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`Case 3:20-cv-18322-BRM-DEA Document 1-1 Filed 12/07/20 Page 1 of 17 PageID: 25
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`EXHIBIT A
`
`EXHIBIT A
`
`

`

`Case 3:20-cv-18322-BRM-DEA Document 1-1 Filed 12/07/20 Page 2 of 17 PageID: 26
`case3:20'CV'18322'BRM'DEA W“)1111111111110110111111111111111 26
`
`US010844435B1
`
`(12) United States Patent
`US 10,844,435 B1
`(10) Patent No.:
`(45) Date of Patent:
`Nov. 24, 2020
`Vijayan
`
`(54) METHOD TO TREAT HYPOTENSION USING
`VASOPRESSIN IN CERTAIN GENOTYPES
`
`(71) Applicant: Par Pharmaceutical, Inc., Chestnut
`Ridge, NY (US)
`
`(72)
`
`Inventor: Saji Vijayan, Chester Springs, PA (US)
`
`(73) Assignee: PAR PHARMACEUTICAL, INC.,
`Chestnut Ridge, NY (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 16/932,351
`
`(22)
`
`Filed:
`
`Jul. 17, 2020
`
`(51)
`
`Int. Cl.
`CI2Q 1/6883
`A61P 9/02
`A61K 38/095
`(52) us. Cl.
`CPC .......... CI2Q 1/6883 (2013.01); A61K 38/095
`(2019.01); A61P 9/02 (2018.01); C12Q
`2600/106 (2013.01)
`
`(2018.01)
`(2006.01)
`(2019.01)
`
`(58) Field of Classification Search
`CPC
`C12Q 1/6883; C12Q 2600/106; A61P 9/02;
`A61K 38/095
`
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`
`
`6/2016 Kenney .................. A61K47/10
`9,375,478 B1*
`6/2017 Kenney
`A61K38/22
`9,687,526 B2*
`8/2017 Kenney
`A61K47/02
`9,744,209 B2*
`8/2017 Kenney
`A61K47/10
`9,744,239 B2*
`9/2017 Kenney
`G01N 30/88
`9,750,785 B2*
`3/2018 Kenney
`.. A61K31/045
`9,919,026 B2*
`4/2018 Grobe ......
`.. A61K 31/404
`9,937,182 B2 *
`4/2018 Kenney
`A61K47/02
`9,937,223 B2*
`2009/0298711 A1* 12/2009 Russell
`................ C12Q 1/6883
`506/16
`
`2015/0374698 A1
`2015/0377876 A1
`2018/0228806 A1
`
`12/2015 Grobe et a1.
`12/2015 Grobe et a1.
`8/2018 Grobe et a1.
`
`OTHER PUBLICATIONS
`
`Argenziano et a1.; “A prospective randomized trial of arginine
`vasopressin in the treatment of vasodilatory shock after left ven-
`tricular assist device placement;” Circulation; 1997; 96 (9 Suppl);
`pp. 286-290.
`Choong et a1.; “Vasopressin in pediatric shock and cardiac arrest;”
`Pediatr Crit Care Med; 2008; 9; pp. 372-379.
`Holmes et a1.; “Science review: Vasopressin and the cardiovascular
`system part 1-receptor physiology;” Crit Care; 2003; 7; pp. 427-
`434.
`Jochberger et a1.; “The vasopressin and copeptin response to infec-
`tion, severe sepsis, and septic shock;” Crit Care Med; 2009; 37; pp.
`476-482.
`Landry et a1.; Vasopressin Deficiency Contributes to the Vasodila-
`tion of Septic Shock, Circulation; 1997; 95; pp. 1122-1125.
`
`
`
`Landry et a1.; “The pathogenesis of vasodilatory shock;” N Engl J
`VIed; 2001; 345; pp. 588-595.
`Levin et al.; “Association between arginine vasopressin 1a receptor
`(AVPRla) promoter region polymorphisms and prepulse inhibi-
`tion;” Psychoneuroendocrinology; 2009; 34(6) p. 901-908.
`VIatsumoto et al.; “Characterization of a recombinant soluble form
`of human placental leucine aminopeptidase/oxytocinase expressed
`in Chinese hamster ovary cells;” Eur J Biochem; 2000; 267(1); pp.
`46-52.
`VIekontso-Dessap et a1.; “Risk factors for post-cardiopulmonary
`bypass vasoplegia in patients with preserved left ventricular func-
`tion;” Ann Thorac Surg; 2001; 71(5); pp. 1428-1432.
`Vlohring et a1.; “Greatly enhanced pressor response to antidiuretic
`hormone in patients with impaired cardiovascular reflexes due to
`idiopathic orthostatic hypotension;” J Cardiovasc Pharmacol; 1980;
`2(4); pp. 367-376.
`VIoses et a1.; “Urinary and metabolic clearances of arginine vaso-
`pressin in normal subjects;” Am J Physiol;1986; 251 (Regulatory
`Integration Comp. Physiol. 20); pp. R365-R370.
`\Iakada et al. “Leucyl/cystinyl aminopeptidase gene variants in
`septic shock;” Chest; 2011; 139(5); pp. 1042-1049.
`Russell J.; “Vasopressin in vasodilatory and septic shock;” Curr
`Opin Crit Care; 2007; 13; pp. 383-391.
`Russell et. al.; “Vasopressin versus Norepinephrine infusion in
`patients with septic shock;” N Engl J Med; 2008; 358 (9) pp.
`877-887.
`Vasostrict (vasopressin injection, USP) [package insert]. Par Phar-
`maceutical Companies, Inc.; Chestnut Ridge (NY); 2019, 2 pages.
`Wallis et a1.; “Vasopressin is a physiological substrate for the
`insulin-regulated aminopeptidase IRAP;” Am J Physiol Endocrinol
`Metab; 2007; 293(4); pp. E1092-E1102 (first published on Aug. 7,
`2007).
`Ramirez-Exposito et a1.; “A PCR-RFLP method for detection of the
`LNPEP encoding human insulin-regulated aminopeptidase (IRAP)
`rs4869317 polymorphism;” Indian J Med Res; Jul. 2016; 144(1);
`pp. 120-123.
`Kondo et a1.; “The clinical course and pathophysiological investi-
`gation of adolescent gestational diabetes insipidus: a case report”
`BMC Endocrine Disorders; Jan. 30, 2018; 18(1):4 (8 pages); doi:
`10.1186/s12902-018-0234-6.
`“The Use of Vasopressin for Septic Shock;” date May 6, 2003,
`accessed online at http://www.surgicalcriticalcare.net/Guidelines/
`vasopressinpdf on Jul. 3, 2020. (Year: 2003).
`Hajjar et a1.; “Vasopressin versus Norepinephrine in Patients with
`Vasoplegic Shock after Cardiac Surgery;” Anesthesiology, vol. 126,
`pp. 85-93. (Year: 2017).
`Anantasit et a1.; “Serious Adverse Events Associated with Vasopress-
`sin and Norepinephrine Infusion in Septic Shock;” Critical Care
`Medicine, 2014. vol. 42, No. 8, pp. 1812-1820. (Year: 2014).
`Kristensen et a1.; “High-throughput methods for detection of genetic
`variation;” BioTechniques; Feb. 2001; 30:318-332.
`Tsuchihashi et a1.; “Progress in high throughput SNP genotyping
`methods;” The Pharmacogenomics Journal; (2002) 2; pp. 103-110.
`Edenberg et a1.; “Chapter 16: Laboratory methods for high-
`throughput genotypingf’ Cold Spring Harbor Laboratory Press;
`2009; pp. 183-193.
`
`(Continued)
`
`Primary Examiner 7 Marcela M Cordero Garcia
`(74) Attorney, Agent, or Firm 7 Mayer Brown LLP
`
`(57)
`
`ABSTRACT
`
`The present disclosure relates to a method of treating a
`patient experiencing hypotension, comprising genotyping
`for a TT, AA, or AT genotype, and administering a thera-
`peutically effective amount of vasopressin based on geno-
`type to maintain a target blood pressure.
`
`6 Claims, 2 Drawing Sheets
`
`

`

`Case 3:20-cv-18322-BRM-DEA Document 1-1 Filed 12/07/20 Page 3 of 17 PageID: 27
`Case 3:20-cv-18322-BRM-DEA Document 1-1 Filed 12/07/20 Page 3 of 17 PageID: 27
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`US 10,844,435 B1
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Young et a1.; “Deconstructing the sources of genotype-phenotype
`associations in humans;” Science; Sep. 27, 2019; 365(6460); pp.
`1396-1400 (Author Manuscript; 18 pages).
`Moses et a1.; “Effects of Sodium Intake, Furosemide, and Infusion
`of Atrial Natriuretic Peptide on the Urinary and Metabolic Clear-
`ances ofArginine Vasopressin in Normal Subjectsg” J Clin Endocrinol
`Metab; 1990; 70: 222-229.
`Varpula et a1.; “Hemodynamic variables related to outcome in septic
`shock;” Intensive Care Med (2005) 31:1066-1071.
`Moman et a1.; “Impact of individualized target mean arterial pres-
`sure for septic shock resuscitation on the incidence of acute kidney
`injury: a retrospective cohort study;” Ann. Intensive Care (2018)
`8:124 (10 pages).
`
`* cited by examiner
`
`

`

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`U.S. Patent
`
`Nov. 24, 2020
`
`Sheet 1 0f2
`
`US 10,844,435 B1
`
`
`
`Type of vasodilatory
`shock
`
`
`
`
`
`
`Post- cardiotomy
`Sepsis
`
`
`
`
`AA or AT rs4869317
`TT rs4869317 genotype
`AA or AT rs4869317
`TT rs4869317 genotype
`or status unknown
`genotype
`or status unknown
`genotype
`
`
`
`
`Initial Dose:
`Initial Dose:
`Initial Dose:
`Initial Dose:
`0.03 units/minute
`0.03 units/minute
`0.01 units/minute
`0.01 units/minute
`
`
`
`Titration:
`Titration:
`Titration:
`Titration:
`titrate up by 0.005
`titrate up by 0.005
`titrate up by 0.005
`titrate up by 0.05
`units/minute as needed
`units/minute as needed
`units/minute as needed
`units/minute as needed
`at 10- to 15-minute
`at 10- to 15-minute
`at 10- to 15-minute
`at 10- to 15-minute
`
`intervals.
`intervals.
`intervals.
`intervals.
`
`
`
`
`
`
`
`
`
`
`Maximum Dose:
`0.1 units/minute
`
`Maximum Dose:
`0.121 units/minute
`
`Maximum Dose:
`0.07 units/minute
`
`Maximum Dose:
`0.085 units/minute
`
`
`
`After target blood pressure has been maintained for 8 hours without the use 0'
`catecholamines, taper Vasostrict® by 0.005 units/minute every hour as
`tolerated to maintain target blood pressure.
`
`
`
`
`
`Figure 1
`
`

`

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`
`U.S. Patent
`
`Nov. 24, 2020
`
`Sheet 2 0f 2
`
`US 10,844,435 B1
`
`
`
`Type of vasodilatory
`shock
`
`
`
`
`
`
`Post- cardiotomy
`Sepsis
`
`
`
`
`AA or AT rs4869317
`'I'I' rs4869317
`AA or AT rs4869317
`'I'I' rs4869317
`genotype
`genotype or status
`genotype
`genotype or status
`unknown
`unknown
`
`
`
`
`Initial Dose:
`Initial Dose:
`Initial Dose:
`Initial Dose:
`0.03 units/minute
`0.03 units/minute
`0.01 units/minute
`0.01 units/minute
`
`
`
`Titration:
`Titration:
`Titration:
`Titration:
`titrate up by 0.005
`titrate up by 0.005
`titrate up by 0.005
`titrate up by 0.05
`units/minute as needed
`units/minute as needed
`units/minute as needed
`units/minute as needed
`at 10- to 15-minute
`at 10- to 15-minute
`at 10- to 15-minute
`at 10- to 15-minute
`
`intervals.
`intervals.
`intervals.
`intervals.
`
`
`
`
`
`
`
`
`
`
`Maximum Dose:
`0.073 units/minute
`
`Maximum Dose:
`0.1 units/minute
`
`Maximum Dose:
`0.051 units/minute
`
`Maximum Dose:
`0.07 units/minute
`
`
`
`After target blood pressure has been maintained for 8 hours without the use 0'
`catecholamines, taper Vasostrict® by 0.005 units/minute every hour as
`tolerated to maintain target blood pressure.
`
`
`
`
`
`Figure 2
`
`

`

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`US 10,844,435 B1
`
`1
`METHOD TO TREAT HYPOTENSION USING
`VASOPRESSIN IN CERTAIN GENOTYPES
`
`TECHNICAL FIELD
`
`invention relates to the field of treating
`The present
`hypotension and related conditions.
`
`BACKGROUND
`
`Vasopressin is a neurohypophyseal peptide hormone with
`diverse actions that are mediated by tissue-specific recep-
`tors, which are classified into V1 vascular, V2 renal, V3
`pituitary, oxytocin, and P2 purinergic subtypes. The chemi-
`cal name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-
`Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L-
`Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide.
`The
`molecular formula is C46H65N15012S2 with a molecular
`weight of 1084.23 Da.
`VASOSTRICT® (vasopressin injection, USP) was
`approved by the United States Food and Drug Administra-
`tion in 2014 to increase blood pressure in adults with
`vasodilatory shock (e.g., post-cardiotomy or sepsis) who
`remain hypotensive despite treatment with fluids and cat-
`echolamines. VASOSTRICT® is a solution for intravenous
`
`(IV) administration available as 20 units/mL in a single dose
`vial and 200 units/ 10 mL (20 units/mL) in a multiple dose
`vial.
`
`overdosage with
`that
`art
`the
`in
`known
`is
`It
`VASOSTRICT® can be expected to manifest as conse-
`quences of vasoconstriction of various vascular beds (pe-
`ripheral, mesenteric, and coronary) and as hyponatremia. It
`was additionally known in the art that overdosage with
`VASOSTRICT® may lead less commonly to ventricular
`tachyarrhythmias (including Torsade de Pointes),
`rhab-
`domyolysis, and non-specific gastrointestinal symptoms.
`The enzyme leucyl/cystinyl aminopeptidase (“LNPEP” or
`“vasopressinase”) degrades vasopressin and is primarily
`responsible for the short (~4 to ~24 minute) half-life of
`vasopressin (Nakada et al., “Leucyl/Cystinyl Aminopepti—
`dase Gene Variants in Septic Shock,” Chest 139 (5): 1042-49
`(2011)). For this reason, Nakada et al. hypothesized that
`genetic variations in the vasopressin pathway genes, includ-
`ing the gene that encodes for LNPEP, may cause a down-
`stream clinical effect in patients experiencing septic shock.
`They screened available DNA from 616 septic shock
`patients who participated in the Vasopressin and Septic
`Shock (VASST) trial, a multicenter, randomized, double
`blind, controlled trial evaluating the efficacy of vasopressin
`versus norepinephrine (Russell et. al.; “Vasopressin Versus
`Norepinephrine Infusion in Patients with Septic Shock,” N.
`Engl. J. Med. 358 (9): 877-887 (2008)). From these, Nakada
`and coworkers identified 230 single nucleotide polymor-
`phisms (SNPs) and screened those for any association with
`mortality rate seen in the VASST trial. It was found that the
`major [T] allele of LNPEP rs4869317 [A/T] SNP correlated
`with an increase in the 28-day mortality. 1d. From this, a
`major allele model (TT vs. AA/AT genotype) was estab-
`lished. Nakada et al. found that patients of the TT genotype
`appeared to have a higher hazard ratio compared with the
`AA or AT (a/k/a TA) genotyped patients and also appeared
`to have exhibited an increase in vasopressin clearance over
`the AA or AT genotyped patients.
`Anantasit et al. (“Serious Adverse Events Associated With
`Vasopressin and Norepinephrine Infusion in Septic Shock,”
`Crit. Care Med. 42 (8): 1812-20 (2014)) also analyzed
`patients from the above-referenced VASST trial. Anantasit
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`hypothesized that SNPs of candidate genes of the vasopres-
`sin pathway and/or plasma arginine vasopressin (AVP) lev-
`els could predict serious adverse events in patients who had
`septic shock who received vasopressin.
`1d. Anantasit
`reported that septic shock patients with the TT/TA genotype
`had statistically significant higher AVP blood levels than
`those with the AA genotype. 1d. at FIG. 2. Anantasit also
`concluded that patients who had the AA genotype had
`significantly higher rates of serious adverse events, but that
`the mechanism of this association requires further investi-
`gation.
`Therefore, because of the unpredictable nature of phar-
`maceutical dosing to achieve safety and efficacy, there is a
`need in the art to better understand the dosing, efficacy and
`safety of vasopressin administration in patients having the
`TT, AA and AT genotypes.
`
`SUMMARY
`
`The present disclosure satisfies the above need and relates
`to methods of treating patients experiencing hypotension,
`particularly in patients having or evincing the TT, AA, or AT
`genotype. In light of what was known from the above
`literature, Applicant surprisingly found that patients with the
`AA or AT genotype have lower serum concentrations of
`vasopressin and increased clearance while TT genotype
`patients exhibited increased serum concentrations and lower
`vasopressin clearance as compared to the AA or AT geno-
`typed patients. The treatment methods described herein
`generally comprise determining whether the patient is the
`TT, AA, or AT genotype, and then administering a dosing
`regimen of vasopressin based on genotype. The methods of
`the present invention result in improved survival rates and/or
`reduction of adverse events in TT, AA, and AT genotype
`patients who experience acute conditions, such as shock.
`In one embodiment, the present disclosure relates to a
`method of increasing blood pressure in a patient having the
`AA or AT genotype and experiencing po st-cardiotomy shock
`by administering to such patient a dose of vasopressin that
`is
`higher
`than
`the
`currently
`labeled
`dose
`for
`VASOSTRICT®. Such increased dose may be achieved by
`increasing one or more of (a) the starting dose; (b) the
`titration dose; and/or (0)
`the maximum dose.
`In some
`embodiments, the total increased dose is at least 5% higher
`than the labeled dose for VASOSTRICT®, or about 5% to
`40% higher, or about 10% to 30% higher, or about 15% to
`25% higher, or about 20% higher, or about 30% higher than
`the labeled dose for VASOSTRICT®.
`
`In another embodiment, the present disclosure relates to a
`method of increasing blood pressure in a patient having the
`AA or AT genotype and experiencing septic shock by
`administering to such patient a dose of vasopressin that is
`higher than the currently labeled dose for VASOSTRICT®.
`Such increased dose may be achieved by increasing one or
`more of (a) the starting dose; (b) the titration dose; and/or (c)
`the maximum dose.
`In some embodiments,
`the total
`increased dose is at least 5% higher than the labeled dose for
`VASOSTRICT®, or about 5% to 40% higher, or about 10%
`to 30% higher, or about 15% to 25% higher, or about 20%
`higher, or about 30% higher than the labeled dose for
`VASOSTRICT®.
`
`The present disclosure further relates to a method of
`increasing blood pressure in a patient having the TT geno-
`type and experiencing post-cardiotomy shock by adminis-
`tering to such patient a dose of vasopressin that is lower than
`the currently labeled dose for VASOSTRICT®. Such low-
`ered dose may be achieved by decreasing one or more of (a)
`
`

`

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`US 10,844,435 B1
`
`3
`the
`the titration dose; and/or (c)
`(b)
`the starting dose;
`maximum dose. In some embodiments, the total decreased
`dose is at
`least 5% lower than the labeled dose for
`VASOSTRICT®, or about 5% to 40% lower, or about 10%
`to 30% lower, or about 15% to 25% lower, or about 20%
`lower, or about 30% lower than the labeled dose for
`VASOSTRICT®.
`
`In another embodiment, the present disclosure relates to a
`method of increasing blood pressure in a patient having the
`TT genotype and experiencing septic shock by administer-
`ing to such patient a dose of vasopressin that is lower than
`the currently labeled dose for VASOSTRICT®. Such low-
`ered dose may be achieved by decreasing one or more of (a)
`the starting dose;
`(b)
`the titration dose; and/or (c)
`the
`maximum dose. In some embodiments, the total decreased
`dose is at
`least 5% lower than the labeled dose for
`VASOSTRICT®, or about 5% to 40% lower, or about 10%
`to 30% lower, or about 15% to 25% lower, or about 20%
`lower, or about 30% lower than the labeled dose for
`VASOSTRICT®.
`
`In some aspects, the present disclosure relates to a method
`of increasing blood pressure in a human patient with post-
`cardiotomy shock, comprising: (a) determining whether the
`patient has the LNPEP genotype AA or AT; (b) if the patient
`has the AA or AT genotype, intravenously administering to
`the patient a pharmaceutical formulation comprising vaso-
`pressin at a starting dose of about 0.03 units/minute; and (c)
`if a target blood pressure is not achieved at the starting dose,
`titrating the vasopressin dose upward by 0.005 units/minute
`at intervals of about 10 to 15 minutes up to a maximum dose
`wherein the maximum dose is at least 5% higher than a
`maximum dose for a patient who does not have the AA or AT
`genotype. For example, the starting dose for the patient
`having the AA or AT genotype is about 0.03 units/minute,
`and the maximum dose for the patient having the AA or AT
`genotype is about 0.1 to 0.15 units/minute. Alternatively, the
`maximum dose for the patient having the AA or AT genotype
`is about 0.121 units/minute.
`
`In another embodiment, the present disclosure relates to a
`method of increasing blood pressure in a human patient with
`septic shock, comprising:
`(a) determining whether the
`patient has the LNPEP genotype AA or AT; (b) if the patient
`has the AA or AT genotype, intravenously administering to
`the patient a pharmaceutical formulation comprising vaso-
`pressin at a starting dose of about 0.01 units/minute; and (c)
`if a target blood pressure is not achieved at the starting dose,
`titrating the vasopressin dose upward by 0.005 units/minute
`at intervals of about 10 to 15 minutes up to a maximum dose
`wherein the maximum dose is at least 5% higher than a
`maximum dose for a patient who does not have the AA or AT
`genotype. For example, the starting dose for the patient
`having the AA or AT genotype is about 0.01 units/minute,
`and the maximum dose for the patient having the AA or AT
`genotype is about 0.07 to 0.1 units/minute.
`In certain
`aspects, the maximum dose for the patient having the AA or
`AT genotype is about 0.085 units/minute.
`The present disclosure further relates to a method of
`increasing blood pressure in a human patient with post-
`cardiotomy shock, comprising: (a) determining whether the
`patient has the LNPEP genotype AA or AT; (b) if the patient
`has the AA or AT genotype, intravenously administering to
`the patient a pharmaceutical formulation comprising vaso-
`pressin at a starting dose of about 0.03 units/minute; and (c)
`if a target blood pressure is not achieved at the starting dose,
`titrating the vasopressin dose upward by 0.005 units/minute
`at intervals of about 10 to 15 minutes up to a maximum dose
`wherein the maximum dose is at least 10% higher than a
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`
`maximum dose for a patient who does not have the AA or AT
`genotype. For example, the maximum dose for the patient
`having the AA or AT genotype is about 0.121 units/minute
`achieved with about 18 continuous titrations in about 3 to
`4.5 hours.
`
`In another embodiment, the present disclosure relates to a
`method of increasing blood pressure in a human patient with
`septic shock, comprising:
`(a) determining whether the
`patient has the LNPEP genotype AA or AT; (b) if the patient
`has the AA or AT genotype, intravenously administering to
`the patient a pharmaceutical formulation comprising vaso-
`pressin at a starting dose of about 0.01 units/minute; and (c)
`if a target blood pressure is not achieved at the starting dose,
`titrating the vasopressin dose upward by 0.005 units/minute
`at intervals of about 10 to 15 minutes up to a maximum dose
`wherein the maximum dose is at least 10% higher than a
`maximum dose for a patient who does not have the AA or AT
`genotype. For example, the maximum dose for the patient
`having the AA or AT genotype is about 0.085 units/minute
`achieved with 15 continuous titrations in about 2.5 to 3.75
`hours.
`the increased doses needed to
`In other embodiments,
`successfully treat a AA or AT genotype patient may be linear
`based on the percent increase in clearance versus an other-
`wise comparable TT genotype patient. For example, when
`the percent increase in clearance in a AA or AT genotype
`patient is about 5%, 10%, 20%, 30%, 40%, 50%, 60%, etc.,
`then the dose is increased linearly by about 5%, 10%, 20%,
`30%, 40%, 50%, 60%, etc. In other embodiments,
`the
`amount of increased dose needed to maintain target blood
`pressure is not linearly related to the percent decrease in
`clearance. For example, when the percent increase in clear-
`ance in an AA or AT genotype patient is about 5%, 10%,
`20%, 30%, 40%, 50%, 60%, etc., then the dose is increased
`by about 1% to 50%, or about 2% to 40%, or about 5% to
`35%, or about 10% to 30%, or about 15% to 25%.
`Additionally, the decreased doses needed to successfully
`treat a TT genotype patient may be linear based on the
`percent decrease in clearance versus an otherwise compa-
`rable AA/AT genotype patient. For example, when the
`percent decrease in clearance in a TT genotype patient is
`about 5%, 10%, 20%, 30%, 40%, 50%, 60%, etc., then the
`dose is decreased linearly by about 5%, 10%, 20%, 30%,
`40%, 50%, 60%, etc. In other embodiments, the amount of
`decreased dose needed to maintain target blood pressure is
`not linearly related to the percent decrease in clearance. For
`example, when the percent decrease in clearance in a TT
`genotype patient is about 5%, 10%, 20%, 30%, 40%, 50%,
`60%, etc., then the dose is decreased by about 1% to 50%,
`or about 2% to 40%, or about 5% to 35%, or about 10% to
`30%, or about 15% to 25%.
`Additional embodiments of the present methods, compo-
`sitions and the like will be apparent from the following
`description, drawings, examples, and claims. As can be
`appreciated from the foregoing and following description,
`each and every feature described herein, and each and every
`combination of two or more of such features, is included
`within the scope of the present disclosure provided that the
`features included in such a combination are not mutually
`inconsistent. The order of method steps stated herein are
`non-limiting and may vary yet achieve the objectives of the
`present invention. In addition, any feature or combination of
`features may be specifically excluded from any embodiment
`or aspect. Additional aspects and embodiments are set forth
`in the following description and claims, particularly when
`considered in conjunction with the accompanying examples
`and drawings.
`
`

`

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`US 10,844,435 B1
`
`5
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The foregoing features of embodiments will be more
`readily understood by reference to the following detailed
`description, taken with reference to the accompanying draw-
`ings, in which:
`FIG. 1 is a flow chart of a dosing recommendation for
`patients with the TT rs4869317 Genotype, or AA/AT
`rs4869317 Genotype, or genotype status unknown.
`FIG. 2 is a flow chart of a dosing recommendation for
`patients with the TT rs4869317 Genotype, or AA/AT
`rs4869317 Genotype, or genotype status unknown.
`
`DETAILED DESCRIPTION
`
`The various aspects and embodiments will now be fully
`described herein. These aspects and embodiments may,
`however, be embodied in many different forms and should
`not be construed as limiting; rather, these embodiments are
`provided so the disclosure will be thorough and complete,
`and will fully convey the scope of the present subject matter
`to those skilled in the art. All publications, patents and patent
`applications cited herein, whether supra or infra, are hereby
`incorporated by reference in their entirety.
`Unless defined otherwise, all
`terms and phrases used
`herein include the meanings that the terms and phrases have
`attained in the art, unless the contrary is clearly indicated or
`clearly apparent from the context in which the term or phrase
`is used. Although any methods and materials similar or
`equivalent to those described herein can be used in the
`practice or testing of the present invention, particular meth-
`ods and materials are now described.
`Unless otherwise stated, the use of individual numerical
`values are stated as approximations as though the values
`were preceded by the word “about” or “approximately.”
`Similarly, the numerical values in the various ranges speci-
`fied in this application, unless expressly indicated otherwise,
`are stated as approximations as though the minimum and
`maximum values within the stated ranges were both pre-
`ceded by the word “about” or “approximately.” In this
`manner, variations above and below the stated ranges can be
`used to achieve substantially the same results as values
`within the ranges. As used herein, the terms “about” and
`“approximately” when referring to a numerical value shall
`have their plain and ordinary meanings to a person of
`ordinary skill in the art to which the disclosed subject matter
`is most closely related or the art relevant to the range or
`element at issue. The amount of broadening from the strict
`numerical boundary depends upon many factors. For
`example, some of the factors which may be considered
`include the criticality of the element and/or the effect a given
`amount of variation will have on the performance of the
`claimed subject matter, as well as other considerations
`known to those of skill in the art. As used herein, the use of
`differing amounts of significant digits for different numerical
`values is not meant to limit how the use of the words “about”
`
`or “approximately” will serve to broaden a particular
`numerical value or range. Thus, as a general matter, “about”
`or “approximately” broaden the numerical value. Also, the
`disclosure of ranges is intended as a continuous range
`including every value between the minimum and maximum
`values plus the broadening of the range afforded by the use
`of the term “about” or “approximately.” Consequently, reci-
`tation of ranges of values herein are merely intended to serve
`as a shorthand method of referring individually to each
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`separate value falling within the range, and each separate
`value is incorporated into the specification as if it were
`individually recited herein.
`A. Introduction
`
`Vasopressin can be used to regulate plasma osmolality
`and volume, and diseases and conditions related to the same
`in a patient. For example, vasopressin can be used to
`modulate blood pressure, and can be indicated in a subject
`who is hypotensive despite treatment with fluid and cat-
`echolamines. Thus, vasopressin can be used in the treatment
`of, for example, vasodilatory shock, post-cardiotomy shock,
`sepsis, septic shock, cranial diabetes insipidus, polyuria,
`nocturia, polydypsia, bleeding disorders, Von Willebrand
`disease, hemophilia, platelet disorders, cardiac arrest, liver
`disease, liver failure, hypovolemia, hemorrhage, esophageal
`variceal hemorrhage, hypertension, pulmonary hyperten-
`sion, renal disease, polycystic kidney disease, blood loss,
`injury, hypotension, Meniere disease, uterine myomas, brain
`injury, and mood disorder. Formulations of vasopressin can
`be administered to a subject undergoing, for example, sur-
`gery or hysterectomy.
`The vasopressin formulations described herein are used to
`achieve a target blood pressure desired by the treating
`physician. In certain aspects, the target blood pressure for a
`healthy human adult can range from about 90/60 to about
`120/80 mm Hg, or can range from about 80/50 to about
`110/70 mm Hg, or from 70/40 to about 100/60. Hyperten-
`sion can be a blood pressure reading above about 120/80,
`and can be classified as hypertensive crisis when there is a
`spike in blood pressure and blood pressure readings reach
`about 180/110 or higher. Hypertensive crisis can be precipi-
`tated by, for example, stroke, myocardial infarction, heart
`failure, kidney failure, aortic rupture, drug-drug interactions,
`and eclampsia. Symptoms of hypertensive crisis can include,
`for example, shortness of breath, angina, back pain, numb-
`ness, weakness, dizziness, confusion, change in vision,
`nausea, and difficulty speaking.
`Vasodilatory shock can be characterized by low arterial
`blood pressure due to decreased systemic vascular resis-
`tance. Vasodilatory shock can lead to dangerously low blood
`pressure levels and can be corrected via administration of
`catecholamines or vasopressin formulations. Vasodilatory
`shock can be caused by,
`for example, sepsis, nitrogen
`intoxication, carbon monoxide intoxication, hemorrhagic
`shock, hypovolemia, heart failure, cyanide poisoning, met-
`formin intoxication, and mitochondrial disease.
`Post-cardiotomy shock can occur as a complication of
`cardiac surgery and can be characterized by, for example,
`inability to wean from cardiopulmonary bypass, poor hemo-
`dynamics in the operating room, development of poor hemo-
`dynamics post-surgery, and hypotension.
`B. Vasopressin Compositions and Dosing
`Various vasopressin pharmaceutical formulations are use-
`ful in the present invention. Vasopressin can be formulated
`as an aqueous formulation or a lyophilized powder, which
`can be diluted or reconstituted just prior to use. Upon
`dilution or reconstitution, the vasopressin solution may be
`refrigerated for long-term stability. In some embodiments, a
`pharmaceutical composition of the invention can be formu-
`lated for long-term storage of vasopressin at room tempera-
`ture in the presence of one or more suitable pharmaceuti-
`cally-acceptable
`excipients.
`The
`pharmaceutically-
`acceptable
`excipient(s)
`can increase
`the half-life of
`vasopressin when stored at any temperature, such as room
`temperature.
`The
`presence
`of
`the
`pharmaceutical
`excipient(s) can decrease the rate of decomposition of
`vasopressin at any temperature, such as room temperature. A
`
`

`

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`US 10,844,435 B1
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`7
`number of vasopressin formulations and their use are dis-
`closed in US. Pat. Nos. 9,925,233; 9,744,209; and 9,750,
`785, which are incorporated herein by reference.
`One non-limiting formulation is vasopressin injection,
`USP (20 units/mL) for intravenous injection, as described in
`the prescribing information for VASOSTRICT®. The vaso-
`pressin formulations according to the present disclosure may
`be diluted to a variety of concentrations using normal saline
`(0.9% sodium chloride) or 5% dextrose in water (DSW),
`e.g.: About 0.01 to 2 units/mL, or about 0.05 to 1.5 units/mL,
`or about 0.1 to 1 units/mL, or about 0.06 units/mL, or about
`0.07 units/mL, or about 0.08 units/mL, or about 0.09 units/
`mL, or about 0.1 units/mL, or about 0.2 units/mL, or about
`0.3 units/mL, or about