencentration—time profiles following single and multiple doses.
`
`On both the first day and 28 days after once daily dosing of 5 — 50 mg, plasma
`concentrations reached a maximum at 1.0 to 1.5 hours post—dose. The elimination half—
`life of lenalidomide (CC-5013) ranged from 3 to 4 hours on Days 1 and 28 at all doses.
`As would be predicted from the single dose phannacokinetics, there was no observable
`accumulation of the drug in plasma upon multiple dosing. AUCO-oo and Cmax increased
`in a dose-proportional manner over the dose—range of 5 to 50 mg. No time— or dose—
`dependency in the pharrnacokinetics of lenalidomide was observed.
`
`10
`
`

`

`FDA Table 2. Applicant’s Table 12 from page 26 of the Summary of Clinical
`Pharmacology Studies
`
`PK Parameters After Doses of 5—50 mg, Single and Multiple
`Table 12:
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`FDA Figure 2. Applicant’s Figure 8. from page 27 of the Summary of Clinical
`Pharmacology Studies
`
`Figure 8:
`
`Day I Geometric Mean Plasma Concentrations of leaalidomide (CC-
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`Pharmacology Studies
`
`Figure 9:
`
`Day 28 Geometric Mean Plasma Concentrations of lenaiidomitle (CC-
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`2.2.5.2 How does the PK of the drug. and its major active metabolites in
`healthy volunteers compare to that in patients?
`
`FDA Table 3. (below), compares the phannacokinetics of lenalidomide in healthy
`subjects and patients.
`
`
`FDA Table 3. Comparison of PK parameters in healthy subjects and patients receiving single
`doses of 5 - 50 mg
`
`1398/142 =
`PK-003 =
`1398/271 (001) =
`% change (healthy
`healthy
`healthy
`patients
`compared to patients)
`
`5 - 50 mg, n=17
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`5 - 50 mg, n=27
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`
`Clearance was 62% greater in healthy subjects than in patients, similarly, tl/2 was
`reduced (17%) in healthy subjects. The Applicant conducted an analysis of the
`differences between healthy subjects and patients receiving single 100 mg doses. The
`results are shown below (FDA Table 4.). As indicated in the table, the Applicant
`attributes the differences between the populations as due to differences in renal function
`and age between the groups.
`
`FDA Table 4. Applicant’s Table 13 from page 29 of the Summary of Clinical
`Pharmacology Studies
`
`APPEARS THlS WAY
`
`ON ORIGINAL
`
`l3
`
`

`

`Table 13:
`
`Comparison between single oral 100 mg doses from studies 1393!142
`andl393§180 in healthy subjects and CDC—S‘Ol—OOI in relapsed multiple
`myeloma patients
`
`(CC-5033 1398-142
`
`CC—SC‘IS l398l'180
`
`' CDQEJI-Ofll
`
`PK Parameter
`
`(Day 1, single dose 50 mg
`Adjusted to 180 mg for
`AUC- & Cmas}01der,
`relapsed EEM patients
`
`N = 6
`Healthy Vohmteers
`
`(Day 1, single dose} N = 5
`Health}; Volunteers
`
`3,5143%
`
`
`
`AUC h, [agér’lnlj
`
`~
`
`9499i42‘t‘b
`
`
`
`1513 : 339,-:3 1982 i1?%
`
`1.0 (range. 615.2}
`
`1.6 (range 0.5-1.5)
`
`t—l.="3 [if]
`
`x
`
`
`CL‘F {mlfmia}
`277 i 26%
`*The dammed clearance in relapsed multiple. myeiema patients is related to the age-asseciat’ed decrease in
`clearance of the older patients compared to the younger, healthy subjects.
`
`2.2.5.3 What are the characteristics of drug absorption?
`
`Lenalidomide is highly hydrophilic, but showed low permeability in the Caco—2 system.
`More consistent with its lipophilicity, lenalidomide showed high permeability in the
`PAMPA system. The discrepancy between the systems is unknown, but potentially could
`be explained by a difference in the presence of transporters or differences in
`membrane structure. Consistent with the Caco—2 data, the Applicant classifies
`lenalidomide as a low permeability substance.
`
`2.2.5.4 What are the characteristics of drug distribution? (Include protein
`binding.)
`
`Values for the volume of distribution appear in FDA Table 3. of this document. Mean
`plasma protein binding was 23%, in human subjects with multiple myeloma and 29% in
`healthy human volunteers.
`
`Does the mass balance study suggest renal or hepatic as the major
`2.2.5.5
`route of elimination?
`
`A mass balance study was not conducted. EXcretion results, which will be discussed in
`section 2.2.5.7, identify renal elimination of parent as the primary route of elimination.
`
`2.2.5.6 What are the characteristics of drug metabolism? (This may
`include data on extraction ratio; metabolic scheme; enzymes responsiblefor
`metabolism; fractional clearance ofdrug.)
`
`14
`
`

`

`In in vitro studies using'non-radio—labeled lenalidomide, there was no clear signal that
`lenalidomide metabolism occurred in human liver microsomes. Similarly, there was no
`clear evidence of significant metabolism of lenalidomide by cDNA expressed human
`P450 isoenzymes in Supersomes.
`
`In order to confirm the results of the non—radiolabelled studies, duplicate studies were
`performed using radiolabelled lenalidomide. In pooled human liver microsomes there
`was no in vitro metabolism of lenalidomide at a protein concentration of 1 mg/mL after
`10 or 60 minutes of exposure. Similarly, after a 60 minute incubation with Supersomes.
`(100 pmol P450/mL), there was no evidence of lenalidomide (10 pM) metabolism. It was
`concluded that lenalidomide was resistant to Phase I metabolism.
`
`.
`
`14
`
`In isolated human hepatocytes [ C]—lenalidomide was added to yield final concentrations
`of l, 5, and 25 pM and incubations at 37°C were performed for 0, l, 2, 4, or 6 hours.
`14
`Both negative controls (without hepatocytes) and positive controls (with [ C]-7—
`Ethoxycoumarin) were used in this experiment. There was no metabolism of
`lenalidomide after 6 hours of exposure. It was concluded that lenalidomide was resistant
`to both Phase I and Phase II metabolism.
`
`While excretion :in urine failed to recover as much as 43% of the administered dose (see
`Section 2.2.5.7.), there is no data measuring lenalidomide metabolites in human matrices
`ex vivo or following incubation with human biomaterial in vitro.
`'
`14
`Following oral and intravenous administration of [ C]—lenalidomide to cynomolgus
`monkeys, the primary metabolic pathway was by hydrolysis of the piperidine dione ring
`which formed two isomeric hydrolysis products. The urine and feces both contained ring-
`hydrolyzed compounds as well as significant proportions of unchanged drug (23%—53%
`of the administered dose in urine; up to 28% of the dose in feces). Minor metabolites
`identified in the feces included 2 glucose conjugates; N-acetyllenalidomide, a
`hydroxylated metabolite, and a N—dehydrogenated metabolite.
`
`Following oral administration to rats, the main compound identified in plasma was parent
`compound and the main metabolites were isomers of a hydrolysis product of
`lenalidomide. The major component in urine and feces was the parent compound, but
`hydrolysis metabolites, N—acetyl conjugate isomers, and glucose conjugate isomers of
`lenalidomide were also present.
`
`2.2.5.7 What are the characteristics of drug excretion?
`
`Neither a mass balance study nor measurement of drug or drug-derived moieties in feces
`' has been performed.
`'
`
`In healthy male subjects receiving 5 or 20 mg of REVILMID, 57 — 79% of the dose was
`recovered as parent in urine within 48 h (FDA Table 5.). Nearly all of the recovery
`occurred in the first 24 h (all of the 12 subjects excreted < 1.5% of the dose during the 24
`h period from 24 h to 48 h).
`
`15
`
`

`

`
`
`FDA Table 5. % dose excreted in urine; n = 11 (n = 6@ 5 mg, n = 5 @20 n_ig)
`
`0 - 48 h
`24 — 48 h
`
`56.8 - 78.8
`
`0.6 - 1.4
`
`Based on PK parameters, what is the degree of linearity or
`2.2.5.8
`nonlinearity in the dose—concentration relationship?
`
`The Applicant’s Figures A. and B. from page 62 of the study report for study 1398/ 142
`and Table M. from page 64 of the same report summarize the pharmacokinetics in
`healthy subjects receiving single doses up to 400 mg. They are reproduced below as FDA
`Figure-4. and FDA Table 6.
`
`FDA Figure 4. Applicant’s Figures A. and B. from page 62 of the study report for
`study 1398/142.
`'
`
`APPEARS THlS WAY
`ON ORIGINAL
`
`l6
`
`

`

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`FDA Table 6. Applicant’s Table M from page 64 of the study report for study
`1398/142.
`
`Table M:
`
`Summary of Plasma Pharmacokineflc Parameter Values of CC-5013 (Faster!)
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`The concentration-time profiles pharmacokinetics were not “simple” in that secondary
`peaks were observed for some subjects at all dose levels. In the majority of subjects, the
`first peak was the maximum plasma level attained (Cmax). Following the occurrence of
`peak concentrations, plasma levels declined in a multi—phasic manner. At higher doses,
`plasma levels remained quantifiable for a longer period of time (median terminal—phase
`half—life at 5 mg was 18 h compared to 48 h at