Population pharmacokinetics tools and uses thereof

• US 10,325,687 B2
• Filed: 12/06/2014
• Issued: 06/18/2019
• Est. Priority Date: 12/06/2013
• Status: Active Grant

• Current Assignee: Bioverativ Therapeutics Inc. (Sanofi )
• Original Assignee: Bioverativ Therapeutics Inc. (Sanofi )
• Inventors: Jiang, Haiyan
• Primary Examiner(s): Zeman, Mary K
• Application Number:
  US15/101,756
• Publication Number:
  US 20160306945A1
• Time in Patent Office: 1,655 Days
• CPC Class Codes: A61K 38/37 Factors VIII
• CPC Class Codes: A61K 38/4846 Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
• CPC Class Codes: C07K 14/755 Factors VIII , e.g. factor VIII C (AHF), factor VIII Ag (VWF)
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C12N 9/644 Coagulation factor IXa (3.4.21.22)
• CPC Class Codes: C12Y 304/21022 Coagulation factor IXa (3.4.21.22)
• CPC Class Codes: G06N 7/01 Probabilistic graphical models, e.g. probabilistic networks
• CPC Class Codes: G16C 20/30 Prediction of properties of chemical compounds, compositions or mixtures
• CPC Class Codes: G16C 20/70 Machine learning, data mining or chemometrics
• CPC Class Codes: G16C 20/90 Programming languages; Computing architectures; Database systems; Data warehousing
• CPC Class Codes: G16H 20/10 relating to drugs or medications, e.g. for ensuring correct administration to patients
• CPC Class Codes: G16H 40/67 for remote operation
• CPC Class Codes: G16H 50/50 for simulation or modelling of medical disorders

Abstract

The present invention is directed to computer based pharmacokinetics systems, such as. web-based pharmacokinetics systems, and their use to predict a dose and a dosing interval for a patient in need of a clotting factor therapy.

Claims

1. A method of treating hemophilia in a subject in need thereof comprising

(i) calculating a therapeutic dose of a chimeric clotting factor and/or a dosing interval of the chimeric clotting factor for the subject using a web-based application that is accessible through a web server, wherein the application is programmed to implement a clotting factor population pharmacokinetic (popPK) model for said chimeric clotting factor and a Bayesian estimation program to calculate the therapeutic dose and/or dosing interval;

and,

(ii) administering the chimeric clotting factor at the calculated therapeutic dose and/or the dosing interval to the subject wherein

(a) the chimeric clotting factor comprises a FVIII polypeptide and a neonatal Fc receptor binding partner (FcRn BP), and the clotting factor popK model for the chimeric clotting factor comprises the parameters in Table 18, 24 or 25;

or

(b) the chimeric clotting factor comprises a FIX polypeptide and an FcRn BP, and the clotting factor popK model for the chimeric clotting factor comprises the parameters in Table 10, 13 or 14.

2. The method of claim 1, further comprising entering clotting factor pharmacokinetic (PK) information of the subject, body weight and/or age of the subject, and/or desired treatment outcome.

3. The method of claim 2, further comprising updating the popPK model based on the subject'"'"'s clotting factor PK information.

4. The method of claim 1, wherein the application continuously updates the popPK model based on newly inputted clotting factor PK information of the subject.

5. The method of claim 1, further comprising, before the calculating, inputting a body weight of the subject, the subject'"'"'s age, or both.

6. The method of claim 1, further comprising inputting a rise of plasma clotting factor activity level desired following the administrating.

7. The method of claim 1, further comprising, before the calculating, measuring a clotting factor activity level in plasma at various time points after an initial dose of the chimeric clotting factor, wherein the subject'"'"'s clotting factor PK information is, optionally contemporaneously, calculated based on the chimeric clotting factor activity level.

8. The method of claim 7, further comprising, before the measuring, administering an initial dose of the chimeric clotting factor.

9. The method of claim 8, wherein the initial dose is a fixed interval dose.

10. The method of claim 1, wherein the clotting factor popPK model is updated, optionally contemporaneously, and is, optionally immediately, available through the web server.

11. The method of claim 1, wherein the clotting factor popPK model is updated, optionally immediately, after the subject'"'"'s clotting factor PK information is added to the application and wherein an updated clotting factor popPK model is available for a next use.

12. The method of claim 1, wherein the chimeric clotting factor comprises a FVIII polypeptide and an FcRn BP, and the clotting factor popK model for the chimeric clotting factor comprises the parameters in Table 18, 24 or 25.

13. The method of claim 1, wherein the chimeric clotting factor comprises FIX polypeptide and an FcRn BP, and the clotting factor popK model for the chimeric clotting factor comprises the parameters in Table 10, 13 or 14.

14. The method of claim 1, wherein the FcRn BP an Fc domain or albumin.

15. The method of claim 1, wherein the FIX polypeptide or the FVIII polypeptide is a human FIX polypeptide or a human FVIII polypeptide, respectively.

16. The method of claim 1, wherein the FIX polypeptide or the FVIII polypeptide is a mutant FIX polypeptide or a mutant FVIII polypeptide, respectively.

17. The method of claim 1, wherein the FVIII polypeptide has a full or partial deletion of the B domain.

18. The method of claim 1, wherein the dosing regimen is a prophylaxis regimen.

19. The method of claim 1, wherein the dosing regimen is an on-demand regimen.

20. The method of claim 14, wherein the Fc domain is a human Fc domain.

21. The method of claim 2, wherein the subject'"'"'s clotting factor PK information comprises subject'"'"'s endogenous level of clotting factor, pre-PK dose through, clotting factor PK dose, post clotting factor PK dose, or a combination thereof.

22. The method of claim 2, wherein the desired treatment outcome data is the desired rise in plasma clotting factor activity level following the administration.

23. The method of claim 1, wherein the calculations further provide estimated PK data for the subject comprising clotting factor half-like, time to 1%, time to 3%, time to 5%, percentage of recovery, Cmax, or a combination thereof.