Ex vivo methods for drug discovery, development and testing

• US 10,176,887 B1
• Filed: 11/14/2006
• Issued: 01/08/2019
• Est. Priority Date: 11/14/2005
• Status: Active Grant

• Current Assignee: Organ Recovery Systems, Inc. (Shanghai Genext Medical Technology Co., Ltd.)
• Original Assignee: Organ Recovery Systems, Inc. (Shanghai Genext Medical Technology Co., Ltd.)
• Inventors: Brassil, John, Curtis, Christopher G., Kravitz, David
• Primary Examiner(s): Pauls, John A
• Application Number:
  US11/598,800
• Time in Patent Office: 4,438 Days
• CPC Class Codes: G01N 33/00 Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
• CPC Class Codes: G16H 10/20 for electronic clinical trials or questionnaires
• CPC Class Codes: G16H 40/20 for the management or administration of healthcare resources or facilities, e.g. managing hospital staff or surgery rooms
• CPC Class Codes: G16H 50/50 for simulation or modelling of medical disorders
• CPC Class Codes: G16H 50/70 for mining of medical data, e.g. analysing previous cases of other patients

Abstract

Methods for assaying properties in tissues or organs of drugs and other chemical compounds and substances include ex vivo normothermic perfusion with a fluid containing a test substance to obtain data regarding the tissue or organ, the substance and/or an interaction of the substance and the tissue or organ. The data can be used as, for example, part of a submission to a government regulatory organization.

Claims

1. A method of developing a pharmaceutical product, comprising:

passing a perfusate comprising at least one substance to be evaluated through at least one metabolically active human organ selected from the group consisting of liver, lung, kidney, heart, pancreas, testes, thymus, adrenal gland, and lymph nodes that has been permanently removed from its origin and is unsuitable for transplantation, wherein the perfusate is delivered via a perfusion apparatus;

collecting data derived from the perfused organ and storing the data in a computer-readable medium, wherein the data is evaluated via a computer analysis to identify similarities or patterns;

including at least one of the following;

substance absorption by the organ, substance bioavailability, substance toxicity, substance interaction with at least one other substance, substance therapeutic effect, substance metabolite generation or liver clearance of the substance;

quantifying a functional state of the at least one metabolically active human organ selected from the group consisting of liver, lung, kidney, heart, pancreas, testes, thymus, adrenal gland, and lymph nodes by including positive and negative controls in a perfusate that does not contain the at least one substance to be evaluated that is passed through the least one metabolically active human organ after perfusing the at least one metabolically active human organ with the perfusate that contains the at least one substance to be evaluated, wherein the at least one metabolically active human organ selected from the group consisting of liver, lung, kidney, heart, pancreas, testes, thymus, adrenal gland, and lymph nodes acts as its own control; and

continuing or terminating development of the substance into a pharmaceutical product based upon an analysis of the collected data.

2. The method of claim 1, comprising using the collected data in at least one pharmaceutical development phase selected from the group consisting of:

discovery, pre-clinical, phase I, phase II, phase in and phase IV.

3. The method of claim 1, further comprising passing a second substance through the organ.

4. The method of claim 1, wherein the organ is diseased.

5. The method of claim 1, wherein the passing comprises perfusing the organ with a first fluid that does not contain the substance, followed by perfusing the organ with a second fluid that contains the substance;

wherein

the first fluid that does not contain the substance is delivered via a perfusion apparatus, and

the second fluid that contains the substance is delivered via a perfusion apparatus.

6. The method of claim 1, wherein the data are collected by collecting at least one perfusate sample, taking at least one biopsy from the organ, and collecting at least one bodily fluid sample or a mixture thereof.

7. The method of claim 6, wherein the data are collected by taking a biopsy from the organ.

8. The method of claim 6, wherein the organ is selected from the group consisting of:

liver, kidney, lung, pancreas and heart.

9. The method of claim 8, wherein the organ is a liver, and is perfused with a perfusate delivered via a perfusion apparatus, the perfusate comprising at least one of the following:

37-150 mg/l N-acetylcysteine, 5-20 mg/l ATP, 12-50 μ

M dibutylcyclic AMP, 1-4 μ

g superoxide dismutase (in 5% acid), 50-200 μ

M glycocholic acid, or 25-100 μ

M glycochenodeoxycholic acid.

10. The method of claim 9, wherein the perfusate further comprises 50-200 μ

g ³H-mannitol.

11. The method of claim 8, wherein the data are collected by collecting a bodily fluid sample and the bodily fluid sample comprises bile or bile duct excretions.

12. The method of claim 8, wherein the organ is a kidney, and is perfused with a perfusate delivered via a perfusion apparatus, the perfusate comprising 1-5 μ

l/l noradrenaline and/or 1-4.5 ml/l dexamethasone.

13. The method of claim 8, wherein the data are collected by collecting a bodily fluid sample and the bodily fluid sample comprises urine or ureter filtrate.

14. The method of claim 8, wherein the organ is an organ selected from the group consisting of liver, kidney, lung, pancreas and heart.

16. The method of claim 8, wherein the data are collected by collecting a bodily fluid sample.

17. The method of claim 8, wherein the data are collected by collecting a bodily fluid sample and the bodily fluid sample comprises pancreatic excretions.

18. The method of claim 1, wherein the organ is perfused through a perfusate comprising type-matched human red blood cells.

19. The method of claim 1, wherein the data are collected using microdialysis.

20. The method of claim 1, wherein the data are collected via conducting an MRI, CT or PET.

21. The method of claim 1, wherein the data are collected via spectroscopic testing selected from the group consisting of light, infrared and ultraviolet spectroscopic techniques.

22. The method of claim 1, wherein the data are collected via solid state tissue probe testing, which comprises using at least one pH probe.

23. The method of claim 1, wherein the organ is a heart, and the data are collected via conducting an electrocardiogram.

24. The method of claim 1, wherein

the metabolically active human organ is a lung, and

the step of collecting data derived from the perfused organ comprises:

assessing inhaled drug performance by quantitating ventilatory function, drug preparation stability, drug absorption via the airways, drug uptake from the blood, drug metabolism, clearance and retention, and extent of edema.

25. The method of claim 1, wherein

the metabolically active human organ is a kidney, and

the perfusate used is derived from a liver perfusion experiment in which a test compound has been perfused through a human liver.

26. The method of claim 1, wherein the metabolically active human organ is a heart, and

the step of collecting data derived from the perfused organ comprises:

measuring and monitoring the electrolytes levels, glucose levels, a PO₂ A-V difference, and a PCO₂ A-V difference in the perfusate.

27. The method of claim 1, wherein the metabolically active human organ is a pancreas.

28. The method of claim 1, wherein the metabolically active human organ or tissue is selected from the group consisting of thymus, adrenal gland, and lymph nodes.

15. The method of 14, wherein

the organ is a liver,

the at least one substance and the positive and negative controls are delivered via matched blood-based perfusate at physiological flow rates to the liver, and

the step of collecting data derived from the perfused organ comprises:

determining the nature and extent of uptake, metabolism and clearance of the at least one substance,

assessing biliary elimination and mass-balance of the at least one substance, and

preforming measurements of the subsequent partitioning of metabolites between blood and bile.