CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -742
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW; S 2
`
`

`

`ti it) “t
`
`Pharmacometrics Review
`
`Office of Clinical Pharmacology
`
`NDA:
`
`_
`
`21 -742
`
`Nebivolol
`Compound:
`May 31, 2007
`Submission Dates:
`Mylan Bertek
`Applicant:
`2nd cycle review (Standard)
`Type of submission:
`Yaning Wang, Ph.D.
`Pharmacometrics Reviewer:
`
`icondary Reviewer:
`Jogarao Gobburu, Ph.D.
`
`ls higher exposure of nebivolol, e.g. observed in poor metabolizers (PM),
`associated with more suppression of adrenal function,
`luteinizing hormone, or
`testosterone levels in male?
`
`No. Exposure response analyses were performed for nebivolol based on data
`from Study NEB—PK—03 (Effects of Nebivolol on Adrenal Function, Luteinizing
`Hormone, and Testosterone Levels in Healthy Male Volunteers). Detailed study
`design is referred to Dr. Keren Hicks’
`review. Nine safety endpoints were
`measured in Study NEB-PK—OB, whichincluded area under the curve from time
`zero to 120 minutes (AUCO-120 min) of ACTH—stimulated (IV dose of 250 pg)
`serum cortisol levels, AUCO-120 min of serum aldosterone levels after the N
`administration of ACTH (250 pg),
`sex hormone binding globulin,
`total
`testosterone level, free testosterone level, mean luetinizing hormone value, peak
`post-ACTH cortisol level, peak post-ACTH aldosterone above basal level, and
`peak post-ACTH cortisol above basal level. Under nebivolol 10 mg QD regimen,
`steady state trough concentration for either l—nebivolol or d-nebivolol was not
`found to be related to change in any of the 9 safety endpoint after 7 weeks of
`treatment in healthy male volunteers despite that 4 poor metabolizers achieved
`significantly higher exposure of l-nebivolol or d-nebivolol (Table 1, Figure 1 and
`Figure 2). The exposure of l~nebivolol or d—nebivolol was set to be zero for
`subjects taking placebo. No significant difference was observed between placebo
`and nebivolol groups in terms of change from baseline for any of the 9 endpoints
`(Table 2). The only endpoint suggesting a relationship with nebivolol exposure is
`free testosterone level as indicated by the marginal Significant p-values in both
`regression analysis and t—test._However,
`the direction of this relationship is
`opposite of hormone suppression, which is highly influenced by one outlier
`observation in nebivolol group (patient 59038 with 18 unit
`increase in free
`testosterone level at the end of study). The same influence was also observed for
`total testosterone level.
`Four poor metabolizers had higher peak post—ACTH
`aldosterone above basal level compared to either extensive metabolizers (EM) or
`placebo subjects (Table 3). Overall, these results do not support the observation
`from animal data which suggested suppression of male hormone by nebivolol.
`
`

`

`*
`
`Endgoint
`- Area Under Curve
`
`I
`
`Groug
`' Nebivolol
`
`N Mean 'Lower Ugger
`42
`-0.58
`-2.87'
`1.72 ”
`
`P—value
`"
`
`(0-120 min)
`Aldosterone
`
`Placebo
`Difference
`
`48
`
`1.01
`
`-0.30
`
`2.33
`
`Area Under Curve
`
`(0-120 min) Cortisol
`
`-
`Free Testosterone
`Level
`
`Free Testosterone
`Leve|*
`.
`
`Mean Luetinizing
`Hormone Value
`
`Peak Post-ACTH
`Aldosterone Above
`Basal
`
`*
`Peak Post-ACTH
`Cortisol
`
`(Nebivolol-Placebo)
`Nebivolol
`'
`
`Placebo
`Difference
`
`(Nebivolol-Placebo)
`Nebivolol
`Placebo
`Difference
`
`(Nebivolol-Placebo)
`Nebivolol
`Placebo
`Difference
`
`(Nebivolol-Placebo)
`Nebivolol
`Placebo
`Difference
`
`‘~
`
`(Nebivolol-Placebo)
`Nebivolol
`Placebo
`Difference
`
`(Nebivolol—Placebo)
`Nebivolol
`Placebo
`Difference
`
`' —1.59
`0.44
`
`0.77
`
`-4.12
`-0.93
`
`-0.54
`
`0.94
`1.80
`
`2.07
`
`42
`
`48
`
`.
`
`-0.33 —2.19
`1.00
`-0.10
`42
`48 —0.25
`-1.10
`
`1.53 '
`2.10
`0.60
`
`1.25
`0.59
`-0.25
`
`0.84
`0.04
`0.11
`
`-0.10
`-0.14'
`-1.10
`
`—0.29
`-0.44
`~0.23
`
`41
`48
`
`42
`48
`
`—0.07 —0.64
`-0.20
`-1.77
`42
`48 —0.32
`-1.68
`
`0.12
`0.20
`0.28
`
`-1.93
`-0.56
`-0.40
`
`42
`48
`
`Peak Post-ACTH
`Cortisol Above
`
`(Nebivolol-Placebo)
`Nebivolol
`Placebo
`
`—0.08 —1.08
`0.11
`-1.41
`42
`48 —1.08
`-2.41
`
`Basal
`
`Difference
`
`Sex Hormone
`
`Binding Globulin
`‘
`
`(Nebivolol—Placebo)
`Nebivolol
`
`' Placebo
`Difference
`
`-0.79
`1.20
`-0.57 —1.93
`
`0.60
`
`-0.50
`
`42
`
`48
`
`2.60
`1.32
`0.60
`
`1.97
`0.52
`0.45
`
`0.49
`1.37
`1.05
`
`2.16
`0.96
`0.96
`
`0.92
`1.64
`0.24
`
`3.18
`0.80
`
`1.70
`
`0.21
`
`0.73
`
`0.07
`
`0.14
`
`0.80
`
`0.91
`
`0.87
`
`0.23
`
`0.18
`
`Testosterone, Total
`
`42
`48
`
`—1 .17
`26.64
`-2.90
`
`-2.88
`-6.66
`-31.74
`
`0.54
`59.95
`25.95
`
`(Nebivolol-Placebo)
`Nebivolol
`Placebo
`Difference
`
`lNebivolol—Placebo)
`29.54
`-13.67
`72.75
`0.18
`* Without an influential point in nebivolol group
`
`Table 3. ANO VA comparison results for peak post-A CTH aldosterone abo V8 basal
`[6 V6]
`
`

`

`95% Cl
`Lower Upper
`Estimate
`~ Group
`2.30
`11.50
`6.90
`Nebivolol (PM)
`-2'.44
`0.55
`-0.94
`Nebivolol (EM)
`-1.64
`1.01
`-0.31
`Placebo
`0.004
`2.43
`12.00
`7.21
`Difference (PM-Placebo)
`0.002
`3.01
`12.68
`7.84
`Difference (PM-EM)
`-2.63
`1.37
`-0.63
`Difference EM-Piacebo
`0.532
`* Not adjusted for multi
`pie comparisons; PM, poor metabolizers; EM, extensive
`metabolizers.
`
`P-value*
`
`-
`
`,.
`
`N
`4
`38
`48
`
`Appears This Way
`on Original
`
`

`

`Yaning Wang
`9/17/2007 02:46:50 PM
`BIOPHARMACEUTICS
`
`Jogarao Gobburu
`9/17/2007 03:07:11 PM
`BIOPHARMACEUTICS
`
`

`

`Quitr
`
`CLINICAL PHARMACOLOGY & BIOPHARNIACEUTICS REVIEW
`NDA:
`21-742
`N000
`
`Submission Dates:
`Generic Name:
`
`.
`
`_
`
`2/21, '2/22 2005
`Nebivolol
`
`.
`
`Dosage Form & Strength:
`
`Tablets 2.5, 5, and 10 mg
`
`. Indication:
`
`Applicant:
`
`Submission:
`
`Hypertension
`
`Bertek Pharmaceuticals Inc.
`
`Original NDA, responses to the FDA comments
`
`Primary Reviewers:
`Elena V. Mishina, Ph.D.
`
`
`Background
`
`Reference is made to the NBA 21 -742, nebivolol tablets, which is currently under review In the
`February 10,2005 letter the Agency provided the OCPB comments to the sponsor The
`submission contains the sponsor’s responses to. the OCPB comments.
`
`Response to comment 1.
`The sponsor is satisfied with comment 1 regarding the granting the requested biowaiver for the
`2.5 mg dosage strength of the nebivolol tablet.
`
`Response to comment 2.
`The dissolution data for nebivolol tablets was reevaluated based on the available data to date.
`The dissolution specification of NLT M (Q) in 30 minutes is recommended for the 2.5, 5, and
`10 mg tablets strength.
`
`Response to comment 3.
`The FDA pointed out that due to a failure to assess the active metabolites in the clinical studies,
`the sponsor could not explain why the striking differences in the levels of the parent drug in
`extensive (EM) and poor metabolizers PM) of CYP 2D6 did not show any differences in the drug
`effect.
`.
`
`The sponsor argued that the pharmacokinetics of the active metabolites was assessed. in. this
`NDA. This argument was based on the ‘rnass——balanCe study (reports NEBI-0136 and NEBI—0142)
`where the metabolism of nebivolol was characterizedin 3 EM and 3 PM healthy subjects. In this
`study performedin healthy subjects, the total radioactivity was detectable in urine and feces up
`to 17 days, and it was detected up to 7 days in whole blood and plasma. The half-life of the total
`radioactivity in whole blood in EMS blood was calculated as 86 hours (2 subjects, 39 and 132
`hours) and in PMs 73 hours (N=3) and 44 hours (1 EM subject) and 60 hours (3PMs) in plasma.
`The distribution andexcretion of the active metabolites (4— hydroxy (A8), 8- and 5—hydroxy (A6),
`4 8- and 4 ,5—dihydroxy (A3) and their corresponding glucuronides (G8. G6, and G3) were
`properly assessed.
`In general, all these active metabolites and their glucuronides were formed in
`EM subjects and not
`in PM subjects. However,
`their contribution to the pharmacodynamic
`
`

`

`"Effects was not assessed and the final conclusions only speculated that the similar effecfin PMs
`and EMS is possibly due to the effect of the active metabolites111 EMs which substituted the
`effect ofthe parent drugin PMs.
`'
`‘
`Glucuronide Conjugates
`The mass balance study showed that the major metabolites of nebivolol are glucuronides of the
`unchanged drug, which was reported as GUD. The drugis represented by two stereoisomers, d-
`and l-neb1volol from which only d-nebivolol has beta-blocking activity. Moreover, the 5-, and 8~ '
`hydroxy metabolites of both stereoisomers can form glucuronides as well.
`,In the clinical '
`pharmacology studies, the sponsor assayed in bulk all glucuronides and reported that ‘the main '
`active metabolite, glucuronide of the unchanged parent drug, was measuredin studies NEBI 126,
`127, 270, 136, 142, 124 125, 2118, and 302’. In the above mentioned studies glucuronide ‘
`conjugates (bulk measurements) were assessed up to 24 (majority of studies) and up to 96 hours
`in studies 125 (5 patients) and 124 (7 patients). The attempt to describe the pharmacokinetic
`properties of the mixture of more then a dozen substances which have different chemical and
`physiologic properties does not make any sense. Moreover, in all these studies (except for the
`mass balance studies (136 and 142), the half life of the ”glucuronides was calculated in the
`range of 3 to 15 hours (EMS) and up to 30 hours in PMs while the total radioactivity was
`detectedin plasma up to 7 days. This indicates that the characterization of the pharmacokinetic
`profile was not complete In addition, when the AUC values measured to the last data point were
`compared to the extrapolated AUC values, 3 the measured part represented less than 50%.
`Therefore based on these data,
`the characterization of the terminal phase of the plasma .
`concentrations vs time profile was impossible and the half-life, clearance, and volume of
`distribution values calculated‘by the sponsor for the glucuronides cannot be considered reliable.
`Therefore, the Agency concluded that the pharmacokinetics of the main metabolites of nebivolol
`(glucuronide conjugates) was not properly characterized.
`In conclusion,
`1.
`The mass balance study properly characterized the metabolic profiles of d- and l—
`nebivolol in 3 EM and 3PM healthy subjects; however, the described groups were
`very small to adequately describe the variability and only 2 out of 3 subjects in the
`EM group had similar results.
`None of the active metabolites (4-hydroxy, 8— and 5—hydroxy, 4,8- and 4,5-dihydroxy—
`nebivolol and their correspOnding glucuronides were measured in the clinical studies
`to evaluate their impact into the overall pharmacodynamic effect.
`The sponsor attempted to describe the pharmacokinetics of the major metabolite of
`nebivOlol, namely, glucuronide of unchanged drug. However, the assay measured the
`sum of glucuronide conjugates of d— and l—nebivolol and above mentioned active
`metabolites. This approach. is not acceptable and the pharmacokinetic parameters .
`calculated by the sponsor do not reflect the properties of any specific metabolite,
`'
`'
`
`2.
`
`3.
`
`Response to comment 4.
`The relationship between pharmacokinetics and pharmacodynamics of nebivolol was not
`established. The
`reasons
`include
`poor
`study design and
`inability
`to measure
`all
`pharmacologically active moieties.
`
`Sponsor:
`
`Appears This Way
`On Original
`
`

`

`The estimated placebo—subtracted trough-to—peak ratio of diastolic blood pressiire was
`approximately 0 9 or greater at all doses. Although this limited degree in fluctuation is ideal
`with respect to clinical efi‘icacy it makes pharmacokinetic modeling extremely d17‘cult Since
`patients maintained on nebivolol appear to have a relatively stable reduction in bloodpressure
`eflorts to construct a pharmacodynamic relationship are somewhat limited.
`
`FDA-comment:
`The sponsor claims that the obtained data do not show a proper pattern for the relationship
`between PK and PD
`
`Sponsor: The PK/PD analysis conducted previously is believed to adequately reflect the
`pharmacoaynamic performance ofnebivololfor thefollowing reasons:
`
`a. The pharmacokinetics of nebivolol and related moieties is well understood and
`. was taken into account
`_
`FDA comment:
`
`The pharmacokinetics of d- and l—nebivolol was previously described in studies NEBI—l26 and
`NEBI-127. In these studies, the limitation of the assay for the low doses of drug and failure to
`obtain plasma samples at least up to 3 half-lives led to poor characterization of the nebivolol
`pharmacokinetics particularly for the low doses and for the PM subjeCts. Nevertheless,
`the
`parameters estimated in these studies by the non-compartmental method were used by the
`sponsor as a comparator of the population model estimated parameters. Moreover, all parameters
`(exceptfor clearance (CL) and volume of distribution of the central compartment, (Vd)) obtained
`in healthy subjects were fixed for the patient population data analysis in order to estimates the
`patient’s CL and V.’ The sponsor assumed that the pharmacokinetics of d— and l~nebivolol in
`healthy subjects and patients were similar but this assumption was never tested. Although the
`pharmacokinetic parameters estimated for d— and l—nebivolol were sited as “comparable” for the
`1 healthy and patient population,
`the clearance in the patient population was reduced for d-
`nebivolol by 20%,
`in EMs and 55% in PMs; and for l—nebivolol, no change for EMS and
`increased 2.5 times for PMs).
`
`b. Nebivolol—related moieties follow a similar plasma concentration versus time
`profile as nebivolol and its glucuronides and as such correlate with nebivolol as
`well as one another
`
`FDA comment:
`
`Pharmacokinetics of all three moieties measured in the clinical studies: d-, 1-. nebivolol and
`nebiVOlol glucuronides were quite different with respect to all parametersD_— and l-nebivolol _
`plasma concentrations were added at all sampling times and this combined quantity was used for
`the PK and PK/PD modeling; however, only d—nebivolol has a pronounced beta-blocking
`activity. The exposure to d—nebivolol was much smaller (both AUC and Cmax) and the half—life
`shorter compared to l—nebivolol.
`In studies in healthy subjects (NEBI-126 and NEBl—127),
`nebivolol glucuronides were inadequately characterized for the low doses of nebivolol (2.5 and 5
`mg). The sponsor failed to measure the plasma Concentrations of the nebivolol glucuronides for
`EMS (not enough assay sensitivity) and for PMs,
`the plasma concentrations of nebivolol
`glucuronides were not measured long enough to characterize the terminal phase of elimination
`
`I.
`
`l M H
`
`7
`
`

`

`"and the estimations of the AUC‘values and clearance values were deemed not—acceptable. -
`-’ Therefore, the spOnsor’s .clairn regarding the similarity in pharmacokinetics of the measured-
`nebivolol moieties in plasma is not supported by the submitted results.
`
`c. Sampling measurements were designed to be clinically practical within the
`confines of the stuabz and to assess both maximal and minimal responses of
`concentrations and eflects
`d. The data was based on a population PK data set, providing a large number of _
`measures overa broad range of dosage regimens (1.25 to 40mg/day) and clinical
`scenarios in mild-to—moderate hypertensive patients.
`
`FDA comment:
`i
`The plasma sampling in this study was poorly designed. Although the number of samples (3-4
`per subject) was sufficient,
`the sampling occurred only at
`the peak and trough plasma
`concentrations and there was no information about the plasma concentration profiles in between
`these points. The Population PK Guidance for the industry recommends having 3-4 plasma
`samples per patientswhich are obtained in a few intervals to properly characterize the hill
`plasma concentration time profile.
`'
`'
`In conclusion, the population model described the pharmacokinetics of d— and l-nebivolol with a
`lot of assumptions and particularly was based on the parameters obtained from healthy subjects.
`Due to poor study design, the pharmacokinetic profiles were not properly characterized and the
`effects of the important covariates were not assessable.
`.
`
`Sponsor: Our analysis suggests that a saturable efi'ect model best describes therelationship
`between nebi‘volol plasma concentration and diastolic blood pressure [NEB-302PKPD], which
`may explain the relatively high trough—to—peak ratio for blood pressures and may in part explain
`nebivolol’s similar eflectiveness in patients classified as either EMS or PMs.
`
`FDA comments:
`
`1.
`
`2.
`
`The sponsor’s estimated ECSO values (50% of the drug concentration responsible for
`the maximal effect) are not correlated with the activity of Bl—adrenoceptor (Ki 7-8
`mol/L or 5-15 ng/mL, Maack et al 2001). The sponsor’s estimation of EC50 for the
`sitting diastolic blood pressure was 0.068 ng/mL. This value is 220 fold higher than
`Ki Moreover,
`the average d—nebivolol plasma concentrations measured in Study
`NEBI—302 was about 6 ng/mL, this value was the same order of magnitude as the Ki
`value The ECSO values estimated by the sponsor do not reflect the Ki for [3—
`adrenoceptor activity of nebivolol. TheECSO value for heart rate was estimatedby
`the sponsor as 0 016 ng/mL The same comments as above for DBP are applicable for
`the heart rate response model.
`
`The data available in this study did not allow to evaluate if there is a lag time between
`the pharmacokinetics and pharmacodynamics of the drug. The model proposed by the
`sponsor is not able to rule this out. The hysteresis could only be assessed if the full
`plasma concentration vs. time profile with the corresponding PD measurements was
`taken into consideration.
`
`

`

`i 3.
`
`the PK/PD‘ model proposed by the sponsor" is not
`Based on all of the above,
`acceptable The attempt to describe the data with a linear PK/PD model (FDA
`reviewer) did not lead to a better model fit
`"
`
`Response to comment 5.
`The Agency recommended to evaluate the PK/PD relationship in African—American patients The
`sponsor’s response to perform a small single dose studyin African-American and Caucasian
`patients is acceptable. The protocol ofthis study should be submitted for review
`
`' RECOMMENDATION
`
`-,The Office of Clinical Pharmacology and Biopharmaceutics reviewed the sponsor’s response
`The following dissolution method specifications and method are recommended:
`
`Condition
`Dissolution Medium
`
`FDA Recommendation
`0.01N HCL
`
`Paddle Speed
`' USP Apparatus II
`Volume
`
`'50 rpm
`‘
`900 mL
`
`Specifications
`
`J in 30 minutes
`
`/ The sponsor’s responses to the original FDA comments 3 and 4 are not acceptable. The FDA
`comments to the sponsor responses should be conveyed to the sponsor.
`
`Elena Mishina, Ph. D.
`
`Clinical Pharmacology Reviewer
`
`' Date
`
`
`
`Patrick Marroum, Ph. D.
`Cardio—Renal Team Leader
`
`cc list: NDA 21-742, MehulM, MarroumP, MishinaE, HFD l 10 BIOPHARM
`
`Appears This Way
`On Original
`
`

`

`-Q......---..'.....-_.-..--...._.'._'...I._.'.-_-._.'..._---_---n---..----...-_----u-..........----.--..-..—._.__.-._._-
`"ThisIs a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`-
`
`/s/
`
`.
`
`_._II
`
`.
`
`Elena Mishina
`g5/11/05 02:44:48 PM
`BIOPHARMACEUTICS
`
`V
`
`Patrick Marroum
`
`5/11/05 03:08:56 PM
`BIOPHARMACEUTICS
`
`

`

`Clinical Pharmacology Review NBA 21—242, Nebivolol
`
`,
`
`.
`
`-
`
`1/28/2005
`
`[(98/ 011’
`
`'
`- CLINICAL PHARMACOLOGY & BIOPHARMACEUTICS REVIEW
`
`NDAQ
`21-742
`. N000,
`‘
`-
`.
`I
`,
`
`Submission Dates:
`
`v
`
`'4/30, 6/24, 7/9, 7/14, 7/15, 10/27, 11/12, 11/16, 11/19,
`
`Brand Name:
`
`. Generic Name:
`
`11/23, 11/30, 12/15, 12/212004
`
`
`Nebivolol
`
`Dosage Form & Strength: -
`
`Tablets 2.5, 5, and 10 mg
`
`Indication:
`
`Applicant:
`
`Submission:
`
`Divisions:
`
`Hypertension
`
`Bertek Pharmaceuticals Inc.
`
`Original NDA
`
`DPEI and Cardio-Renal‘Drug Products, HFD-l 10
`
`Primary Reviewers:
`
`Elena V, Mishina, Ph.D.
`
`'
`
`Pharmaco‘metrics Consult:
`
`Elena V. Mishina, PhD.
`
`Robert Kumi, PhD.
`
`Team Leaders;
`Patrick Marroum, PhD.
`
`Page 1 0f302
`
`

`

`_ Clinical Pharmacology Review NBA 21-742, Nebivolol
`
`.
`
`, 112812005
`
`‘
`
`
`Table of Contents
`
`1
`
`EXECUTIVE SUMMARY ................................................................................................... 14
`
`1.1 RECOMMENDATIONS: ............................................ 14
`1.2
`‘
`'
`1.3
`
`1.3. 1
`1.3.2
`
`
`
`2
`
`3
`
`4
`
`QUESTION BASED REVIEW...............................................................
`
`2.1~
`2.2
`2.3
`2.4
`2.5
`2.6
`
`GENERAL A'ITRIBUI'ES .....................................................................................................................;. 24
`GENERAL CLINICAL PHARMACOLOGY ............................................. _........................................
`’
`
`INTRINSIC FACTORS ............................................................................................................................ 41
`EXTRINSIC FACTORS .......................................................
`
`GENERAL BIOPHARMACEUTICS .......................................
`
`.......................................... 49
`ANALYTICAL SECTION
`
`DETAILED LABELING RECOMMENDATIONS............................................................................... 51
`
`APPENDICES ....................................................................................................................................'
`
`55
`
`I
`
`OCPB PROPOSED LABEL ........................... 3.................... -. .............................'...................................... 55
`4.1
`INDIVIDUAL STUDY REVIEWS.......................3 ....................................................................................... 67
`4.2
`Single Dose,Dose—Propor1ionality Phannacokinetic Study ofNebivolol Hydrochloridein Healthy
`4.2. 1
`' Volunteers Characterized According to Their Metabolizing Status (NEBI— 0126) ......................................... 67
`4.2.2
`Single-Dose, Relative Bioavailability and Food Eflect Study ofNebivolol Hydrochloride in Healthy
`Volunteers CharacterizedAccording to Their Metabolizing Status (NEBI— 0127) ....................................... .. 81
`4.2.3
`A Phase I Open-Label Single-Dose Study Assessing the Pharmacokineties ofNebivolol HCL and
`the Formation ofMetabolites in Healthy Volunteers (NEBI- 0223)............................................................... 92
`4.2.4
`A Phase I Open Label Multiple Dose Study Assessing the Pharmacokinetics ofNebivolol HCL and
`the Formation ofMetabolites in Healthy Volunteers (NEBI- 02 70)............................................................... 98
`4.2.5
`The plasma protein binding and distribution in blood ofrac— nebivolol and ofits two enantiomers
`in rats, dogs and humans........................................................................................................................... 109
`4 2. 6
`A Phase I, Open Label Study Investigating the Effects ofHepatic Impairment on the Single Dose
`Phannaco/a'netics ofNebivolol Hydrochloride (NEBI- 0124) .....................................................................1 l I
`4. 2 7
`A Phase 1, Open- Label Study Investigating the Eflects ofRenal Impairment on the Single Dose
`Phannacokinetics ofNebivolol Hydrochloride (NEBI- 125) ........................................................................ 118
`4.2.8
`Absorption, Metabolism, and Excretion ofNebivolol in Healthy Male Volunteers after a Single
`Oral Dose of15mg I4C- Nebivolol HCL (NEBI- 0136).............................................................................. 127
`4.2. 9
`Metabolism of[14C]- Nebivololin Human. Mass Balance and Metabolite Profling/Identification
`in Plasma and Excreta (NEBI-142)............................................................................................................ 131
`4.2.10
`Anin vitro Study on the Microsomal Metabolism ofd— andl—Nebivololin Human Liver
`* Microsome‘s (NEBI- 0157) .....................................................................................
`I44
`
`‘-
`*
`. 4.2.11 '- Anin vitro Evaluation ofNebivolol as an Inhibitor ofHuman Cytochrome P450 Enzymes(NEBI—
`
`-- I 58) 1 53
`,
`4.2.12
`A Randomized, Parallel Group SafetyEvaluation ofElectrocardiographic Intervals And Blood
`Pressurein Normal Healthy Volunteers after Nebivolol, Atenolol, Moxifloxacin, or Placebo Administration
`after Single and Repeated Doses (NEB 122) ............................................................................................... [59
`4.2.13
`A Double—Blind, Multi—Center, Randomized, Placebo-Controlled. Parallel Group Dosing
`Evaluating the Eflects ofNebivolol on Blood Pressure in Patients with Mild to Moderate Hypertension WEB-
`302)
`I 70
`.
`4.2.14
`Population Pharmacokinetic Data Analysis NEBI—302 .............................................................. I72
`4. 2. I 5
`Pharmacokinetic/Pharmacodvnamic Modeling NEBI—302 ......................................................... 1 86
`4.2.16
`Dissolution ............................................................................................................................... I 93
`4.2.1 7
`Assay Information Relevant to Drug—Drug Interaction Evaluations............................................ I 98
`
`.
`
`Page 2 Of302
`
`

`

`Clinical Pharmacology Review NBA 21-742, Nebivolol
`
`I
`
`1/28/2005
`
`A Phase 1 Open-LabelMultiple- Dose Study Assessing the Phannacokinetic Interaction of“
`42 18
`Hydrochlorothiazide and Nebivolol HCIin Healthy Volunteers.................................................................. [99
`4.2.19
`A Phase I Open— Label Study Comparing the Interaction ofNebivolol HCl on the Pharmacokinet‘ics
`.ofDigoxinin HealthyVolunteers 206
`. 4.2. 20
`A Phase I Open- Label Study Comparing the Interaction ofSteady— state Nebivolol HCl on the
`Pharmacokinetic and Pharmacodynamics of Watflzrin SodiumIn Healthy Volunteers ................................ 214
`4 2. 21
`A Phase I Open- Label Multiple- Dose Study Assessing the Pharmacola'netic Interaction Between
`Fluoxetine HCl and Nebivolol HClin Healthy Volunteers.......................................................................... 222
`4.2.22
`A Phase IOpen—Label Multiple—Dose StudyAssessing the Pharmacokinetic Interaction Between
`Furosemide and Nebivolol HCIIn Healthy Volunteers (NEBI-0213) .......................................................... 227
`4. 2 23
`A Phase I Open-Label Multiple-Dose Study Assessing the Pharmacola'netic Interaction Between
`_
`Spironolactone and Nebivolol HCIin Healthy Volunteers (NEBI-0214) ..................................................... 236
`42 24
`A Phase I Open-Label Multiple-Dose Study ofthe Effect ofNebivolol HCl on the Phannacokinetics
`ofSpironolactone in HealthyVolunteers ................ 242
`4.‘.225
`A Phase I Open-Label Multiple—Dose Study Assessing the Pharmaeokinetic Interaction Between
`Ramipril and Nebivolol HCI in Healthy Volunteers (Protocol NEBI-0220) ................................................. 247
`4. 2 26
`A Phase I Open-Label Single-Dose Study ofthe Pharmacokinetic Interaction between Nebivolol
`HCl and Losartan Potassium in Healthy Volunteers (NEBI-02104) ............................................................ 256
`4.2. 27
`A Phase I Open-Label Study ofthe Eflect ofRepeatedDose Activated Charcoal on the
`Phannacokinetics ofNebivolol HCl in Healthy Volunteers (#3 NEBI-02118) .............................................. 265
`4.2.28
`An in vitro study on protein binding interactions ofrac—nebtvolol with other drugs in human plasma
`275
`
`4.3
`4.4
`
`FILING AND REVIEW FORM ........................3...................................................................................... 279
`SPONSOR’S PROPOSED PACKAGE INSERT ..... ..................................................................................... 281
`
`,/
`
`Page 3 of 302
`
`

`

`Clinical Pharmacology Review NBA 21-742, Nebivolol
`
`.
`
`-
`
`“28/2005
`
`
`
` List of Tables 7 PM
`Table 1: SummaryofK1 values for nebivo1ol, its enantiomers, proposed metabolites, other
`known metabolites, and commonly prescribed B—blockers ................................................. 29
`Table 2: Descriptive statistics obtained for clearance fiom the posthoc estimates: comparisons of
`1 EMS vs. PMs and Caucasians vs. Blacks for d-.and l-nebivolol30
`Table 3: Comparison of the pharmacokinetic parameters of d-nebivolol after single and multiple
`10 mg dose ofnebivolol
`................................................................................................ 33
`Table 4: Comparison of the pharmacokinetic parameters of l—nebivolol after single and multiple
`.10 mg dose of nebivolol .................................................................................................... 33
`Table 5: Comparison ofmean (%CV) clearance values estimated1n healthy subjects andin
`patients using NCA or NONMEM..................................................................................... 34
`Table 6: Profiles of Metabolites1n Pooled (0-168 hr) Urine (% of Dose)................................... 39
`Table 7: Profiles of Metabolites in Pooled (0-168 hr) Feces (% of Dose)................................... 40
`Table 8: Summary of nebivolol solubility ................................................................................. 47
`Table 9: Nebivolol Tablets Composition ................................................................................... 48
`Table 10: DrugDescr1pt10n................. 68
`Table 11: Assay Characteristics for d- and l-Nebivolol............................................................. 68
`Table 12: Demographic Data.................................................................................................... 69
`Table 13: Mean (%CV) d—Nebivolol PK Parameters ................................................................ 70
`Table 14: Mean (%CV) l—Nebivolol Parameters ....................................................................... 70
`Table 15: Mean (% CV) dose—normalizedpharmacokinetic parameters for d-nebivolol ............ 72
`Table 16: Mean (% CV) dose-normalized pharmacokinetic parameters for 1~nebivolol............. 72
`Table 17: Geometric Mean Ratio (%) and 90% CI for the Dose-Normalized Parameters of d-
`Nebivolol .......................................................................................................................... 73
`Table 18: Geometric Mean Ratio (%) and 90% CI for the Dose-Normalized Parameters of l-
`Nebivolol ..............................................................._........................................................... 73
`Table 19: Mean (%CV) d,l-Nebivolol Parameters .................................................................... 75 ~
`Table 20: Mean (% CV) dose-normalized pharmacokinetic parameters for d,l—nebivolol .......... 75
`Table 21: Geometric Mean Ratio (%) and 90% CI for the Dose-Normalized Parameters of d,l—
`Nebivolol .......................................................................................................................... 76
`Table 22: Mean (% CV) pharmacokinetic parameters for nebivolol glucuronides ..................... 76
`Table 23: Mean (% CV) dose-normalized pharmacokinetic parameters for nebivolol
`glucuronides ...................................................................................................................... 77
`Table 24: Geometric Mean Ratio and 90% CI for PK Parameters of Neb1vo lol Glucuronides... 78
`Table 25: Drug Description ...................................................................................................... 82
`Table 26: p Assay Characteristics for d— and l-NebivoloL........................................................,...82
`,. __-,:.‘Table 27: Subject Demographics.‘.,......‘.............................'
`................................... 83
`Table :28: Mean (%CV) d-Nebivolol PK Parameters ................................................................ 84
`Table 29: Mean (%CV) l-Nebivolol PK Parameters ................................................................. 86
`Table 30: Mean (%CV) d,l~Nebivolol PK Parameters .............................................................. 88
`Table 31: Mean (%CV) Nebivolol Glucuronides PK Parameters .............................................. 89
`Table 32: Assay Characteristics for d— and l-Nebivolol ............................................................. 93
`Table 33: Demographic Data‘ ..................................................................... 93
`Table 34: Mean (CV) d-Nebivolol PK parameters .................................................................... 94
`Table 35: Mean (CV) l-Nebivolol PK parameters ..................................................................... 94
`Table 36: Mean (CV) d,l-Nebivolol PK parameters .................................................................. 94
`
`Page 4 of 302
`
`

`

`Clinical Pharmacology Review NBA 21-742, Nebivolol
`
`,
`
`:
`
`'
`
`'
`
`1/28/2005
`
`..................T....f.‘.......98
`'Table 37 Assay Characteristics for -d- and l-NebiVolol..........
`Table 38: Assay for non-conjugated plus conjugated nebivolol ................................................ 99
`. Table 39: DemographicData........ 100
`Table 40: Mean (%CV) d-nebivolol PK parameters (single dose, Day 1) ................................ 100
`Table 41: Mean (%CV) d—nebivolol PK parameters (multiple doses, Day 14) ......................... 101
`Table 42: Mean (%CV) 1-Nebivolol PK parameters (single dose,,_ Day 1) ............. -. .................. 101
`Table 43: Mean (%CV) l-Neb