Ex vivo methods for drug discovery, development and testing
Inventors
Brassil, John • Curtis, Christopher G. • Kravitz, David
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10176887-B1
Publication Date
2019-01-08
Expiration Date
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.
Core Innovation
A method of developing a pharmaceutical product is provided by passing a perfusate comprising at least one substance to be evaluated through at least one metabolically active human organ selected from liver, lung, kidney, heart, pancreas, testes, thymus, adrenal gland, and lymph nodes. The organ is permanently removed from its origin and is unsuitable for transplantation, and the perfusate is delivered via a perfusion apparatus so that data derived from the perfused organ are obtained for development of the substance into a pharmaceutical product.
Data derived from the perfused organ are collected and stored in a computer-readable medium, and the data are evaluated via computer analysis to identify similarities or patterns. The evaluation includes at least one of substance absorption by the organ, substance bioavailability, substance toxicity, substance interaction with at least one other substance, substance therapeutic effect, and substance metabolite generation or liver clearance of the substance, and is used to guide continuing or terminating pharmaceutical development based upon an analysis of the collected data.
The functional state of the metabolically active human organ is quantified by including positive and negative controls in a perfusate that does not contain the substance to be evaluated. The positive and negative controls are passed through the organ after the organ is perfused with the perfusate that contains the substance to be evaluated, and the metabolically active human organ acts as its own control for functional state quantification.
Claims Coverage
The provided material contains two independent claims. The inventive features include ex vivo perfusion of permanently removed, transplant-unsuitable metabolically active human organs with a perfusate containing a substance to be evaluated; computer-based evaluation of organ-derived data for development decisions; and quantification of functional state using positive and negative controls such that the organ acts as its own control, with a further liver-specific elaboration for blood-based delivery and metabolite-related biliary measurements.
Ex vivo perfusion of permanently removed transplant-unsuitable metabolically active human organs with a test-substance perfusate
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.
Computer evaluation of organ-derived data for substance development
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; and continuing or terminating development of the substance into a pharmaceutical product based upon an analysis of the collected data.
Positive and negative controls for functional state quantification
Quantifying a functional state of the at least one metabolically active human organ 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 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 acts as its own control.
Liver-specific matched blood-based delivery and biliary metabolite partitioning measurements
The organ is a liver, wherein 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 measuring the subsequent partitioning of metabolites between blood and bile.
Across the independent claims, the core coverage is directed to a pharmaceutical development method using ex vivo perfusion of permanently removed, transplant-unsuitable metabolically active human organs with a test-substance perfusate delivered through a perfusion apparatus, followed by collecting organ-derived data and using computer analysis to identify similarities or patterns relevant to development decisions. Functional state quantification is performed using positive and negative controls so the organ acts as its own control, and a further claim component specifies a liver embodiment with matched blood-based perfusate delivery and measurements covering uptake, metabolism and clearance, biliary elimination and mass-balance, and metabolite partitioning between blood and bile.
Stated Advantages
Documented Applications
No documented applications found
Interested in licensing this patent?