CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`205029Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`NDA number
`Submission type
`Submission date
`Applicant name
`Proposed brand name
`Generic name
`Dosage form
`Dosage strengths
`Proposed indication
`OCP division
`OND division
`Primary reviewer
`Team leader
`
`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`205029
`Standard 505(b)(2)
`12/04/2012
`Belcher Pharmaceuticals, LLC
`
`Epinephrine, USP
`Sterile solution for injection (1 mL ampule)
`1 mg/mL
`To increase systemic arterial blood pressure in acute
`hypotensive states associated with septic shock
`Division of Clinical Pharmacology 1
`Division of Cardiovascular and Renal Products
`Sudharshan Hariharan, Ph.D.
`Rajanikanth Madabushi, Ph.D.
`
`TABLE OF CONTENTS
`
`1. Executive Summary.....................................................................................................................2
`1.1. Summary of Clinical Pharmacology Findings......................................................................2
`1.2. Phase 4 Requirements / Commitments .................................................................................3
`1.3. Recommendations.................................................................................................................3
`2. Question Based Review ...............................................................................................................4
`2.1. Disposition following i.v. administration..............................................................................4
`2.2. Mechanism of action and effect on hemodynamic variables................................................5
`2.3. Dose-response: Healthy subjects ..........................................................................................6
`2.4. Dose-response: Septic shock patients ...................................................................................7
`2.5. Impact of intrinsic factors .....................................................................................................9
`2.6. Impact of extrinsic factors ..................................................................................................10
`3. Appendix: Individual publication reviews.................................................................................12
`3.1. Epinephrine: Disposition ....................................................................................................12
`3.2. Epinephrine: MoA/Pharmacodynamics..............................................................................14
`3.3. Dose-response: Healthy subjects ........................................................................................24
`3.4. Dose-response: Septic shock patients .................................................................................29
`3.5. Impact of intrinsic factors ...................................................................................................35
`3.6. Impact of extrinsic factors ..................................................................................................38
`
`Reference ID: 3369769
`
`(b) (4)
`
`

`

`Epinephrine
`NDA 205029
`
`1. EXECUTIVE SUMMARY
`
`Belcher Pharmaceuticals, LLC is seeking approval of Epinephrine, USP [1 mg/mL, 1 mL
`ampule] via the 505(b)(2) pathway for increasing systemic arterial blood pressure in acute
`hypotensive states associated with septic shock. The proposed dosing regimen in septic shock
`patients is 0.05 to 2.0 μg/kg/min administered as continuous i.v. infusion titrated closely to
`achieve a target mean arterial pressure (MAP). The sponsor is relying on the safety information
`from Twinject [NDA 020800, approved May 2003] as the listed drug, an auto-injector approved
`for use in the emergency treatment of severe Type I allergic reactions. The sponsor relies on the
`published literature to support the non-clinical, clinical pharmacology and clinical efficacy of the
`proposed drug product. A literature based 505(b)(2) submission for epinephrine in support of the
`proposed indication was agreed upon by the Division of Cardiovascular and Renal Products
`during the pre-IND and pre-NDA meetings held on 02/03/2012 and 07/25/2012, respectively.
`
`The clinical pharmacology package for this application primarily consists of published literature
`addressing the following topics – (i) pharmacokinetics (PK), (ii) pharmacodynamics (PD), (iii)
`dose-response in healthy and target population, and (iv) impact of intrinsic and extrinsic factors
`on PK and PD of epinephrine.
`
`1.1. Summary of Clinical Pharmacology and Biopharmaceutics Findings
`
`The key clinical pharmacology features of epinephrine are summarized below:
`
`(cid:120) When administered intravenously, epinephrine rapidly disappears from the plasma with an
`effective half-life of <5 min. Time to reach pharmacokinetic steady state following continuous
`i.v. infusion is approximately 10 min.
`
`(cid:120) Following i.v. infusion, epinephrine has a quick onset of blood pressure response (<5 min). The
`time to offset the drug effect is approximately 10-15 min.
`
`(cid:120) There is a trend for dose-dependent increase in blood pressure and heart rate with increasing
`doses of epinephrine [0.001 to 0.2 μg/kg/min] in healthy subjects.
`
`(cid:120)
`
`(cid:120)
`
`In septic shock patients, there is an increase in mean arterial pressure with i.v. infusions of
`epinephrine. However, a naïve-pooled analysis shows a similar change from baseline MAP
`response over a wide range of epinephrine infusion rates suggesting a high degree of inter-patient
`variability.
`
`Intrinsic factors such as age, body weight and disease severity may affect the pharmacokinetics
`of epinephrine. However, due to quick onset and offset of effect, dose-adjustment based on
`exposure changes is not necessary as epinephrine is to be administered in a controlled clinical
`setting titrated to a target response. Similarly, drug interactions affecting the PK or PD of
`epinephrine also does not warrant any dose adjustment.
`
`Reference ID: 3369769
`
`2
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`

`

`Epinephrine
`NDA 205029
`
`1.2. Phase 4 Requirements / Commitments
`No Phase 4 Requirements / Commitments are proposed at this point of time.
`
`1.3. Recommendation
`The Office of Clinical Pharmacology (OCP/DCP1) recommends approval of epinephrine based
`on its effect on MAP in septic shock patients.
`
`Reference ID: 3369769
`
`3
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`

`

`Epinephrine
`NDA 205029
`
`2. QUESTION BASED REVIEW
`
`An abridged version of the question based review is used to address specific clinical
`pharmacology issues of epinephrine related to this submission. Review of individual publications
`pertaining to the clinical pharmacology aspects of epinephrine can be found in the Appendix.
`
`2.1. What are the disposition characteristics of epinephrine?
`
`Epinephrine is rapidly cleared from the plasma following an i. v. administration with an effective
`half-life of <5 min. A pharmacokinetic steady state following continuous i.v. infusion is achieved
`within 10-15 min. Epinephrine is not effective after oral administration because it is rapidly
`conjugated and oxidized in the gastrointestinal mucosa and liver. Absorption from subcutaneous
`tissues occurs relatively slowly because of local vasoconstriction and the rate may be further
`decreased due to systemic hypotension in cases such as septic shock. Following an intramuscular
`injection, absorption is relatively rapid, however, in emergencies such as septic shock, it is
`necessary to administer epinephrine intravenously. Pharmacokinetics of epinephrine is dose
`proportional in the infusion dose range of 0.026 to 1.67 ug/kg/min in the target population i.e.,
`septic shock [Fig l].
`
`600
`
`y = 210.3x1-07
`R2 = 0.896
`
`0
`
`
`
`Epinephrineplasmaconcentration,[nM]
`
`
`
`
`
`0.0
`
`0.2
`
`0.4
`
`0.6
`
`0.8
`
`1.0
`
`1.2
`
`1.4
`
`1.6
`
`1.8
`
`Epinephrine infusion rate [pg/kglmin]
`
`Figure 1: Epinephrine plasma concentration as a flmction of infusion rate at steady state
`showing dose linearity in the range 0.026 to 1.67 uglkg/min.
`
`Epinephrine is extensively metabolized with only a small amount being excreted unchanged.
`Both endogenous and exogenous epinephrine is preferentially metabolized by catechol—O-methyl
`transferase [COMT] in extraneuronal pathways, with less epinephrine being deaminated by
`monoamine oxidase [MAO]. COMT and MAO are abundantly expressed in the liver, kidneys
`
`Reference ID: 3369769
`
`

`

`Epinephrine
`NDA 205029
`
`and other extraneuronal tissues. The relative contribution of organs/tissues in the removal of
`circulating exogenous epinephrine from plasma is liver (32%) > kidneys (25%) > skeletal muscle
`(20%) > mesenteric organs (12%). Metanephrine is the extraneuronal O-methylated metabolite
`of epinephrine which is further metabolized to vanillylmandelic acid (VMA), an inactive
`metabolite. Following i. v. administration, metabolites of epinephrine are primarily eliminated in
`the urine. Metabolic profile of epinephrine is shown in Figure 2.
`
` Figure 2: Metabolic profile of
`
`epinephrine [Axelrod 1959]
`
`2.2. What is the proposed mechanism of action of epinephrine? How does it affect the
`important hemodynamic variables?
`
`Epinephrine is a non-selective B- and a-adrenergic agonist. The affinity towards B— is greater than
`a—adrenergic receptors. Epinephrine increases blood pressure by 3 mechanisms: a direct
`myocardial stimulation that increases the strength of ventricular contraction (positive inotropic
`action); an increased heart rate (positive chronotropic action) — both these actions are mediated
`by Bl-adrenergic receptors; and vasoconstriction in many vascular beds — mediated by (11-
`adrenergic receptors.
`
`Table I briefly outlines the efl'ect of epinephrine on cardiac function and blood pressure. Heart
`rate [HR], stroke volume [SV] and in turn cardiac output [CO=SV x HR] are increased due to the
`chronotropic and inotropic actions of epinephrine. An increase in CO leads to a corresponding
`increase in systolic arterial blood pressure [SBP]. However, the magnitude of effect on diastolic
`and mean arterial pressure may depend on the doses of epinephrine used. At relatively small
`doses of 0.1 rig/kg, systemic vascular resistance [SVR] and diastolic blood pressure [DBP] are
`shown to decrease due to the action of epinephrine on Bz-adrenergic receptors causing peripheral
`vasodilation. But, at higher doses, peripheral vasoconstriction mediated by action on the al-
`adrenergic receptors takes over thus leading to a modest increase in DBP. Mean arterial pressure
`[MAP] which is a function of both diastolic and systolic arterial blood pressure [MAP=2/3 x
`DBP + 1/3 x SBP] shows a marginal change at lower epinephrine doses with the increase
`becoming evident as with the increase in epinephrine dose.
`
`Reference ID: 3369769
`
`

`

`Table 1: Qualitative changes in cardiac function and blood pressure following epinephrine
`infusion. Symbols denote: ‘+’ increase, ‘0’ no change, ‘-’ decrease
`
`Epinephrine
`NDA 205029
`
`Effect on cardiac function
`
`+
`Heart beat
`Stroke volume ++
`Cardiac output +++
`Arrhythmias
`++++
`
`Effect on blood pressure
`
`Systolic BP
`Diastolic BP
`SVR
`Mean BP
`
`+++
`-,0,+
`-,0,+
`+
`
`2.3. What is the effect of epinephrine on hemodynamic variables in healthy subjects?
`
`Dose-blood pressure effect of epinephrine in healthy volunteers was evaluated in 3 published
`studies. In these studies, epinephrine was administered as a continuous intravenous infusion in a
`step-wise manner in the dose range: 0.01-0.2 μg/kg/min [Ensinger et al], 0.025-0.1 μg/kg/min
`[Stratton et al], and 0.001-0.064 μg/kg/min [Clutter et al]. Infusion times at a dose level were
`generally short, in the range of 10 to 60 min, as the PK steady state is achieved quickly [approx.
`10 min]. Plasma concentration of epinephrine and hemodynamic variables were also measured at
`steady state following each infusion step. Figure 3 shows a scatter of mean change from baseline
`SBP and HR as a function of mean epinephrine plasma concentration across the 3 studies.
`
`Ensinger, 1992
`Stratton, 1985
`Clutter, 1980
`
`3000
`2000
`1000
`Mean epinephrine plasma concentration (pg/mL)
`
`4000
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Mean change from bsl, SBP (mm Hg)
`
`0
`
`0
`
`A
`
`Reference ID: 3369769
`
`6
`
`

`

`Ensinger, 1992
`Stratton, 1985
`Clutter, 1980
`
`40
`
`30
`
`20
`
`10
`
`Mean change from bsl, HR (bpm
`
`Epinephrine
`NDA 205029
`
`B
`
`0
`
`0
`
`3000
`2000
`1000
`Mean epinephrine plasma concentration (pg/mL)
`Figure 3: Plot of mean change from baseline (A) SBP or (B) HR vs epinephrine plasma
`concentration.
`
`4000
`
`Based on a naïve-pooled data of the study and dose level means, there is a trend for
`concentration dependent increase in cumulative response for SBP as well as HR. With increase
`in epinephrine concentration there was an increase in cumulative response to a maximum of 40
`mmHg and 30 bpm mean change from baseline SBP and HR, respectively for 0.2 μg/kg/min
`dose. The term ‘cumulative response’ is used as the drug effect for any given dose was not
`washed out before the administration of the next incremental dose. As for DBP, there was a
`decrease in mean change from baseline at lower epinephrine doses with a trend for approaching
`baseline at higher epinephrine doses [data not shown]. This is typical for epinephrine (cid:71)(cid:88)(cid:72) (cid:87)(cid:82) (cid:533)2-
`(cid:68)(cid:71)(cid:85)(cid:72)(cid:81)(cid:72)(cid:85)(cid:74)(cid:76)(cid:70) (cid:83)(cid:72)(cid:85)(cid:76)(cid:83)(cid:75)(cid:72)(cid:85)(cid:68)(cid:79) (cid:89)(cid:68)(cid:86)(cid:82)(cid:71)(cid:76)(cid:79)(cid:68)(cid:87)(cid:82)(cid:85)(cid:92) (cid:72)(cid:73)(cid:73)(cid:72)(cid:70)(cid:87) (cid:68)(cid:87) (cid:79)(cid:82)(cid:90)(cid:72)(cid:85) (cid:72)(cid:83)(cid:76)(cid:81)(cid:72)(cid:83)(cid:75)(cid:85)(cid:76)(cid:81)(cid:72) (cid:71)(cid:82)(cid:86)(cid:72)(cid:86) (cid:90)(cid:75)(cid:76)(cid:70)(cid:75) (cid:76)(cid:86) (cid:85)(cid:72)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72)(cid:71) (cid:69)(cid:92) (cid:302)1-
`adrenergic peripheral vasoconstriction at higher doses. There is one limitation that the exposure-
`response experience in healthy subjects is at relatively lower dose range than what is currently
`proposed for septic shock patients: 0.05 to 2.0 μg/kg/min.
`
`2.4. Does epinephrine increase MAP in septic shock patients? Is the proposed dosing
`regimen justified?
`
`Dose-blood pressure effect of epinephrine in septic shock patients was evaluated in a study
`published by Moran et al. In this study, epinephrine was administered as the lone vasopressor by
`continuous intravenous infusion in a step-wise manner in the dose range: 3.0 to 18 μg/min [0.04
`to 0.26 μg/kg/min, assuming a 70 kg human]. Hemodynamics was measured at steady state [20
`min] for each infusion rate. Epinephrine dose was titrated by increments of 3 μg/min until the
`endpoints of inotropic therapy were achieved [target MAP was one of the components]. In
`addition to Moran et al, there were other publications which reported the use of epinephrine in
`case of septic shock. However, these publications only report the mean baseline MAP, mean
`target MAP achieved and the individual or mean maximum stabilized dose that was required to
`bring patients to the desired MAP range.
`
`Reference ID: 3369769
`
`7
`
`

`

`Epinephrine
`NDA 205029
`
`Figure 4 shows a scatter of mean change from baseline MAP as a function of mean epinephrine
`infusion rate across studies. It is evident that epinephrine infusions increase MAP in septic shock
`patients. A trend for a dose-dependent increase in MAP was observed within the Moran et al
`study at lower epinephrine infusion rates. However, when mean study level data from all other
`publications were pooled in, there is no trend for a relationship between epinephrine dose and
`mean change from baseline MAP. The lack of a trend may in part due to the naïve pooled
`analysis without adjusting for the study level difference. However, it may also be due to the fact
`that the response to epinephrine is highly variable in septic shock patients. Figure 5 shows the
`maximal epinephrine infusion rates that were required for each individual patient to achieve a
`target MAP of 65 to 75 mmHg across 5 different studies. It is observed that there is a high degree
`of variability in response as seen by epinephrine infusion rates ranging as wide as 0.026 to 1.67
`μg/kg/min to achieve target MAP [Abboud et al]. Therefore, based on the high inter-patient
`variability in epinephrine response, the proposed dosing regimen of 0.05 to 2.0 μg/kg/min in
`septic shock patients is acceptable.
`
`40
`
`30
`
`20
`
`10
`
`Mean change from bsl, MAP (mmHg)
`
`Moran 1993
`Levi 1997
`Seguin 2002
`Seguin 2006
`Wilson 1992
`Mackenzie 1991
`Lipman 1991
`Bollaert 1990
`Le Tulzo 1997
`Abboud 2009
`
`0
`0.80
`0.60
`0.40
`0.20
`0.00
`Mean epinephrine infusion rate (mcg/kg/min)
`
`Figure 4: Plot of mean change from baseline MAP vs mean epinephrine infusion rate across
`studies.
`
`Reference ID: 3369769
`
`8
`
`

`

`Epinephrine
`NDA 205029
`
`Figure 5: Maximal epinephrine infusion rate required per individual patient to achieve a target
`MAP of 65-75 mmHg across 5 studies in septic shock patients.
`
`2.5. What is effect of important intrinsic factors on the PK and PD of epinephrine?
`
`Age
`Wilkie et al evaluated the age-related changes to plasma catecholamines and their hemodynamic
`response, basally and during epinephrine infusion. Plasma epinephrine levels were lower in
`relatively healthy old men when compared to young adults, as reflected by a 1.5- to 2.0-fold
`higher metabolic clearance (MCR) in the former [Fig. 6]. There was a diminished response in
`systolic blood pressure and heart rate to epinephrine infusion in elder subjects compared to
`baseline, though, hemodynamic variables at baseline were elevated compared to that of healthy
`young adults. The diminished hemodynamic response in elder subjects may be because of lower
`epinephrine plasma levels, or diminished end-(cid:82)(cid:85)(cid:74)(cid:68)(cid:81) (cid:85)(cid:72)(cid:86)(cid:83)(cid:82)(cid:81)(cid:86)(cid:76)(cid:89)(cid:76)(cid:87)(cid:92) (cid:76)(cid:17)(cid:72)(cid:17)(cid:15) (cid:533)-adrenoceptors, or to
`decreased parasympathetic tone, or a combination of all. As epinephrine is titrated to a target
`response in MAP, no dosing adjustments are necessary in the elderly. Please see Appendix for
`individual publication review.
`
`Reference ID: 3369769
`
`9
`
`

`

`Epinephrine
`NDA 205029
`
`”SAL
`
`EPINEPHRINE INFUSION
`(42.9 aging/min)
`
`A
`
`600
`
`~
`E 5”
`‘8'
`'g 400
`E; 300
`g 200
`E
`fl
`
`5 100
`
`Young (n 6)
`
`Ohm 6)
`
`B
`
`200
`
`A
`.5
`g
`s
`E 100
`E
`0
`2
`
`
`
`o
`
`30
`
`so
`as
`‘l’imo (min)
`
`75
`
`as so
`
`0
`
`‘
`
`Young
`
`Old
`
`Figure 6: (A) Mean epinephiine plasma—time course and O3) metabolic clearance rate in healthy
`old vs young adults following epinephrine infusion of 0.043 ug/kg/min. Data expressed as mean
`:l: S.D.
`
`Gender and body weight
`Abboud et 0] evaluated the PK of epinephrine and its covariates in septic shock patients. Body
`weight but not gender was shown to influence PK, with higher body weight associated with
`higher plasma clearance of epinephrine. Dose adjustments for epinephrine are not required as
`‘mg/kg’ dosing is employed.
`
`Renal and hepatic impairment
`The PK and PD of epinephrine have not been evaluated in patients with renal or hepatic
`impairment. However, as shown by Eisenhofer et a], kidneys and liver contribute 25% and 32%,
`respectively to the extraneuronal removal of circulating exogenous epinephrine from plasma.
`High levels of COMT are reported to be found in the kidneys, liver and other extraneuronal
`tissues. Hence, it may be expected that kidney or liver dysfimction may lower epinephrine
`clearance. But, dose—adjustments based on PK changes may not be critical, as (i) the clearance of
`epinephrine is not dependent solely on one organ, and (ii) epinephrine is titrated to effect.
`
`2.6. What is the impact of drug interactions on the pharmacokinetics and
`pharmacodynamics of epinephrine?
`
`Drug interactions between epinephrine and (a) entacapone [a selective COMT inhibitor], (b)
`carvedilol [non-selective B—adrenergic blocker] and (c) propranolol [selective B—adrenergic
`
`Reference ID: 3369769
`
`10
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`

`

`Epinephrine
`NDA 205029
`
`(cid:69)(cid:79)(cid:82)(cid:70)(cid:78)(cid:72)(cid:85)(cid:64) (cid:68)(cid:81)(cid:71) (cid:83)(cid:75)(cid:72)(cid:81)(cid:87)(cid:82)(cid:79)(cid:68)(cid:80)(cid:76)(cid:81)(cid:72) (cid:62)(cid:302)-adrenergic blocker] were assessed in 3 studies. Please see
`Appendix for individual publication review.
`
`(cid:120) When co-administered with entacapone, there was modest potentiation of the chronotropic
`effects of epinephrine in turn augmenting the hemodynamic response [HR, SBP]. However, this
`was not accompanied by changes in epinephrine plasma concentrations [Illi et al].
`
`(cid:120) Upon pre-treatment with carvedilol, a non-(cid:86)(cid:72)(cid:79)(cid:72)(cid:70)(cid:87)(cid:76)(cid:89)(cid:72) (cid:533)-adrenergic antagonist, hemodynamic
`responses to epinephrine infusion was significantly attenuated [Hansen et al].
`
`(cid:120) There was a significant decrease in the metabolic clearance of epinephrine when co-administered
`with propranolol and not phentolamine which suggests epinephrine is predominantly cleared by
`(cid:533)-adrenergic mechanisms in humans [Cryer et al].
`
`In addition, Table 2 lists the class of compounds that is expected to affect the pharmacodynamic
`response to epinephrine based on their mechanisms of action. In the absence of dedicated studies,
`providing the direction of the change in epinephrine response is how best these interactions can
`be addressed. However, any dose-adjustments for interacting co-medications may not be
`required as epinephrine infusion rates are titrated to effect in a controlled medical setting with
`continuous monitoring of hemodynamic variables.
`
`Table 2: Class of drugs that may augment or attenuate epinephrine’s pharmacodynamic response
`Drugs potentiating epinephrine’s effect
`Drugs antagonizing epinephrine’s effect
`(cid:120) (cid:533)-blockers: Cardiopulmonary effects are
`(cid:120) (cid:302)-agonists: e.g. phenylephrine
`antagonized, however, systemic vascular
`(cid:120) Sympathomimetics: e.g. isoproterenol
`resistance may be potentiated due to
`(cid:120) Antidepressants
`unopposed (cid:302)-vasoconstriction at high
`(cid:120) MAO/COMT inhibitors
`epinephrine concentrations
`(cid:120) K+ depleting drugs may potentiate
`(cid:120) Vasodilators: e.g. nitrates
`hypokalemia
`(cid:120) Diuretics
`(cid:120) Cardiac glycosides: Potentiates arrhythmia
`(cid:120) Antihypertensives
`
`Reference ID: 3369769
`
`11
`
`

`

`Epinephrine
`NDA 205029
`
`3. APPENDIX: Individual publication reviews
`
`3.1 Epinephrine disposition:
`
`3.1.1 Eisenhofer et al: J Clin Endocrinol Metab. 1995 Oct;80(10):3009-17
`
`Title: Regional release and removal of catecholamines and extraneuronal metabolism to
`metanephrines
`
`The objective of this publication was to examine the regional release (spillover) and removal of
`norepinephrine (NE), epinephrine (E) and normetanephrine (NMN) and metanephrine* (MN)
`upon infusion of radiolabeled catecholamines. Of relevance, this publication provides
`information on bio-distribution, metabolism and key organs responsible for clearance of both
`norepinephrine and epinephrine.
`
`Briefly, [3H]norepinephrine was administered as intravenous infusion alone [n=29] or in
`combination with [3H]epinephrine [n=65] at 1.0-1.5 (cid:541)(cid:38)(cid:76)(cid:18)(cid:80)(cid:76)(cid:81) (cid:87)(cid:82) (cid:28)(cid:23) (cid:86)(cid:88)(cid:69)(cid:77)(cid:72)(cid:70)(cid:87)(cid:86) (cid:82)(cid:73) (cid:90)(cid:75)(cid:82)(cid:80)(cid:15) (cid:20)(cid:23) (cid:90)(cid:72)(cid:85)(cid:72)
`healthy volunteers and the remaining 80, were patients with angina pectoris, heart failure,
`hypertension, heart transplantations, renal artery stenosis, or carcinoma. Concentrations of
`catecholamines and their metabolites were measured in plasma flowing into and out of various
`organs/tissues such as heart, liver, lungs, kidneys, adrenals, mesenteric organs and forearm to
`examine the regional production of metanephrines from circulating and locally released
`catecholamines. Blood samples were generally collected 15 min after the start of radiolabeled
`infusion of the catecholamine(s). It should be noted that not all blood samples leading into or out
`of the various organs were collected from all subjects.
`
`Unlabeled NE, E, NMN and MN were quantified by liquid chromatography with electrochemical
`detection. The eluents leaving the electrochemical cell were timed and collected for subsequent
`quantification of radiolabeled catecholamines and their metabolites using liquid scintillation
`spectroscopy. Inter- and intra-assay precision as defined by %CV were 12.2%, 11.2%, 6.5%,
`11.4% and 4.2%, 3.3%, 1.9%, 3.0% for NMN, MN, NE and E, respectively. These results are
`within the ±15% limit for precision as per FDA guidance for bioanalytical method validation to
`industry.
`
`Key results:
`
`(cid:120) Organs/tissues responsible for the removal of circulating exogenous epinephrine are liver (32%)
`> kidneys (25%) > skeletal muscle (20%) and mesenteric organs (12%) [Table 3]. Other organs
`such as heart and lungs have minimal contribution (4% and 7%, respectively).
`
`(cid:120) Epinephrine is predominantly produced in the adrenals (91%). Extra-adrenal tissues contribute
`small but detectable levels of epinephrine [Table 3].
`
`* Metanephrines (NMN and MN) are the metabolic products of epinephrine and norepinephrine catalyzed
`extraneuronally by catechol-O-methyl transferase
`
`Reference ID: 3369769
`
`12
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`

`Epinephrine
`NDA 205029
`
`0 A small portion (6%) ofplasma metanephrine was derived from metabolism of circulating
`epinephrine. Most plasma metanephrine (91%) was produced within the adrenals from regionally
`released epinephrine [Table 3]. Liver made the largest contribution (38%) to the production of
`metanephrine from circulating catecholamines [Table 3].
`
`0 Liver makes the largest contribution to the removal of circulating metanephrine (37.4%) [Table
`4].
`
`Table 3: Regional spillover [production] and removal rates of epinephrine; spillovers of
`metanephrine derived from epinephrine released locally or removed from plasma. Values
`represent mean :I: S.E.
`
`E
` Spillover
`
`Released E
`
`MN spillover
`Removed E
`
`Total
`
`
`
`Table 4: Regional fractional extraction of metanephrines. Values represent mean 3: SE.
`
`Fractional
`extraction 1%):
`
`MN
`
`
`
`Reviewer ’3 comment: This publication provides an overview of the organs/tissues involved in the
`extraneuronal production of epinephrine and contribution towards the clearance from plasma. It
`also provides information about the regional source of metanephrine formation and its
`subsequent removal from plasma.
`
`Reference ID: 3369769
`
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`Epinephrine
`NDA 205029
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`3.2 Epinephrine MoA/Pharmacodynamics
`
`3.2.1 Floras et al: Hypertension. 1990 Feb;15(2):132-9
`
`Title: Desipramine blocks augmented neurogenic vasoconstrictor responses to epinephrine
`
`The objective of this publication was to examine if systemic epinephrine augments fore arm
`vasoconstriction and heart rate in response to lower body negative pressure (LBNP), even
`following stoppage of short-term epinephrine infusion. Further, inhibition of the augmented
`response to epinephrine was examined following prior uptake with desipramine. LBNP
`procedure stimulates forearm vasoconstriction and tachycardia by triggering norepinephrine
`release.
`
`The study design was randomized, crossover, double-blind, and placebo-controlled with two
`treatment arms – (a) placebo or (b) desipramine [125 mg p.o.], followed by epinephrine infusion.
`Both treatments were separated by at least 1 week apart. Eight healthy male adults [mean age=30
`y] were enrolled in this study. Epinephrine was intravenously infused at 1.5 μg/min [0.021
`μg/kg/min, assuming a 70 kg adult], 2.5 h following ingestion of desipramine or placebo tablets.
`Responses to LBNP were compared before and 30 min after epinephrine infusion which lasted 1
`h. Blood pressure and heart rate were monitored at 1-min interval during LBNP procedure and at
`3-min interval epinephrine infusion. Forearm blood flow was measured at 1-min interval by
`venous occlusion plethysmography in the non-dominant arm. Forearm vascular resistance was
`calculated by dividing mean arterial pressure by the average forearm blood flow. Venous blood
`samples were collected for assay of catecholamines before and at the last minute of LBNP
`procedure. Plasma catecholamines were analyzed by high-performance liquid chromatography
`with electrochemical detection and reported an inter- and intra-assay CV% of 7.5%. These
`results are within the ±15% limit for precision as per FDA guidance for bioanalytical method
`validation to industry.
`
`Key results:
`
`(cid:120) Plasma levels of norepinephrine increased to LBNP stimuli which was further numerically
`augmented following epinephrine infusion [Table 5].
`
`(cid:120)
`
`Increase in norepinephrine plasma levels translated to augmented forearm vascular resistance
`and heart rate following epinephrine infusion [Table 5].
`
`(cid:120) There was no significant augmentation of other hemodynamic variables [SBP, DBP, MAP, and
`FBF] in response to epinephrine infusion [Table 5].
`
`(cid:120) Following prior administration of desipramine, augmented forearm vascular resistance response
`to epinephrine infusion was inhibited [Table 5]. However, norepinephrine plasma levels were
`still numerically augmented following epinephrine infusion [Table 5]. Heart rate also
`numerically increased following epinephrine infusion in the desipramine pre-treatment arm
`[Table 5].
`
`Reference ID: 3369769
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`Epinephrine
`NDA 205029
`
`Table 5: Hemodynamic variables before and 30 min afier 1.5 [lg/min intravenous infusion of
`epinephrine for l h in healthy male adults. Values are expressed as mean i SE.
`
`
`Placebo day
`
`Before epinephrine
`
`After epinephrine
`
`LBNP
`
`Films:
`With
`
`.a-anse
`
`
`Before epinephrine
`
`After epinephrine
`
`
`
`
`LBNP
`
`Change
`'
`
`LBNP
`
`Orange
`with LBNP
`
`Reviewer ’3 comments: Exogenous epinephrine seems to increase norepinephrine plasma
`concentrations by possibly acting on prejunctional B-adrenoceptors triggering the release of
`norepinephrine. Functionally, this is translated to augmented response to forearm
`vasoconstriction and heart rate following LBNP stimuli, but not SBP, DBP and MAP. Moreover,
`pre-treatment with desipramine, a neuronal uptake inhibitor, seem to diminish the augmented
`response to epinephrine, however, without significantly inhibiting endogenous norepinephrine
`release.
`
`Reference ID: 3369769
`
`15
`
`

`

`Epinephrine
`NDA 205029
`
`3.2.2 Jern et al: Hypertension. 1991 Oct;18(4):467-74
`
`Title: Infusion of epinephrine augments pressor responses to mental stress
`
`The objective of the publication was to examine the possible effects and after effects of
`epinephrine on the hemodynamic reactivity to mental stress. The hypothesis tested was that the
`exogenous or circulating epinephrine may augment the simultaneous release of endogenous
`norepinephrine both during and after periods of sympathoadrenal activation and thereby
`contribute to development of stress-linked hypertension.
`
`The study design was randomized, crossover, double-blind, and placebo-controlled with two
`treatment arms – intravenous infusion for 35 min of (a) 0.05 μg/kg/min epinephrine or (b)
`placebo, separated by at least 1 week apart. Mental stress tests, which lasted 15 min, were carried
`out both during the infusion of epinephrine/placebo and 1 h after the end of infusion. Fourteen
`young, normotensive male adults [mean age=27 y, mean weight=77 kg] without a history of
`smoking and cardiovascular disorders were enrolled in this study. Systolic and diastolic blood
`pressure was measured at 1-min intervals non-invasively in the non-dominant arm. Heart rate
`was continuously monitored. Venous blood samples were collected for assay of catecholamines
`at 10, 25, 35, 45, 55, 105, 115 and 125 min following start of infusion. Plasma catecholamines
`were analyzed by high-performance liquid chromatography with electrochemical detection.
`
`Key results:
`
`(cid:120) Following epinephrine infusion, stress-induced heart rate and systolic blood pressure were
`augmented when compared to the placebo arm [Table 6].
`
`(cid:120) As observed in other studies, there was an immediate drop in diastolic blood pressure upon
`infusion with epinephrine during pre-stress period [Table 6]. This drop prevents any
`augmentation of stress-induced diastolic blood pressure response following epinephrine infusion.
`
`(cid:120) There was no change in the epinephrine plasma levels when compared to baseline following
`placebo infusion during periods of stress [Table 6]. Therefore, the increase in stress-induced
`hemodynamic response in the placebo arm cannot be attributed to circulating epinephrine.
`
`(cid:120)
`
`In addition, there was only