Pharmacokinetic-based drug design tool and method

Medicilon's structural biology department offers services supporting structure-based drug discovery from determination of novel targets to final structures. Our platform is one of the earliest established structural biology platforms in China and has been certified by the Shanghai Government. Email:marketing@medicilon.com.cn web:www.medicilon.com

The present invention relates to a pharmacokinetic-based design and selection tool (PK tool) and methods for predicting absoption of an administered compound of interest. The methods utilize the tools, and optionally a separately operable component or subsystem thereof. The PK tool includes as computer-readable components: (1) input/output system; (2) physiologic-based simulation model of one or more segments of a mammalian system of interest having one or more physiological barriers to absorption that is based on the selected route of administration; and (3) simulation engine having a differential equation solver. The invention also provides methods for optimizing as well as enabling minimal input requirements a physiologic-based simulation model for predicting in vivo absorption, and optionally one or more additional properties, from either in vitro or in vivo data. The PK tool of the invention may be provided as a computer system, as an article of manufacture in the form of a computer-readable medium, or a computer program product and the like. Subsystems and individual components of the PK tool also can be utilized and adapted in a variety of disparate applications for predicting the fate of an administered compound. The PK tool and methods of the invention can be used to screen and design compound libraries, select and de novo design drugs, as well as predict drug efficacy in mammals from in vitro and/or in vivo data of one or more compounds of interest. The PK tool and methods of the invention also find use in selecting, designing, and preparing drug compounds, and multi-compound drugs and drug formulations (i.e., drug delivery system) for preparation of medicaments for use in treating mammalian disorders.

The input/output system, simulation engine and simulation model of the PK tool are capable of working together to carry out the steps of (1) receiving as input data, the initial dose of a test compound at the site of administration and permeability and solubility, and optionally dissolution rate and transfer mechanism data; and (2) applying the simulation engine and the simulation model to generate as output data a simulated in vivo absoφtion profile for the test compound that reflects rate, extent and/or concentration of the test sample at a given sampling site for a selected route of administration in a mammalian system of interest. This includes uni- and multidimensional output profiles that collectively reflect parameters of absoφtion, which can be directly or indirectly utilized for characterizing in vivo absoφtion, as well as one or more additional bioavailability parameters including distribution, metabolism, elimination, and optionally toxicity.

The selected routes of administration include enteral (e.g., buccal or sublingual, oral (PO), rectal (PR)), parenteral (e.g., intravascular, intravenous bolus, intravenous infusion, intramuscular, subcutaneous injection), inhalation and transdermal (percutaneous). The preferred route of administration according to the method of the invention is oral administration. The selected route of administration determines the type and/or source of assay or structure-property parameters employed for obtaining a set of input data utilized for generating a simulated in vivo absoφtion profile. That is, artificial, cell or tissue preparations and the like derived from or representative of a physiological barrier to absoφtion for a selected route of administration are chosen to generate the relevant input data for use as input into the PK tool. For instance, input data for simulating fate of a test sample following oral administration can be based on cell culture and/or tissue assays that employ biological preparations derived from or representative of the gastrointestinal tract of a mammal of interest, e.g., gastrointestinal epithelial cell preparations for permeability and transfer mechanism data, and physiological/anatomical fluid and admixing conditions corresponding to the relevant portions of the gastrointestinal tract for solubility and dissolution rate assays. Assays for collecting input data for specialized physiological barriers such as the blood brain barrier may initially assume intravascular delivery and thus instantaneous absoφtion as a first step. In this situation an assay is selected to generate input data relative to the blood brain barrier, which include for instance cell culture and/or tissue assays that employ biological preparations derived from or representative of the interface between systemic blood and the endothelial cells of the microvessels of the brain for a mammal of interest, e.g., blood-brain-barrier microvessel endothelial cell preparations for permeability and transfer mechanism data, and physiological/anatomical fluid and admixing conditions corresponding to the relevant portions of the blood membrane barrier for solubility and dissolution rate assays. A series of assays may be employed to collect input data for two or more barriers to absoφtion. As an example, oral, hepatic, systemic and blood brain barrier assays may be utilized to obtain input data for screening compound libraries for orally delivered compounds that target brain tissue.

The sampling site relates to the point at which absoφtion parameters are evaluated for a test sample of interest. This is the site at which rate, extent and/or concentration of a test sample is determined relative to a selected site of administration, and is separated from the site of administration by at least one physiological barrier to absoφtion. For generating simulated absoφtion profiles, the sampling site preferably is separated from the site of administration by an individual primary barrier to absoφtion, which can be utilized to evaluate additional absoφtion events by secondary barriers to absoφtion so as to sequentially and collectively reflect the summation of absoφtion events at other sampling sites of interest. As an example, the sampling site selected for oral delivery may be the portal vein where the primary barrier to absoφtion is the gastrointestinal lumenal membrane, or systemic blood where a secondary barrier to systemic absoφtion is the liver after the test sample passes from the portal vein through the liver to systemic circulation. Thus the type of physiological barrier(s) residing between a site of administration and a sampling site reflects the type of assay(s) employed for generating the desired input data for use as input data into the PK tool of the invention.

As the selected route of administration determines the barrier(s) to absoφtion and the physiological parameters that affect absoφtion events following administration, it also determines the physiologic-based pharmacokinetic simulation model employed in the PK tool for generation of the simulated in vivo absoφtion profile. By way of example, if the proposed route of administration is oral, then a primary barrier to absoφtion is the lumenal membrane of the gastrointestinal tract, and a secondary event affecting systemic bioavailability is first pass metabolism by the liver. Thus, a given simulation model and its associated parameters for simulating the fate of a compound selected for oral delivery is chosen to represent this scenario. The model would include therefore relevant components of the gastrointestinal tract for administration and absoφtion (i.e., stomach, duodenum, jejunum, ileum, and colon) and a primary sampling site (i.e., portal vein) from which to evaluate a primary absoφtion event. In this instance a secondary barrier to absoφtion for oral delivery is the liver and a secondary sampling site is systemic blood/plasma. This basic approach to choosing a physiologic-based pharmacokinetic model also applies to models employed to simulate absoφtion by target organs and the like, where a physiological barrier to absoφtion is the tissue and/or membrane separating systemic blood from the target organ, such as the blood brain barrier. In this situation if oral delivery is selected as the preferred route of administration for a compound targeting brain tissue, then a gastrointestinal tract model and blood brain barrier model may be implemented separately and or combined through a complementary plasma component of the models for screening puφoses.

The physiological models are selected from a repository of delivery route- specific models stored in a memory, a database, or created de novo drug. Physiological models of the invention include those corresponding to common routes of administration or barriers to absoφtion, such as oral, ocular (eye), transdermal (skin), rectal, intravenous, rectal, subcutaneous, respiratory (nasal, lung), blood brain barrier and the like. For constructing a model de novo, the basic approach is to identify and isolate a primary barrier to a specific absoφtion event from secondary events so that each barrier to absoφtion can be tested and validated in isolation. This involves selecting a site of administration that is separated from a sampling site by a primary physiological barrier to absoφtion and then building a developmental physiological model that incoφorates rate process relations and limitations to describe the isolated absoφtion event. If desired, the secondary events can be added sequentially so that each additional layer of complexity to the model can be tested and validated in isolation from other components of the initial model.

The invention also relates to a method and PK tool for designing compounds based on absoφtion. This aspect of the invention utilizes output of the method and PK tool as the input to a structure-activity relationship (SAR) or quantitative SAR (QSAR) design/selection process, e.g., a SAR and/or QSAR computer-assisted design engineering/selection process. Output of the CAD process is then optionally used as input for the method and PK tool of the invention. SAR and QSAR information may then be incoφorated into a database for subsequent iterative design and selection in the CAD process. For instance, compounds designed using a CAD process may be tested in vitro and/or in vivo for absoφtion parameters such as permeability, solubility, dissolution, and transport mechanism, and optionally one or more additional bioavailability parameters, and the data employed as input into the PK tool and method of the invention (i.e., iterative design). Alternatively, the parameters can be predicted from SAR or QSAR information and utilized as input for the method and PK tool of the invention. In this aspect of the invention, the user also is allowed to vary input parameters for "What if analysis.