Methods for Providing a System of Care for an Oxazaphosphorine Drug Regimen

• US 20110082115A1
• Filed: 05/27/2010
• Published: 04/07/2011
• Est. Priority Date: 11/21/2007
• Status: Active Grant

• Current Assignee: Pabeti, Inc.
• Original Assignee: Accentia Biopharmaceuticals, Inc.
• Inventors: O'Donnell, Francis JR., Santos, Carlos
• Granted Patent: US 9,026,372 B2
• Time in Patent Office: Days
• US Class Current: 514/110
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: G16H 20/10 relating to drugs or medications, e.g. for ensuring correct administration to patients
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

The present invention provides methods of treating subjects with an oxazaphosphorines, methods of identifying subjects that are suitable for oxazaphosphorine treatment, and systems for ensuring the safety and efficacy of a treatment that includes oxazaphosphorine administration.

Claims

1. A system for ensuring the safety or efficacy of a treatment that includes oxazaphosphorine administration, the system comprising:

selecting a set of safety and efficacy factors associated with the safe and effective treatment of a subject with an oxazaphosphorine drug;

defining a set of information to be obtained from a subject including information probative of the set of selected safety and efficacy factors associated with the safe and effective treatment of a subject with an oxazaphosphorine drug;

determining whether treatment that includes an oxazaphosphorine administration can be safe and effective for the subject based on the set of information; and

generating a prescription approval code if it is determined that the treatment including the oxazaphosphorine administration can be safe and effective.

2. The system of claim 1, further comprising transmitting the prescription approval code to the drug manufacturer or administration facility that is to administer the oxazaphosphorine to the subject for which it has been determined that the treatment can be safe and effective.

3. The system of claim 1, wherein the prescription approval code is affixed to, or otherwise associated with, a container containing the oxazaphosphorine, and wherein the prescription approval code associates the container with the subject for which it has been determined that the treatment can be safe and effective.

4. The system of claim 3, wherein the prescription approval code comprises a bar code or other identifier that is specific to the subject.

5. The system of claim 3, further comprising transmitting the container with the prescription approval code to the administration facility that is to administer the oxazaphosphorine to the subject for which it has been determined that the treatment can be safe and effective.

6. The system of claim 3, wherein the information probative of the set of selected safety and efficacy factors associated with the safe and effective treatment of a subject with an oxazaphosphorine drug comprises a radiological assessment of the subject, a functional or quality of life assessment of the subject, or both.

12. The system of claim 1, wherein the one or more safety or efficacy factors include one or more ALDH inhibition factors, one or more ALDH activation factors, or both.

13. The system of claim 12, wherein the one or ALDH inhibition factors includes at least one selected from the group consisting of hormonal contraceptive use, tobacco use, chronic alcohol consumption, and any combinations thereof.

14. The system of claim 13, wherein the one or more ALDH inhibition factors includes at least one ALDH inhibition agent selected from the group consisting of disulfiram, hormonal contraceptive, procarbazine, N-methyltetrazolylthiomethyl bearing beta-lactam, kudzu root product, calcium carbimide, diazepam, chlordiazepoxide, isosorbide dinitrate, nitroglycerine, chlorpropamide, tolazamide, and cephalosporin, or an ALDH inhibiting metabolite thereof.

15. The system of claim 12, wherein the one or more ALDH inhibition factors are one or more anti-cancer agents, antibiotics, or dietary supplements.

16. The system claim 12, herein the one or more ALDH inhibition factors include one or more irreversible inhibitors of ALDH.

17. The system claim 12, wherein the one or more ALDH activation factors are one or more ALDH activation agents selected from the group consisting of coffee, oltipraz, Crucifera vegetable family member, Liliaceae vegetable family member, and Phenobarbital, or an ALDH activating metabolite of any of the foregoing.

18. The system of claim 1, wherein the subject is suffering from cancer and the oxazaphosphorine is to be administered or delivered for treatment of the cancer.

19. The system of claim 1, wherein the subject is suffering from an immune disorder and the oxazaphosphorine is to be administered or delivered for treatment of the immune disorder.

20. The system of claim 19, wherein the immune disorder is selected from the group consisting of an autoimmune disease, an allergic reaction, and transplant rejection.

21. The system of claim 20, wherein the immune disorder is multiple sclerosis.

22. The system of claim 1, wherein the amount of oxazaphosphorine to be delivered or administered is 200 mg/kg intravenously.

23. The system of claim 1, wherein the oxazaphosphorine is to be delivered or administered as a regimen selected from the group consisting of:

intravenous administration of about 40 mg/kg to about 50 mg/kg in divided doses over a period of from about 2 to about 5 days, intravenous administration of about 10 mg/kg to about 15 mg/kg oxazaphosphorine every 7 to 10 days, intravenous administration of about 3 mg/kg to about 5 mg/kg twice weekly, and oral administration of about 2.5 mg/kg to about 3 mg/kg daily for about 60 to about 90 days.

24. The system of claim 1, wherein the oxazaphosphorine is selected from the group consisting of cyclophosphamide, ifosfamide, perfosfamide, trophosphamide, 4-hydroxycyclophosphamide, aldophosphamide, and a pharmaceutically acceptable salt, solvate, prodrug, or active metabolite of any of the foregoing.

25. The system of claim 1, wherein one or more steps of the system are computer-implemented.

26. A computer-readable storage medium holding computer executable instructions for carrying out one or more steps of the system of claim 1.

7. A method for delivering an oxazaphosphorine to subjects in need thereof while restricting access to the oxazaphosphorine by subjects for whom the drug may be contraindicated, said method comprising:

obtaining subject information relating to the existence of one or more contraindication factors; and

permitting delivery of the oxazaphosphorine only after it has been determined that the subject can safely be treated based on the information relating to one or more contraindication factors.

8. The method of claim 7, wherein the one or more contraindication factors comprise one or more ALDH inhibition factors, one or more ALDH activation factors, or both.

9. The method of claim 7, wherein said oxazaphosphorine is delivered to the administration facility in a container, and wherein said method further comprises affixing or otherwise associating an approval code with the container, wherein the approval code is specific to the subject for whom safe treatment has been determined.

10. The method of claim 7, wherein the approval code comprises a bar code or other subject-specific identifier.

11. The method of claim 7, wherein the subject information comprises a radiological assessment of the subject, a functional or quality of life assessment of the subject, or both.

27. A method of providing a system of care with an oxazaphosphorine drug regimen, comprising, carrying out one or more of the following steps prior to administration of the oxazaphosphorine drug regimen:

a. registering a subject and generating a unique identifier for the subject in a computerized storage medium;

b. providing counseling to the subject regarding the risks associated with the administration of the oxazaphosphorine drug regimen, and obtaining the subject'"'"'s informed consent for participation in the regimen;

c. registering results in the storage medium of one or more assays administered to the subject including, but not limited to;

1) two independent pregnancy tests in the case of a female subject,

2) a measure of the level of aldehyde dehydrogenase (ALDH) enzyme in the subject'"'"'s peripheral lymphocytes,

3) a measure of the level of ALDH enzyme in the subject'"'"'s hematogenous stem cells, a measure of the white blood cell (WBC) count of the subject prior to and after the oxazaphosphorine drug regimen,

4) an assay (e.g., PCR assay) for detecting the presence of one or more viruses, such as herpesvirus (HSV), herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpesvirus 6 (HHV-6), herpesvirus 7 (HHV-7), herpesvirus 8 (HHV-8;

also known as Kaposi'"'"'s sarcoma associated herpesvirus (KSHV), respiratory viruses (e.g., adenovirus, influenza, respiratory syncytial virus (RSV)), papovavirus (e.g., papilloma, polyomavirus such as BKV and JCV), measles, hepatitis A (HAV), hepatitis B (HBV), hepatitis C(HCV), enterovirus, parvovirus, rabies virus, Rubella virus, Coxsackievirus, and human lymphotrophic virus;

5) a measure of the QT/QTc interval,

6) a platelet count,

7) a neutrophil count,

8) a radiological assessment of the subject'"'"'s brain volume,

9) a radiological assessment of the presence of gadolinium-enhancing lesions in the subject,

10) a functional disability evaluation score (such as EDSS or MSFC z-score),

11) a record of the subject meeting the qualifying inclusion criteria,

12) the absence of exclusion criteria, or any combination thereof,

d. registering in the storage medium all pharmaceuticals (e.g., supplements and drugs) currently being administered to the subject, and confirming in the storage medium that none of the pharmaceuticals include contraindicated pharmaceuticals or substances;

e. computing an approval status code upon successful completion of steps a-d which corresponds to the subject'"'"'s identifier within the storage medium;

f. transmitting to the administration facility authorization to administer the oxazaphosphorine drug regimen to the subject based on the approval status code, or transmitting to the drug manufacturer authorization to release the oxazaphosphorine to the administration facility based on the approval status code; and

g. administering a suitable antiviral therapy such as gancyclovir for CMV if the assay in step (c)(4) is positive for CMV infection.

28. The method of claim 27, wherein transmitting of (f) comprises transmitting the approval status code to the drug manufacturer or administration facility, and wherein the approval status code is affixed to, or otherwise associated with, a container containing the oxazaphosphorine.

29. The method of claim 28, wherein the approval status code comprises a bar code or other identifier specific to the subject.

30. The method of claim 27, further comprising carrying out at least one of the following steps after administration of the first dose of the oxazaphosphorine drug:

h. monitoring the QT/QTc interval in the subject to ensure cardiac safety during and following administration of the drug regimen;

i. registering in the storage medium the administration of each dose of the oxazaphosphorine drug administered to the subject;

j. registering in the storage medium any adverse events experienced by the subject in conjunction with the administration of the oxazaphosphorine drug;

k. re-computing the approval code and transmitting the re-computed approval code to the care provider prior to administration of the next successive dose of the oxazaphosphorine drug to the subject;

l. administering to the subject one or more prophylactic drugs or pharmaceutical prior to, concurrent with, or after administration of the oxaphosphorine regimen to the subject (such as antibacterials, antivirals, antifungals, mesna, or any combination thereof), and registering the administration of each of the one or more prophylactic drugs or pharmaceutical in the storage medium;

m. administering to the subject one or more biologics after administration of the oxaphosphorine regimen to the subject (such as granulocyte colony stimulating factor (G-CSF)), and registering the administration of each of the biologics in the storage medium;

n. registering in the storage medium the administration to the subject of any necessary supportive care therapies (such as post-therapy immunizations, platelet infusions, blood transfusions, red blood cell (RBC) infusions, or any combination thereof);

o. registering the results in the storage medium of one or more assays administered to the subject;

p. registering in the storage medium a radiological assessment of the subject'"'"'s brain volume;

q. registering in the storage medium a radiological assessment of the presence of gadolinium-enhancing lesions in the subject;

or

r. registering in the storage medium any adverse events potentially disqualifying the subject from receiving further treatment.

31. The method of claim 30, wherein the contraindicated pharmaceutical or substance of (d) is one or more among:

live virus vaccines, allopurinol, pentostatin, cyclosporine, St. John'"'"'s Wort, etanercept, nevirapine, trastuzumab, ondansetron, succinylcholine, digoxin, chloramphenicol, indomethacin.

32. The method of claim 27, wherein the contraindicated pharmaceutical or substance of (d) is one or more among:

grapefruit products, such as dietary supplements that contain grapefruit bioflavonoids, or any combination thereof.

33. The method of claim 27, wherein the contraindicated pharmaceutical or substance of (d) is one or more ALDH inhibition factors, one or more ALDH activation factors, or both.

34. The method of claim 33, wherein the one or ALDH inhibition factors includes at least one selected from the group consisting of hormonal contraceptive use, tobacco use, chronic alcohol consumption, and any combinations thereof.

35. The method of claim 33, wherein the one or more ALDH inhibition factors includes at least one ALDH inhibition agent selected from the group consisting of disulfiram, hormonal contraceptive, procarbazine, N-methyltetrazolylthiomethyl bearing beta-lactam, kudzu root product, calcium carbimide, diazepam, chlordiazepoxide, isosorbide dinitrate, nitroglycerine, chlorpropamide, tolazamide, and cephalosporin, or an ALDH inhibiting metabolite thereof.

36. The method of claim 33, wherein the one or more ALDH inhibition factors are one or more anti-cancer agents, antibiotics, or dietary supplements.

37. The method of claim 33, wherein the one or more ALDH inhibition factors are one or more irreversible inhibitors of ALDH.

38. The method of claim 33, wherein the one or more ALDH activation factors are one or more ALDH activation agents selected from the group consisting of coffee, oltipraz, Crucifera vegetable family member, Liliaceae vegetable family member, and Phenobarbital, or an ALDH activating metabolite of any of the foregoing.

40. The method of claim 30, wherein re-computing of (k) is based upon an algorithm considering the number of doses received, known adverse events and the successful completion of all prophylactic and supportive care.

41. The method of claim 30, wherein the one or more assays of (o) are selected from among:

1) disease-specific assays for markers of unwanted immune disease, such as antibody counts,

2) a measure of the WBC count of the subject,

3) tests for serious infectious disease (such as tuberculosis, HIV, and herpes),

4) a measure of hepatic function,

5) a measure of the level and/or activity of hematopoietic progenitor stem cell ALDH enzyme,

6) tests for cardiovascular disease or insufficiency,

7) PCR blood draws for assessing the need for an antiviral (such as gancyclovir) to prevent CMV pneumonia,

8) tests for allergy to any of the prophylactic drugs or biologics as administered,

9) a radiological assessment of the subject'"'"'s brain volume,

10) a radiological assessment of the presence of gadolinium-enhancing lesions in the subject,

11) a functional disability score assessment (e.g. EDSS or MSFC z-score) to ensure the subject is within the prescribed range of allowable scores, or any combination thereof.

43. The method of claim 27, wherein the subject is suffering from an immune disorder and the oxazaphosphorine is to be administered for treatment of the immune disorder.

44. The method of claim 43, wherein the immune disorder is selected from the group consisting of an autoimmune disease, an allergic reaction, and transplant rejection.

45. The method of claim 43, wherein the immune disorder is multiple sclerosis.

46. The method of claim 27, wherein the amount of oxazaphosphorine to be administered is 200 mg/kg intravenously.

47. The method of claim 27, wherein the oxazaphosphorine is to be administered as a regimen selected from the group consisting of:

intravenous administration of about 40 mg/kg to about 50 mg/kg in divided doses over a period of from about 2 to about 5 days, intravenous administration of about 10 mg/kg to about 15 mg/kg oxazaphosphorine every 7 to 10 days, intravenous administration of about 3 mg/kg to about 5 mg/kg twice weekly, and oral administration of about 2.5 mg/kg to about 3 mg/kg daily for about 60 to about 90 days.

48. The method of claim 27, wherein the oxazaphosphorine is selected from the group consisting of cyclophosphamide, ifosfamide, perfosfamide, trophosphamide, 4-hydroxycyclophosphamide, aldophosphamide, and a pharmaceutically acceptable salt, solvate, prodrug, or active metabolite of any of the foregoing.

49. A computer-readable storage medium holding computer executable instructions for carrying out one or more steps of the method of claim 27.

39. The method of 27, wherein the authorization of (f) is selected from at least one of the following:

1) a telephonic facsimile, paper, or Internet transmission of the subject'"'"'s unique identifier,

2) a telephonic facsimile, paper, or Internet transmission of the subject'"'"'s unique identifier in combination with an approval code for dispensing the oxazaphosphorine drug to the subject,

3) at least one dose of the oxazaphosphorine drug in a container affixed or otherwise associated with the subject'"'"'s unique identifying information, or any combination thereof.

42. The method of 27, wherein the subject is suffering from cancer and the oxazaphosphorine is to be administered for treatment of the cancer.