Methods for increasing blood plasma 2′-deoxyuridine (dUrd) and thymidylate synthase inhibition

• US 10,292,984 B2
• Filed: 02/09/2018
• Issued: 05/21/2019
• Est. Priority Date: 02/14/2017
• Status: Active Grant

• Current Assignee: Isofol Medical AB
• Original Assignee: Isofol Medical AB
• Inventors: Carlsson, Goran U., Gustavsson, Bengt, Odin, Elisabeth, Wettergren, Yvonne, Vedin, Anders
• Primary Examiner(s): Shiao, Rei Tsang
• Application Number:
  US15/893,235
• Publication Number:
  US 20180289711A1
• Time in Patent Office: 466 Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

The present invention provides methods for increasing plasma dUrd levels comprising the administration of 6R-MTHF. The methods of increasing plasma dUrd increase dUrd levels compared to equimolar concentrations of LV. The present invention also provides methods for increasing TS inhibition comprising the administration of 6R-MTHF. The present invention also provides methods for increasing TS inhibition comprising the administration of 6R-MTHF.

Claims

1. A method of increasing plasma concentration of 2′

-deoxyuridine (dUrd) in a human subject comprising;

a. a step of administering 500 mg/m² 5-fluorouracil (5-FU) intravenously as a bolus injection to said human subject;

b. following (a), a step of administering 30, 60, 120, or 240 mg/m² [6R]-5, 10-methylene tetrahydrofolate (6R-MTHF) intravenously as one or more bolus injections to said human subject; and

c. optionally administering a therapeutically effective amount of at least one anticancer agent selected from the group consisting of oxaliplatin, irinotecan, and bevacizumab;

wherein said administration produces an increased plasma concentration of dUrd relative to dUrd plasma concentration in a human subject following administration of an equimolar dose of 5-formyl tetrahydrofolate (LV).

2. The method of claim 1, wherein said human subject suffers from cancer.

3. The method of claim 2, wherein said cancer is colorectal cancer.

7. The method of claim 1, wherein the 6R-MTHF is administered intravenously as more than one bolus injection to said human subject.

8. The method of claim 1, wherein the 6R-MTHF is administered intravenously as two bolus injections to said human subject.

9. The method of claim 1, wherein the 6R-MTHF is administered intravenously as a bolus injection to said human subject approximately 30 minutes following step (a).

10. The method of claim 1, where the 6R-MTHF is administered intravenously as a bolus injection to said human subject approximately 30 and 60 minutes following step (a).

15. The method of claim 1, wherein the 6R-MTHF has a chemical purity greater than 90% and in 95% isomeric excess over [6S]-5, 10-methylene tetrahydrofolate (6S-MTHF).

4. A method of inhibiting thymidylate synthase (TS) in a human subject comprising:

a. a step of administering 500 mg/m² 5-FU intravenously as a bolus injection to said human subject;

b. following (a), a step of administering 30, 60, 120, or 240 mg/m² 6R-MTHF intravenously as one or more bolus injections to said human subject; and

c. optionally administering a therapeutically effective amount of at least one anticancer agent selected from the group consisting of oxaliplatin, irinotecan, and bevacizumab;

wherein said administration produces an increased inhibition of TS relative to TS inhibition in a human subject following administration of an equimolar dose of LV.

5. The method of claim 4, wherein said human subject suffers from cancer.

6. The method of claim 5, wherein said cancer is colorectal cancer.

11. The method of claim 4, where in the 6R-MTHF is administered intravenously as more than one bolus injection to said human subject.

12. The method of claim 4, wherein the 6R-MTHF is administered intravenously as two bolus injections to said human subject.

13. The method of claim 4 wherein the 6R-MTHF is administered intravenously as a bolus injection to said human subject approximately 30 minutes following step (a).

14. The method of claim 4, wherein the 6R-MTHF is administered intravenously as a bolus injection to said human subject approximately 30 and 60 minutes following step (a).

16. The method of claim 4, wherein the 6R-MTHF has a chemical purity greater than 90% and in 95% isomeric excess over [6S]-5, 10-methylene tetrahydrofolate (6S-MTHF).