Methods of treating hemophilia A and population pharmacokinetic tools for determining methods of treatment and uses thereof

Abstract

The present disclosure provides, inter alia, methods for treating hemophilia A, as well as computer-based systems including a software-based pharmacokinetic model system, and uses thereof for determining agent information for a subject suffering from hemophilia A.

Description

[0001] References to electronically submitted sequence listings

[0002] The contents of the Sequence Listing submitted electronically as an XML file (Name: 744011_SA9-488PC_ST26.xml; Size: 33,147 bytes; Creation Date: July 25, 2023) are incorporated herein by reference in its entirety.

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application No. 63 / 370,010 filed on August 1, 2022, U.S. Provisional Application No. 63 / 383,091 filed on November 10, 2022, and U.S. Provisional Application No. 63 / 485,418 filed on February 16, 2023, each of which is incorporated by reference in its entirety for all purposes. Background Art

[0005] Although plasma-derived and recombinant clotting factor products allow people with hemophilia to live longer and healthier lives, hemophilia remains one of the most expensive and complex conditions to manage. Due to its complexity, treatment of hemophilia A with FVIII replacement therapy requires a specific therapeutic management approach for physicians, pharmacies, and patients. Clinicians often assess lifestyle, psychosocial needs, and home environment when evaluating the ability of patients or caregivers to provide appropriate care.

[0006] The current recommended standard of care involves the regular administration of FVIII (conventional prophylaxis) to minimize the number of bleeding episodes. Conventional prophylaxis is associated with improved long-term outcomes, but is a demanding regimen limited by the need for frequent intravenous (IV) administration. See Manco-Johnson et al., N Engl J Med. [New England Journal of Medicine] 357(6):535-44 (2007). FVIII products with extended half-life reduce the frequency of FVIII administration for prophylaxis; however, existing FVIII products that interact with endogenous von Willebrand factor (VWF) have comparable circulating half-lives, which is consistent with the upper limit of the half-life of rFVIII variants due to the endogenous VWF half-life. See, e.g., Pipe et al., Blood. [Blood] 128(16):2007-16 (2016). Summary of the invention

[0007] In particular, provided herein are methods of treating hemophilia A, as well as software-based pharmacokinetic systems and their use for providing dosing information (eg, dosage and dosing interval) to a subject in need of treatment for hemophilia A.

[0008] In some aspects, the disclosure includes a method (e.g., a computer-implemented method) for determining (e.g., calculating, estimating, or providing) dosing information for an individual subject of efanesoctocog alfa. In some embodiments, the method includes receiving information specific to the subject and calculating the efanesoctocog alfa dosing information using a software-based system, wherein the system is programmed to implement a one-compartment efanesoctocog alfa popPK model, wherein the efanesoctocog alfa popPK model includes body weight as a covariate, and wherein the efanesoctocog alfa popPK model does not include the level of von Willebrand factor (VWF) or the level of hematocrit as a covariate. In some embodiments, the method further includes outputting the dosing information of the subject by the software-based system. In some embodiments, the method further includes outputting a suggested dosage regimen by the software-based system. In some embodiments, desired treatment outcome information is also received.

[0009] In some aspects, the present disclosure includes a method (e.g., a computer-implemented method) of estimating (e.g., calculating, determining, or providing) personalized avermitigin alpha dosage information for a subject, the method comprising: (a) receiving subject information and / or desired treatment outcome information by a processing device via an application programmed to operate using an avermitigin alpha popPK model, wherein the received information is transmitted via one or more electronic devices, (b) using at least one software-based system, the avermitigin alpha popPK model and the received information to calculate personalized avermitigin alpha dosage information, and (c) transmitting the calculated personalized avermitigin alpha dosage information of (b) to one or more electronic devices for outputting the information, wherein the avermitigin alpha popPK model includes body weight as a covariate, and wherein the avermitigin alpha popPK model does not include the level of VWF or the level of hematocrit as a covariate.

[0010] In some aspects, the present disclosure includes a method (e.g., a computer-implemented method) of estimating (e.g., calculating, determining, or providing) personalized avermitigin alpha dosage information for a subject, the method comprising: (a) receiving subject information and / or expected treatment outcome information via one or more electronic devices, (b) transmitting the subject information and / or expected treatment outcome information to an application via a processing device, wherein the application is programmed to implement an avermitigin alpha popPK model, (c) receiving from the application personalized avermitigin alpha dosage information calculated using the avermitigin alpha popPK model and the transmitted information of (b), and (d) outputting the personalized avermitigin alpha dosage information via the one or more electronic devices, wherein the avermitigin alpha popPK model includes body weight as a covariate, and wherein the avermitigin alpha popPK model does not include VWF level or hematocrit level as a covariate.

[0011] In some aspects, the disclosure includes a method (e.g., a computer-implemented method) of providing (e.g., calculating, determining, or estimating) an avermectin alpha dosing regimen based on a median popPK, the method comprising: (a) receiving subject information and / or desired treatment outcome information by a software-based system comprising an avermectin alpha popPK model, (b) calculating median PK information by the software-based system using the avermectin alpha popPK model and the received information, and (c) outputting the median PK information by the software-based system, wherein the avermectin alpha popPK model comprises body weight as a covariate, and wherein the avermectin alpha popPK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0012] In some aspects, the disclosure includes a method (e.g., a computer-implemented method) of providing (e.g., calculating, determining, or estimating) an avermectin alpha dosing regimen based on a median avermectin alpha popPK, the method comprising: (a) receiving subject information and / or expected treatment outcome information via one or more electronic devices, (b) transmitting the subject information and / or expected treatment outcome information to an application via a processing device, wherein the application is programmed to implement an avermectin alpha popPK model, (c) receiving from the application median avermectin alpha PK dosing information calculated using the avermectin alpha popPK model and the received information, and (d) outputting the median PK information via the one or more electronic devices, wherein the avermectin alpha popPK model includes body weight as a covariate, and wherein the avermectin alpha popPK model does not include VWF level or hematocrit level as a covariate.

[0013] In some aspects, the present disclosure includes a method (e.g., a computer-implemented method) of providing (e.g., calculating, determining, or estimating) an avancin alpha dosing regimen, the method comprising: (a) receiving, by a processing device, subject information and / or desired treatment outcome information via an application programmed to implement an avancin alpha population pharmacokinetic (popPK) model, wherein the received information is transmitted by one or more electronic devices, (b) calculating, by the application, personalized avancin alpha dosing information using the avancin alpha popPK model and the received information, and (c) transmitting, by the processing device, the dosing information calculated for the personalized avancin alpha dosing regimen of (b) to one or more electronic devices for outputting the information, wherein the avancin alpha popPK model includes body weight as a covariate, and wherein the avancin alpha popPK model does not include VWF level or hematocrit level as a covariate.

[0014] In some aspects, the present disclosure includes a method (e.g., a computer-implemented method) of estimating (e.g., calculating, determining, or providing) individualized subject Avancog α PK information, the method comprising: (a) receiving subject information by a software-based system comprising an Avancog α pop PK model, (b) estimating individualized subject Avancog α PK information by the software-based system using the Avancog α pop PK model and the received information, and (c) outputting the individualized subject Avancog α PK information by the software-based system, wherein the Avancog α pop PK model comprises body weight as a covariate, and wherein the Avancog α pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0015] In some aspects, the present disclosure includes a method (e.g., a computer-implemented method) of estimating (e.g., calculating, determining, or providing) personalized subject ivampicin α PK information, the method comprising: (a) receiving subject information via one or more electronic devices, (b) transmitting the subject information to an application via a processing device, wherein the application is programmed to implement an ivampicin α pop PK model, and wherein the application generates personalized subject ivampicin α PK information using the ivampicin α pop PK model and the transmitted information, (c) receiving the personalized subject ivampicin α PK information from the application, and (d) outputting the personalized subject PK information via the one or more electronic devices, wherein the ivampicin α pop PK model includes body weight as a covariate, and wherein the ivampicin α pop PK model does not include VWF level or hematocrit level as a covariate.

[0016] In some aspects, the present disclosure includes a method (e.g., a computer-implemented method) of estimating (e.g., calculating, determining, or providing) individualized subject ivampicin alpha PK information, the method comprising: (a) receiving subject information through an application programmed to implement an ivampicin alpha popPK model, wherein the received information is transmitted through one or more electronic devices, (b) calculating individualized subject ivampicin alpha PK information of ivampicin alpha through the application using the ivampicin alpha popPK model and the received information, and (c) transmitting the individualized subject ivampicin alpha PK information calculated in (b) to one or more electronic devices through a processing device to output the information, wherein the ivampicin alpha popPK model includes body weight as a covariate, and wherein the ivampicin alpha popPK model does not include VWF level or hematocrit level as a covariate.

[0017] In some aspects, the disclosure includes a method (e.g., a computer-implemented method) of estimating (e.g., calculating, determining, or providing) personalized subject ivampicin alpha PK information, the method comprising: (a) receiving, via one or more electronic devices, information about the subject's weight and (i) an expected increase in plasma factor activity level following administration or (ii) an expected dose or an expected dose interval, (b) transmitting, via a processing device, the information of (a) to an application, wherein the application is programmed to implement an ivampicin alpha popPK model, (c) receiving, from a web-based server and program, personalized subject ivampicin alpha PK information calculated using the ivampicin alpha popPK model and the transmitted information of (b), and (d) outputting, via the one or more electronic devices, the calculated personalized subject ivampicin alpha PK information, wherein the ivampicin alpha popPK model includes weight as a covariate, and wherein the ivampicin alpha popPK model does not include the level of VWF or the level of hematocrit as a covariate.

[0018] In some embodiments of the above methods, the subject information includes the subject's weight.

[0019] In some embodiments of the above methods, the subject information includes the subject's baseline FVIII activity level.

[0020] In some embodiments of the above methods, the subject information includes the subject's self-reported race. In some embodiments of the above methods, the subject information includes whether the subject self-identifies as Asian.

[0021] In some embodiments of the above methods, the subject provides the subject information. In some embodiments of the above methods, a medical professional provides the subject information.

[0022] In some embodiments of the above methods, the subject information does not include the subject's level of VWF or hematocrit.

[0023] In some embodiments of the above methods, the system is programmed to implement a one-compartment avermitogen alpha pop PK model for calculating the dosing information that includes body weight as a covariate, and wherein the avermitogen alpha pop PK model does not include levels of VWF or hematocrit as covariates.

[0024] In some embodiments of the above method, the method further comprises selecting a dosing regimen based on the dosing information.

[0025] In some embodiments of the above methods, the method further comprises selecting a dosing regimen based on the PK information.

[0026] In some embodiments of the above methods, the method further comprises administering ivenomic alpha to the subject according to the selected dosing regimen.

[0027] In some embodiments of the above methods, the dosage information comprises an estimated or predicted level of FVIII activity over time following administration of avermitigin alfa.

[0028] In some embodiments of the above methods, the dosing regimen is a preventive regimen. In some embodiments of the above methods, the dosing regimen is an on-demand regimen. In some embodiments of the above methods, the dosing regimen is for perioperative bleeding management.

[0029] In some embodiments of the above methods, the desired treatment outcome information comprises a desired FVIII activity level. In some embodiments of the above methods, the desired FVIII activity level comprises a minimum FVIII activity level between doses.

[0030] In some embodiments of the above methods, the desired FVIII activity level includes a minimum FVIII activity level at a time point. In some embodiments of the above methods, the time point is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after administration of ivacog alpha. In some embodiments, the time point is about 1 week after administration of ivacog alpha.

[0031] In some embodiments of the above methods, the avermectin alpha pop PK model includes self-reported race as a covariate. In some embodiments of the above methods, the avermectin alpha pop PK model includes whether the subject self-reports Asian as a covariate.

[0032] In some embodiments of the above methods, the subject does not self-report being of Asian descent. In some embodiments of the above methods, the subject self-reports being of Asian descent.

[0033] In some embodiments of the above methods, the avermitogen alpha pop PK model is the avermitogen alpha pop PK model [A].

[0034] In some embodiments, the estimated value of typical clearance (TVCL) in the avage αpopPK model [A] is about 0.433 dL / h, the estimated value of typical volume (TVV) in the avage αpopPK model [A] is about 30.2 dL, the central compartment clearance variability (η1) in the avage αpopPK model [A] is about 0.0354 and / or the central compartment volume variability (η2) in the avage αpopPK model [A] is about 0.0209. In some embodiments, the estimated value of typical clearance (TVCL) in the avage αpopPK model [A] is about 0.433 dL / h, the estimated value of typical volume (TVV) in the avage αpopPK model [A] is about 30.2 dL, the central compartment clearance variability (η1) in the avage αpopPK model [A] is about 0.0354, and the central compartment volume variability (η2) in the avage αpopPK model [A] is about 0.0209. In some embodiments, the estimated value of typical clearance (TVCL) in the avaccine αpopPK model [A] is 0.433 dL / h, the estimated value of typical volume (TVV) in the avaccine αpopPK model [A] is 30.2 dL, the central compartment clearance variability (η1) in the avaccine αpopPK model [A] is 0.0354, and the central compartment volume variability (η2) in the avaccine αpopPK model [A] is 0.0209.

[0035] In some embodiments of the methods disclosed herein, the electronic device is a digital pen, a smartphone, a tablet computer, a personal digital assistant, a handheld computer, a laptop computer, a scanner, a camera, and / or a fax machine.

[0036] Also included is a method (eg, a computer-implemented method) of treating hemophilia A in a subject in need thereof, the method comprising administering to the subject a dosage regimen selected according to any of the methods described above.

[0037] Also disclosed is a system comprising a processor configured to provide dosage or PK information according to any of the above methods. In some embodiments, the system is a network-based system. In some embodiments, the system is a web-based system.

[0038] In some embodiments, the system is programmed to implement a one-compartment avermitogen alpha pop PK model with linear elimination that includes body weight as a covariate for calculating dosing information, and wherein the avermitogen alpha pop PK model does not include levels of VWF or hematocrit as covariates.

[0039] In some embodiments, the system is programmed to implement a one-compartment avermectin alpha popPK model with linear elimination for calculating individualized subject avermectin alpha PK information that includes body weight as a covariate, and wherein the avermectin alpha popPK model does not include the level of VWF or hematocrit as a covariate.

[0040] In some aspects, the present disclosure includes a data processing device, apparatus, or system comprising a processor configured to implement a one-compartment avermitogen alpha popPK model, wherein the avermitogen alpha popPK model comprises body weight as a covariate, and wherein the avermitogen alpha popPK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0041] In some embodiments of the data processing apparatus, device or system described above, the ivenomic alpha popPK model includes self-reported race as a covariate.

[0042] In some embodiments of the data processing apparatus, device or system, the ivenomic alpha popPK model includes whether the subject self-reports being of Asian descent as a covariate.

[0043] In some embodiments of any of the foregoing data processing devices, apparatuses, or systems, the data processing device, apparatus, or system comprises a smartphone, a tablet computer, a personal digital assistant, a palmtop computer, a laptop computer, or a smart watch.

[0044] In some embodiments of any of the above data processing devices, apparatuses or systems, the data processing device, apparatus or system comprises a smartphone. In some embodiments of any of the above data processing devices, apparatuses or systems, the data processing device, apparatus or system comprises a smart watch.

[0045] In some embodiments of any of the above data processing devices, apparatuses or systems, the data processing device, apparatus or system comprising a processor is configured to implement the avermitigin alpha popPK model [A].

[0046] Also disclosed is a computer program comprising instructions which, when executed by a computer, cause the computer to perform any of the above methods.

[0047] In some aspects, the disclosure includes a computer program comprising instructions that, when executed by a computer, cause the computer to implement a one-compartment avermitogen alpha pop PK model, wherein the avermitogen alpha pop PK model comprises body weight as a covariate, and wherein the avermitogen alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0048] In some embodiments of the aforementioned computer program, the avermectin alpha popPK model comprises self-reported race as a covariate. In some embodiments of the aforementioned computer program, the avermectin alpha popPK model comprises whether the subject self-reports being of Asian descent as a covariate.

[0049] In some embodiments of the above computer program, the avermitogen alpha pop PK model is the avermitogen alpha pop PK model [A].

[0050] In some embodiments, the computer program may be accessed through a web server or network server.

[0051] Also disclosed is a computer readable medium containing instructions which, when executed by a computer, cause the computer to provide for performing any of the above methods.

[0052] In some aspects, the disclosure includes a computer-readable medium comprising instructions that, when executed by a computer, cause the computer to implement a one-compartment avermitogen alpha popPK model, wherein the avermitogen alpha popPK model comprises body weight as a covariate, and wherein the avermitogen alpha popPK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0053] In some embodiments of the aforementioned computer-readable medium, the avermectin alpha popPK model comprises self-reported race as a covariate. In some embodiments of the aforementioned computer-readable medium, the avermectin alpha popPK model comprises whether the subject self-reports being of Asian descent as a covariate.

[0054] In some embodiments of the aforementioned computer-readable medium, the avermitogen alpha pop PK model is the avermitogen alpha pop PK model [A].

[0055] In some embodiments, the computer readable medium may be accessed through a web server or network server.

[0056] Included herein is a method for determining (e.g., calculating, estimating, or providing) chimeric protein dosage information for an individual subject, wherein the chimeric protein comprises (i) a Factor VIII (FVIII) protein and (ii) a von Willebrand Factor (VWF) fragment comprising a D' domain of VWF and a D3 domain of VWF.

[0057] In some embodiments, the method comprises receiving subject-specific information and calculating the chimeric protein dosage information using a software-based system, wherein the system is programmed to implement a one-compartment chimeric protein popPK model, wherein the chimeric protein popPK model comprises body weight as a covariate, and wherein the chimeric protein popPK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0058] In some embodiments, the method includes outputting dosage information of the subject by the software-based system. In some embodiments, the method includes outputting a recommended dosage regimen by the software-based system. In some embodiments, desired treatment outcome information is also received.

[0059] The present disclosure provides a method of estimating personalized chimeric protein dosage information for a subject, wherein the chimeric protein comprises (i) a Factor VIII (FVIII) protein and (ii) a von Willebrand Factor (VWF) fragment comprising a D' domain of VWF and a D3 domain of VWF.

[0060] In some embodiments, the method comprises: (a) receiving, by a processing device, subject information and / or desired treatment outcome information via an application programmed to run with a chimeric protein popPK model, wherein the received information is transmitted via one or more electronic devices, (b) using at least one software-based system to calculate individualized chimeric protein dosage information using the chimeric protein popPK model and the received information, and (c) transmitting the individualized chimeric protein dosage information calculated in (b) to one or more electronic devices for outputting the information, wherein the chimeric protein popPK model comprises body weight as a covariate, and wherein the chimeric protein popPK model does not comprise VWF level or hematocrit level as a covariate.

[0061] In some embodiments, the method comprises: (a) receiving subject information and / or expected treatment outcome information via one or more electronic devices, (b) transmitting the subject information and / or expected treatment outcome information to an application via a processing device, wherein the application is programmed to implement a chimeric protein popPK model, (c) receiving from the application personalized chimeric protein dosage information calculated using the chimeric protein popPK model and the transmitted information of (b), and (d) outputting the personalized chimeric protein dosage information via the one or more electronic devices, wherein the chimeric protein popPK model comprises body weight as a covariate, and wherein the chimeric protein popPK model does not comprise VWF level or hematocrit level as a covariate.

[0062] Also included herein is a method of estimating PK information of a chimeric protein for an individualized subject, wherein the chimeric protein comprises (i) a Factor VIII (FVIII) protein and (ii) a von Willebrand Factor (VWF) fragment comprising the D' domain of VWF and the D3 domain of VWF.

[0063] In some embodiments, the method comprises: (a) receiving subject information by a software-based system comprising a chimeric protein popPK model, (b) estimating individualized subject chimeric protein PK information by the software-based system using the chimeric protein popPK model and the received information, and (c) outputting the individualized subject chimeric protein PK information by the software-based system, wherein the chimeric protein popPK model comprises body weight as a covariate, and wherein the chimeric protein popPK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0064] In some embodiments, the method comprises: (a) receiving subject information via one or more electronic devices, (b) transmitting the subject information to an application via a processing device, wherein the application is programmed to implement a chimeric protein popPK model, and wherein the application generates individualized subject chimeric protein PK information using the chimeric protein popPK model and the transmitted information, (c) receiving the individualized subject chimeric protein PK information from the application, and (d) outputting the individualized subject PK information via the one or more electronic devices, wherein the chimeric protein popPK model comprises body weight as a covariate, and wherein the chimeric protein popPK model does not comprise VWF level or hematocrit level as a covariate.

[0065] In some embodiments, the method comprises: (a) receiving subject information through an application programmed to implement a chimeric protein popPK model, wherein the received information is transmitted through one or more electronic devices, (b) calculating chimeric protein PK information of individualized subject chimeric protein using the chimeric protein popPK model and the received information through the application, and (c) transmitting the individualized subject chimeric protein PK information calculated in (b) to one or more electronic devices through a processing device to output the information, wherein the chimeric protein popPK model includes body weight as a covariate, and wherein the chimeric protein popPK model does not include VWF level or hematocrit level as a covariate.

[0066] In some embodiments, the method comprises: (a) receiving, by one or more electronic devices, information about a subject's weight and (i) an expected increase in plasma factor activity level following administration or (ii) an expected dose or an expected dose interval, (b) transmitting, by a processing device, the information of (a) to an application, wherein the application is programmed to implement a chimeric protein popPK model, (c) receiving, from a web-based server and program, individualized subject chimeric protein PK information calculated using the chimeric protein popPK model and the transmitted information of (b), and (d) outputting, by the one or more electronic devices, the calculated individualized subject chimeric protein PK information, wherein the chimeric protein popPK model comprises weight as a covariate, and wherein the chimeric protein popPK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0067] In some embodiments, the subject information includes the subject's weight.

[0068] In some embodiments, the subject information includes the subject's baseline FVIII activity level.

[0069] In some embodiments, the subject information includes the subject's self-reported race. In some embodiments, the subject information includes whether the subject self-identifies as Asian.

[0070] In some embodiments, the subject provides the subject information. In some embodiments, a medical professional provides the subject information.

[0071] In some embodiments, the subject information does not include the subject's level of VWF or hematocrit.

[0072] In some embodiments, the system is programmed to implement a one-compartment chimeric protein popPK model for calculating dosing information that includes body weight as a covariate, and wherein the chimeric protein popPK model does not include the level of VWF or hematocrit as a covariate. In some embodiments, the system is programmed to implement a one-compartment chimeric protein popPK model with linear elimination that includes body weight as a covariate for calculating dosing information, and wherein the chimeric protein popPK model does not include the level of VWF or hematocrit as a covariate. In some embodiments, the system is programmed to implement a one-compartment chimeric protein popPK model for calculating individualized subject PK information that includes body weight as a covariate, and wherein the chimeric protein popPK model does not include the level of VWF or hematocrit as a covariate. In some embodiments, the system is programmed to implement a one-compartment chimeric protein popPK model with linear elimination that includes body weight as a covariate for calculating individualized subject PK information, and wherein the chimeric protein popPK model does not include the level of VWF or hematocrit as a covariate.

[0073] In some embodiments, the method further comprises selecting a dosage regimen based on the dosage information. In some embodiments, the method further comprises selecting a dosage regimen based on the PK information. In some embodiments, the method further comprises administering the chimeric protein to the subject according to the selected dosage regimen.

[0074] In some embodiments, the dosing information includes estimated or predicted FVIII activity levels over time following administration of the chimeric protein.

[0075] In some embodiments, the dosing regimen is a preventive regimen. In some embodiments, the dosing regimen is an on-demand regimen. In some embodiments, the dosing regimen is for perioperative bleeding management.

[0076] In some embodiments, the desired treatment outcome information includes the desired FVIII activity level. In some embodiments, the desired FVIII activity level includes the minimum FVIII activity level between doses. In some embodiments, the desired FVIII activity level includes the minimum FVIII activity level at a time point. In some embodiments, the time point is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after administration of the chimeric protein. In some embodiments, the time point is about 1 week after administration of the chimeric protein.

[0077] In some embodiments, the chimeric protein popPK model includes self-reported race as a covariate. In some embodiments, the chimeric protein popPK model includes whether the subject self-reports as Asian as a covariate. In some embodiments, the subject does not self-report as Asian. In some embodiments, the subject self-reports as Asian.

[0078] Included herein is a method of treating hemophilia A in a subject in need thereof, the method comprising administering to the subject a dosage regimen selected according to the methods disclosed herein.

[0079] Also provided is a device or system comprising a processor configured to provide dosing or PK information according to the methods disclosed herein.

[0080] The present disclosure further provides a data processing device, apparatus or system comprising a processor, the processor being configured to implement a one-compartment chimeric protein popPK model, wherein the chimeric protein popPK model comprises body weight as a covariate, and wherein the chimeric protein popPK model does not comprise the level of VWF or the level of hematocrit as a covariate. In some embodiments, the chimeric protein popPK model comprises self-reported race as a covariate. In some embodiments, the chimeric protein popPK model comprises whether the subject is self-reported as Asian as a covariate. In some embodiments, the data processing device, apparatus or system comprises a smartphone, a tablet computer, a personal digital assistant, a handheld computer, a laptop computer or a smart watch. In some embodiments, the data processing device, apparatus or system comprises a smartphone and / or a smart watch.

[0081] Included herein is a computer program comprising instructions that, when executed by a computer, cause the computer to perform a method disclosed herein (e.g., a method comprising a chimeric protein popPK model), wherein the chimeric protein popPK model comprises body weight as a covariate, but does not comprise the level of VWF or the level of hematocrit as a covariate. In some embodiments, the chimeric protein popPK model comprises self-reported race as a covariate. In some embodiments, the chimeric protein popPK model comprises whether the subject self-reports as Asian as a covariate.

[0082] Provided herein is a computer-readable medium comprising instructions that, when executed by a computer, cause the computer to provide for performing a method disclosed herein (e.g., a method comprising a chimeric protein popPK model), wherein the chimeric protein popPK model comprises body weight as a covariate, but does not comprise the level of VWF or the level of hematocrit as a covariate. In some embodiments, the chimeric protein popPK model comprises self-reported race as a covariate. In some embodiments, the chimeric protein popPK model comprises whether the subject self-reports as Asian as a covariate.

[0083] In some embodiments, the FVIII polypeptide has a deletion of amino acids 746 to 1648 corresponding to mature FVIII (SEQ ID NO:7), the first ELNN polypeptide is inserted into the FVIII polypeptide immediately downstream of amino acid 745 corresponding to mature FVIII (SEQ ID NO:7), and the first ELNN polypeptide comprises an amino acid sequence that is at least about 90% identical to the amino acid sequence of SEQ ID NO:8.

[0084] In some embodiments, the VWF fragment comprises the D' domain of VWF and the D3 domain of VWF, the VWF fragment is mutated to replace the cysteine ​​involved in VWF dimerization with alanine, the second ELNN polypeptide comprises an amino acid sequence at least about 90% identical to the amino acid sequence of SEQ ID NO:9, and the linker comprises an amino acid sequence at least about 90% identical to the amino acid sequence of SEQ ID NO:10.

[0085] In some embodiments, the first ELNN polypeptide comprises the sequence of SEQ ID NO:8, and the second ELNN polypeptide comprises the amino acid sequence of SEQ ID NO:9.

[0086] In some embodiments, the chimeric protein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO:3, and the second polypeptide comprises an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO:6, and wherein the first polypeptide and the second polypeptide are covalently linked by two disulfide bonds between the first Fc region and the second Fc region.

[0087] In some embodiments, the chimeric protein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises the amino acid sequence as shown in SEQ ID NO:3, and the second polypeptide comprises the amino acid sequence as shown in SEQ ID NO:6, and wherein the first polypeptide and the second polypeptide are covalently linked through two disulfide bonds between the first Fc region and the second Fc region. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1 is a visual representation of a software-based system that may be used in the methods disclosed herein.

[0089] Figure 2 is a visual representation of an exemplary web-based system that may be used in accordance with the methods disclosed herein.

[0090] Figure 3 A schematic diagram of an example computing system 400 is shown.

[0091] Figure 4 is a graph showing individual clearance of ivenomic alpha (dL / h) versus baseline VWF level (IU / dL) in adult and adolescent patients.

[0092] Figure 5 It is a diagram showing the simulated steady-state FVIII activity measured over time using the ivantrin α population PK model [A] (50 IU / kg) in patients aged ≥12 years old based on clinical data derived from a phase I coagulation assay. Also shown are the observed FVIII activities from clinical data. The solid line is the simulated median FVIII activity (IU / dL). The dotted line is the simulated 5th and 95th percentiles.

[0093] Fig. 6A is a graph showing the baseline corrected FVIII activity time profile on Day 1 from Adult / Adolescent Study EFC16293. Data for all patients are shown. LLOQ = 1 IU / dL Figure 6B is a graph showing the baseline-corrected FVIII activity time profiles from the adult / adolescent study EFC16293 at Day 1 (solid line) and Week 26 (dashed line). Only data for sequential group patients are shown.

[0094] Figure 7 Correlations between 4 continuous covariates at baseline are shown. WTKGB is baseline weight (median 78.3, excluding EFC16295). BH is baseline race (median 43, excluding EFC16295). BVWF is baseline VWF (median 112, excluding EFC16295).

[0095] Fig. 8A and Figure 8B is to show the population prediction (PRED) ( Fig. 8A ) and individual prediction (IPRED)( Figure 8B ) compared to the observed FVIII activity values ​​(DV; data values) in phase I. The black line is the uniform line. The gray line is the less smooth line. Fig. 8A R for group prediction 2 =0.92. Figure 8B R of individual predictions 2 =0.97.

[0096] Fig. 9 It is a set of figures showing the performance of the Avancog α population PK model [A] using visual prediction check (VPC). The open circles show the observed data. The solid line shows the median simulated by the model. The dotted line shows the 5th and 95th percentiles simulated by the model. The shading around each dotted line represents the 90% CI around the 5th and 95th percentiles simulated. The shading around each solid line shows the 90% CI around the median simulated.

[0097] Fig. 10A and Fig. 10B The PRED( Fig. 10A ) and IPRED( Fig. 10B ) compared to DV. The gray line is the unity line. 2 As shown in black line, the black line is the regression line between the observed values ​​and the predicted values.

[0098] Fig.11 is a graph showing the steady-state C trough , C maxss A set of graphs showing the distribution of the time when the FVIII activity level reaches 40 IU / dL.

[0099] Fig.12 The steady-state C trough , C maxss A set of graphs showing the distribution of the time when the FVIII activity level reaches 40 IU / dL.

[0100] Fig.13 is a graph showing OSC F VIII activity over time for major surgery and major bleeding in patients aged 6 years and younger. Solid grey line: median of simulation for 30 IU / kg dose. Circled grey line: median of simulation for 50 IU / kg dose. Solid black line: 5th and 95th percentiles of simulation. Dashed lines indicate OSC activity at 80 IU / kg and 40 IU / kg.

[0101] Fig.14 is a graph showing simulated FVIII activity for a dose of 50 IU / kg avermitog alfa followed by 30 IU / kg every 3 days until day 14 in a virtual adult and adolescent population.

[0102] Fig.15 is a graph showing simulated OSC FVIII activity over time for all age groups. DETAILED DESCRIPTION

[0103] With the advent of alternative products that extend half-life, treatment goals are expanding to include long-term outcomes associated with high sustained plasma FVIII activity levels (such as long-term joint protection) in addition to the goal of low annual bleeding rate (ABR). Ivanoclot alpha circulates independently of endogenous von Willebrand factor (VWF) and provides high sustained FVIII activity (see, e.g., Chhabra et al. Blood. [Blood] 2020; 135(17): 1484-1496 and Konkle et al., N Engl J Med [New England Journal of Medicine] 2020; 383: 1018-1027 (Ivanoclot alpha is referred to as BIVV001), the entire contents of each of these documents are incorporated herein by reference for all purposes).

[0104] The present disclosure provides, inter alia, methods of treatment and software-based systems for estimating PK information of avermectin alpha for individual subjects for treating hemophilia A. For example, methods of estimating PK information of avermectin alpha for individual subjects using a software-based system are included. In some embodiments, the software-based system applies an avermectin alpha population PK model [A] to estimate dosage information for subjects receiving avermectin alpha as a FVIII replacement therapy.

[0105] The present disclosure provides, among other things, methods of treatment and software-based systems for estimating or quantifying the risk of bleeding in the presence of high sustained FVIII activity. In some embodiments, the software-based system can apply an Avancog alpha population pharmacokinetic / pharmacodynamic model to quantify the risk of bleeding in the presence of high sustained FVIII activity compared to the standard of care.

[0106] definition

[0107] The term "about" is used herein to mean approximately, roughly, roughly or around. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the upper and lower boundaries of the numerical value. Typically, the term "about" can modify the numerical value above and below the stated value by, for example, a change of more than or less than 10% (higher or lower). In some embodiments, the term indicates a deviation from the numerical value ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05% or ±0.01%. In some embodiments, "about" indicates a deviation from the numerical value ±10%. In some embodiments, "about" indicates a deviation from the numerical value ±5%. In some embodiments, "about" indicates a deviation from the numerical value ±4%. In some embodiments, "about" indicates a deviation from the numerical value ±3%. In some embodiments, "about" indicates a deviation from the numerical value ±2%. In some embodiments, "about" indicates a deviation from the numerical value ±1%. In some embodiments, "about" indicates a deviation from the numerical value shown by ±0.9%. In some embodiments, "about" indicates a deviation from the numerical value shown by ±0.8%. In some embodiments, "about" indicates a deviation from the numerical value shown by ±0.7%. In some embodiments, "about" indicates a deviation from the numerical value shown by ±0.6%. In some embodiments, "about" indicates a deviation from the numerical value shown by ±0.5%. In some embodiments, "about" indicates a deviation from the numerical value shown by ±0.4%. In some embodiments, "about" indicates a deviation from the numerical value shown by ±0.3%. In some embodiments, "about" indicates a deviation from the numerical value shown by ±0.1%. In some embodiments, "about" indicates a deviation from the numerical value shown by ±0.05%. In some embodiments, "about" indicates a deviation from the numerical value shown by ±0.01%.

[0108] It should be understood that wherever herein an aspect is described using the language "comprising," other similar aspects described using "consisting of" and / or "consisting essentially of" are also provided.

[0109] As used herein in the context of hemophilia A, the term "prophylactic treatment" refers to a therapy administered in advance for the treatment of hemophilia A, wherein such treatment is intended to prevent or reduce the severity of one or more symptoms of hemophilia A, such as bleeding episodes (e.g., one or more spontaneous bleeding episodes) and / or joint damage. In order to prevent such symptoms (e.g., bleeding episodes and progression of joint disease) or reduce their severity, hemophilia A patients may receive regular infusions of clotting factors (e.g., avermitigin alfa) as part of a prophylactic treatment regimen.

[0110] The term "on-demand treatment" or "episodic treatment" refers to the administration of FVIII replacement therapy (such as avermitog alpha) "as needed" in response to symptoms of hemophilia A (e.g., a bleeding episode (such as a spontaneous bleeding episode or a traumatic bleeding episode)) or prior to an activity that may cause bleeding. In some embodiments, the on-demand treatment may be administered to a subject at the onset of bleeding (such as after an injury) or when bleeding is expected (such as before surgery). In some embodiments, the on-demand treatment may be administered prior to an activity that increases the risk of bleeding (such as a contact sport). In some embodiments, the on-demand treatment may be administered to a subject who is receiving prophylactic treatment, for example, if a supplemental FVIII replacement protein dose is administered to treat a bleeding episode or prior to strenuous activity. In some embodiments, the on-demand treatment is administered as a single dose. In some embodiments, the on-demand treatment is administered as a first dose, followed by one or more additional doses. In some embodiments, the on-demand regimen is for perioperative bleeding management.

[0111] In some embodiments, a bleeding episode begins at the first sign of bleeding and ends 72 hours after the last treated bleeding, wherein any bleeding symptoms or injections at the same location separated by less than or equal to 72 hours are considered to be the same bleeding episode. See Blanchette V. (2006) Haemophilia 12: 124-7. In some embodiments, any injection to treat a bleeding episode more than 72 hours after the previous injection is considered to be the first injection to treat a new bleeding episode at the same location. In some embodiments, any bleeding at a different location is considered to be a separate bleeding episode, regardless of the time since the last injection.

[0112] Methods provided herein can be applied to subjects requiring preventive treatment or paroxysmal / on-demand treatment. In certain embodiments, subjects requiring preventive treatment or paroxysmal / on-demand treatment suffer from hemarthrosis, muscle bleeding, oral bleeding, hemorrhage, bleeding into muscle, oral bleeding, trauma, head trauma (trauma capitis), gastrointestinal bleeding, intracranial bleeding, intraperitoneal bleeding, intrathoracic bleeding, fracture, central nervous system bleeding, retropharyngeal space bleeding, retroperitoneal space bleeding and iliopsoas sheath bleeding. In certain embodiments, subjects need to undergo surgical treatment, including, for example, surgical prevention or perioperative management. In certain embodiments, surgery is minor or major surgery. Exemplary surgery includes tooth extraction, tonsillectomy, inguinal herniotomy, synovectomy, craniotomy, osteosynthesis, trauma surgery, intracranial surgery, intraperitoneal surgery, intrathoracic surgery, joint replacement surgery (e.g., total knee replacement, hip replacement, etc.) heart surgery and cesarean section.

[0113] As used herein, "treat" and "treating" in the context of hemophilia A include, for example, reducing the severity of hemophilia A; ameliorating one or more symptoms associated with hemophilia A; providing a beneficial effect to a subject with hemophilia A, but not necessarily curing hemophilia A; and / or preventing one or more symptoms associated with hemophilia A.

[0114] In some embodiments, treating hemophilia A includes preventing one or more symptoms of hemophilia A (e.g., spontaneous bleeding). In some embodiments, treating hemophilia A includes reducing the likelihood of a bleeding episode or alleviating the severity of a bleeding episode. In some embodiments, treatment is prophylactic treatment. In some embodiments, treatment is treatment on demand. In some embodiments, treatment includes reducing the frequency of one or more symptoms of hemophilia A (e.g., spontaneous or uncontrollable bleeding episodes).

[0115] As used herein, the term "perioperative management" means the use of ivag alpha before, during or after a surgical procedure (e.g., surgery). The use of "perioperative management" for one or more bleeding episodes includes surgical prophylaxis before (i.e., preoperative), during (i.e., intraoperative) or after (i.e., postoperative) surgery to prevent one or more bleeding or bleeding episodes before, during and after surgery, or to reduce or inhibit spontaneous and / or uncontrollable bleeding episodes.

[0116] As used herein, "baseline" plasma FVIII levels are the lowest plasma FVIII levels measured in a subject before the dose is administered. In some embodiments, activity above baseline before the dose can be considered as residual FVIII activity from a previous treatment, and the half-life of the previous treatment can be used to decay over time and subtract it from the PK data after the dose of Avancog α. In some embodiments, the baseline FVIII activity level is the FVIII activity level in the patient's blood (e.g., assessed with plasma) when hemophilia A is not treated.

[0117] The terms "patient" and "subject" are used interchangeably herein and refer to people. Subjects may include, for example, individuals who have been diagnosed with hemophilia A and are susceptible to spontaneous and / or uncontrollable bleeding episodes. Subjects may also include individuals who are in danger of one or more uncontrollable bleeding episodes before a certain activity (e.g., surgery, sports activity, or any strenuous activity). In certain embodiments, the subject has a baseline FVIII activity of less than 0.5%, less than 1%, less than 2%, less than 2.5%, less than 3%, or less than 4%. In certain embodiments, the subject suffers from severe hemophilia A, defined as <1IU / dL (<1%) endogenous FVIII activity. In certain embodiments, the subject has no coagulation disorder except hemophilia A.

[0118] As used herein, the terms "ELNN polypeptide" and "ELNN" are synonymous and refer to polypeptides of extended length that contain non-naturally occurring substantially non-repetitive sequences (e.g., polypeptide motifs) that are primarily composed of hydrophilic small amino acids, and that have a low degree of secondary or tertiary structure or no secondary or tertiary structure under physiological conditions. Such extended length polypeptides include unstructured hydrophilic polypeptides containing repetitive motifs of 6 natural amino acids (G, A, P, E, S and / or T). In some embodiments, the ELNN polypeptide comprises a plurality of motifs having 6 natural amino acids (G, A, P, E, S, T), wherein these motifs are identical or comprise a combination of different motifs. When connected to the VWF fragment or FVIII sequence disclosed herein to produce a chimeric polypeptide or protein, the ELNN polypeptide can confer certain desired pharmacokinetic, physicochemical and pharmaceutical properties. Such desired properties include, but are not limited to, enhanced pharmacokinetic parameters and solubility characteristics. ELNN polypeptides are known in the art, and non-limiting descriptions of ELNN polypeptides, referred to as XTEN polypeptides, and examples thereof are available in Schellenberger et al., (2009) Nat Biotechnol 27(12): 1186-90; Brandl et al., (2020) Journal of Controlled Release 327: 186-197; and Radon et al., (2021) Advanced Functional Materials 31, 2101633 (pp. 1-33), the entire contents of each of which are incorporated herein by reference.

[0119] As used herein, "software-based system" refers to an algorithm or set of algorithms that can be implemented by a processing device. The software-based system can be embodied in software, including but not limited to firmware, resident software, microcode, etc., and can take the form of a computer program product accessible from a computer-available or computer-readable medium, which provides a program code for use by a computer or any instruction execution system or in combination with the computer or any instruction execution system. For the purposes of this description, a computer-available or computer-readable medium can be any device that can contain, store, communicate, propagate or transmit a program for use by an instruction execution system, device or apparatus or in combination with the instruction execution system, device or apparatus. The medium can be an electronic, magnetic, optical, electromagnetic, infrared or semiconductor system (or device or apparatus) or a propagation medium. Examples of computer-readable media include semiconductor or solid-state memory, magnetic tape, removable computer floppy disk, random access memory (RAM), read-only memory (ROM), hard disk and optical disk (including compact disk read-only memory (CD-ROM), read / write compact disk (CD-R / W) and DVD). Non-limiting examples of software-based systems include network-based systems and web-based systems.

[0120] As used herein, the term "processing device" refers to a data processing system suitable for storing and / or executing program code to implement a software-based system, and may include at least one processor directly or indirectly coupled to a memory component via a system bus. The one or more processors (electronic circuits that execute instructions constituting the program code) may be instantiated by a microprocessor, a microcontroller, a multi-core processor, an array processor, or a vector processor. The memory component may include a local memory, a bulk memory, and a cache memory utilized during the actual execution of the program code, which cache memories provide temporary storage of at least some program codes to reduce the number of times that the code must be retrieved from the bulk memory during execution. Input / output or I / O devices (including but not limited to keyboards, displays, pointing devices, touch screens, audio, etc.) may be coupled to the system directly or by intervening I / O controllers. A network adapter may also be coupled to the system so that the processing device can be coupled to other processing devices or remote printers or storage devices by intervening a dedicated or public network. Modems, cable modems, and Ethernet cards are just the types of several network adapters currently available. The processing device may also be a shared data processing system (such as a network-based (eg, web-based) server system accessible via a network (such as the Internet)) that can access and execute program code to implement a software-based system.

[0121] Description of Ivancholine Alpha

[0122] Ivancog alpha is described in the following documents: Chhabra et al. Blood [blood] 2020; 135 (17): 1484-1496, Konkle et al., N Engl J Med [New England Journal of Medicine] 2020; 383: 1018-1027, and the International Nonproprietary Names for Pharmaceutical Substances (INN) WHO Drug Information [International Nonproprietary Names for Pharmaceutical Substances (INN) WHO Drug Information], 2019, Volume 33, Issue 4, Pages 828-30, the entire contents of each of which are hereby incorporated by reference in their entirety. In patients with FVIII deficiency, Ivancog alpha temporarily replaces the lost FVIII required for effective hemostasis. Ivancog alpha comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 3, the first polypeptide being covalently bound to a second polypeptide comprising an amino acid sequence of SEQ ID NO: 6, wherein the first polypeptide and the second polypeptide are covalently bound to each other via a disulfide bond. Avancog alpha can be produced, for example, in a human embryonic kidney (HEK) cell line by recombinant DNA technology. For example, the cell line can express rFVIIIFc-ELNN polypeptide (SEQ ID NO: 1), rVWF-ELNN-Fc polypeptide (SEQ ID NO: 4) and soluble PACE enzyme. Non-limiting examples of nucleotide sequences encoding rFVIIIFc-ELNN polypeptide (SEQ ID NO: 2) and rVWF-ELNN-Fc polypeptide (SEQ ID NO: 5) can be found in Table 7 below. The amino acid sequence of the rFVIIIFc-ELNN polypeptide without a signal peptide (SEQ ID NO: 3) and the amino acid sequence of the rVWF-ELNN-Fc polypeptide without a signal peptide or the D1D2 portion of VWF (SEQ ID NO: 6) can be found in Table 7 below.

[0123] In some embodiments, for subjects receiving prophylactic treatment with ivag alpha, the methods disclosed herein can be used to determine individualized subject information (e.g., plasma FVIII levels of subjects at a specific time point or a group of time points). Based on the individual subject information, the dosage and / or dosage interval of ivag alpha can be adjusted to achieve individual treatment goals, such as minimum plasma FVIII levels (e.g., trough values).

[0124] In some embodiments, for a subject receiving on-demand treatment with ivacog alpha, if the subject's bleeding is not controlled or is unsatisfactory after administration of ivacog alpha at the initially recommended dose and dose interval, the methods disclosed herein can be used to determine dosage information for the individual subject. Based on this individual subject's dosage information, the dose and / or dose interval of ivacog alpha can be adjusted to achieve improved bleeding control.

[0125] In some embodiments, the methods disclosed herein can be used to estimate a subject's minimum FVIII level between doses.

[0126] The subject's plasma FVIII activity levels can be monitored (eg, a primary coagulation assay) to confirm that adequate FVIII levels have been achieved and maintained as clinically indicated. FVIII activity can be measured by any method known in the art. A variety of tests are available to assess the function of the coagulation system: activated partial thromboplastin time (aPTT) test, chromogenic assays, ROTEM assays, prothrombin time (PT) test (also used to determine INR), fibrinogen test (usually performed by Clauss method), platelet count, platelet function tests (usually performed by PFA-100), TCT, bleeding time, mixing tests (whether the abnormality is corrected if the subject's plasma is mixed with normal plasma), coagulation factor assays, antiphospholipid antibodies, D-dimer, genetic tests (e.g., factor V Leiden, prothrombin mutation G20210A), dilute Russell's viper venom time (dRVVT), miscellaneous platelet function tests, thromboelastography (TEG or Sonoclot), thromboelastometry ( For example, ), or euglobulin lysis time (ELT).

[0127] The aPTT test is a performance indicator that measures the efficacy of both the "intrinsic" (also called the contact activation pathway) and the common coagulation pathway. This test is generally used to measure the coagulation activity of commercially available recombinant coagulation factors (e.g., FVIII). It is usually used in conjunction with the prothrombin time (PT) that measures the extrinsic coagulation pathway. (See, e.g., Kamal et al., Mayo Clin Proc., 82(7):864-873 (2007)). In some embodiments, the following assay is used to test aPTT, in which XP Analyzer (Siemens Healthcare Diagnostics) FVIII activity was measured by FSL activated PTT reagent (Siemens Medical Diagnostics).

[0128] In some embodiments, the aPTT assay can also be used to assess the efficacy of the chimeric polypeptide prior to administration to a subject. (Hubbard AR et al. J Thromb Haemost 11:988-9 (2013)). In some embodiments, the aPTT assay can be further used in conjunction with any of the assays described herein before or after administration to a subject.

[0129] In some embodiments, the models provided herein provide FVIII activity calculations and information corresponding to the activity as measured by the aPTT test. For example, the Avancog alpha popPK model [A] provides FVIII activity calculations and information corresponding to the activity as measured by the aPTT test.

[0130] ROTEM analysis provides information on the overall dynamics of hemostasis: clotting time, clot formation, clot stability and lysis. The different parameters of thromboelastometry depend on the activity of the plasma coagulation system, platelet function, fibrinolysis or a number of factors that influence these interactions. This assay can provide a comprehensive insight into secondary hemostasis.

[0131] The chromogenic assay mechanism is based on the principle of the coagulation cascade, in which activated FVIII accelerates the conversion of factor X to factor Xa in the presence of activated factor IX, phospholipids and calcium ions. Factor Xa activity is assessed by hydrolysis of a p-nitroaniline (pNA) substrate that is specific for factor Xa. The initial release rate of p-nitroaniline measured at 405 nM is proportional to the factor Xa activity and, therefore, to the FVIII activity in the sample. In some embodiments, the chromogenic assay is a BIOPHENFVIII:C assay (Hyphen Biomed, Neurville sur Oise, France). In some embodiments, a chimeric polypeptide comprising a FVIII polypeptide has a chimeric polypeptide (e.g., KOGENATE HELIXATE XYNTHA / REFACTO

[0132] and ) comparable FVIII activity.

[0133] In some embodiments, chromogenic assays can also be used to assess the efficacy of the chimeric polypeptide prior to administration to a subject. (Hubbard AR et al. J Thromb Haemost 11:988-9 (2013)). Chromogenic assays can be further used in conjunction with any of the assays described herein before or after administration to a subject.

[0134] Subject dosage information

[0135] For most currently available FVIII replacement therapies, the required FVIII dose for each subject is calculated using the following formula:

[0136] Number of Factor VIII units required (IU) = body weight (kg) x [B]

[0137] Expected FVIII increase (IU / dL or % of normal) x 0.5 (IU / kg / IU / dL)

[0138] This calculation provides a general estimate of a subject's dosage requirements based on body weight and desired increase in FVIII activity level as subject-specific variables.

[0139] Disclosed herein is a model [A] for determining or estimating dosing information for hemophilia A subjects receiving FVIII replacement therapy with avermectin alfa. The avermectin alfa popPK model [A] is represented as follows:

[0140]

[0141] Model [A] abbreviations are: CL, central compartment clearance; TVCL, estimate of typical clearance; WT, body weight (kg); ASIAN, indication of Asian race (0 for non-Asian and 1 for Asian); η1, variability of CL; V, central compartment volume; TVV, estimate of typical volume; η2, variability of V; k, central compartment elimination rate; Rate, infusion rate; A1, amount of primary (OS) FVIII activity in the central compartment; and C, primary (OS) FVIII activity in the central compartment.

[0142] Investigations of covariates that influence FVIII activity have historically focused on VWF concentration. However, in the ivampicin alpha popPK data and models disclosed herein, VWF concentration was not found to be a covariate. Without being bound by any scientific theory, it is noteworthy that ivampicin alpha clearance is independent of endogenous VWF. Hematocrit level was also found not to be a covariate.

[0143] For the avermitogen alpha popPK model disclosed herein, central compartment clearance (CL) and central compartment volume (V) were found to be dependent on body weight. Asian race was also identified as a covariate for CL.

[0144] In some embodiments, race is the self-reported race of the subject. For example, the subject may self-report from a group of possible options including the option "Asian". In some embodiments, if the subject decides not to report race, for the purpose of the model, the subject is considered not to be Asian. In some embodiments, when self-reported race information is not collected or cannot be collected, for the purpose of the model, the subject is considered not to be Asian. In some embodiments, the subject who self-reports as Asian self-identifies as East Asian descent or ancestry. In some embodiments, the subject who self-reports as Asian self-identifies as Southeast Asian descent or ancestry. In some embodiments, the subject who self-reports as Asian self-identifies as Central Asian descent or ancestry. In some embodiments, the subject who self-reports as Asian self-identifies as North Asian descent or ancestry. In some embodiments, the subject who self-reports as Asian self-identifies as West Asian descent or ancestry. In some embodiments, the subject self-identifies as East Asian descent or ancestry. In some embodiments, the subject self-identifies as South Asian descent or ancestry. In some embodiments, the subject self-identifies as Central Asian descent or ancestry. In some embodiments, the subject self-identifies as Southeast Asian descent or ancestry. In some embodiments, the subject self-identifies as West Asian descent or ancestry.

[0145] Some embodiments include administering a dose of ivag alpha to a human subject in need thereof at a dosing interval, wherein the dose and / or dosing interval is identified using the subject's weight and / or self-reported race rather than the subject's VWF or hematocrit level. The present disclosure provides methods for administering a dose of ivag alpha to a human subject in need thereof at a dosing interval, wherein the dose and / or dosing interval is identified by applying the ivag alpha model [A] disclosed herein.

[0146] The Avancog alpha model [A] disclosed herein can be used to determine individual subject dosage information in order to evaluate and / or confirm subject treatment goals. The individual subject dosage information can be used to determine the dosage and / or dosage interval of Avancog alpha in future treatments. The treatment goal can include, for example, higher plasma FVIII levels over a long period of time.

[0147] In some embodiments, the therapeutically effective dose of avermitog alpha is about 50 IU / kg. In some embodiments, a dose of about 50 IU / kg is administered to a subject once a week. In some embodiments, a dose of about 50 IU / kg is administered to a subject once every about 7 days. In some embodiments, an initial dose of about 50 IU / kg is administered to a subject, followed by 50 IU / kg or 30 IU / kg every 2-3 days as needed.

[0148] In some embodiments, the methods disclosed herein are applied to determine individualized interval prevention for a subject. As used herein, the term "individualized interval prevention" means using ivacog alfa at an individualized dose and / or dosage interval or frequency to prevent or inhibit the occurrence of one or more spontaneous and / or uncontrollable bleeding or bleeding episodes, or to reduce the frequency of one or more spontaneous and / or uncontrollable bleeding or bleeding episodes.

[0149] In certain embodiments, the treatment goal of the subject includes achieving high FVIII plasma activity levels and / or high trough levels. As used herein, "trough levels" in hemophilia subjects are measured values ​​of the lowest concentrations reached by factor therapy (e.g., ivagoceptin alpha therapy) before administering the next dose. The methods disclosed herein can be used to determine subject dosage information to achieve specific FVIII plasma activity levels and / or trough levels. In hemophilia A subjects, it has been demonstrated that the administration of ivagoceptin alpha can successfully achieve high FVIII plasma activity levels and / or high trough levels.

[0150] In some embodiments, the administration of ivampin alpha to a subject achieves a 40% or higher FVIII activity level for about 1, 2, 3, or 4 days. In some embodiments, the administration of ivampin alpha to a subject achieves a higher FVIII activity level for about 1, 2, 3, or 4 days. In some embodiments, the administration of ivampin alpha to a subject achieves a FVIII activity level of at least 40% for at least three days. In some embodiments, the administration of ivampin alpha to a subject achieves a FVIII activity level of at least 50% for about 4 days. In some embodiments, the ivampin alpha model [A] is used to determine individual subject dosage information so as to achieve a FVIII activity level of at least 40% in a subject for about 1, 2, 3, or 4 days.

[0151] Methods for estimating subject-individualized dosing information, subject-individualized PK information, and subject-median PK information Laws, systems and storage media

[0152] The present invention includes a method for estimating (e.g., calculating, determining, or providing) personalized avermectin alpha dosage information for an individual subject, the method comprising: (a) receiving subject information and / or desired treatment outcome information by an application program programmed to run with an avermectin alpha popPK model (e.g., an avermectin alpha popPK model [A]), b) calculating personalized avermectin alpha dosage information using the avermectin alpha popPK model and the received information, and c) outputting the calculated personalized avermectin alpha dosage information of (b). Further disclosed is a method as described herein, the method further comprising selecting a dosage regimen based on the output personalized dosage information of (c), and administering avermectin alpha to the subject according to the selected dosage regimen. One or more of the above steps can be performed using a software-based system, a network-based system, a computing system, or a combination of the aforementioned systems. For example, an exemplary network-based system can be used to obtain estimated individualized dosage information for a subject, individualized PK information for a subject, and median PK information for a subject.

[0153] In some embodiments, (a) further comprises receiving subject information via a software-based system.

[0154] In certain embodiments, the subject information includes age, self-reported race and / or weight. Additional subject information may further include diagnosed (baseline) FVIII levels, PK assays, PK sampling time, dosage history (if PK samples are taken from multiple doses), actual dose, FVIII activity level, etc.

[0155] In some embodiments, the output information includes, for example, PK profiles, PK parameters such as incremental recovery (Cmax / dose), mean retention time, terminal t1 / 2, clearance, Vss, AUC / dose, dose and associated troughs, and interval and associated troughs.

[0156] For example, to evaluate individualized subject PK, the system may suggest that the user input 2-3 optimized PK sampling time points. In this case, the system output may include a PK curve and one or more selected PK parameters.

[0157] As another example, to select an individualized dosing regimen using the outputted subject PK parameters discussed in the previous paragraph, (i) the dose selected for acute treatment can be based on user input of the expected rise in plasma FVIII activity levels after the dose, (ii) the dose selected for prevention can be based on user input of the expected dosing interval, or (iii) the selected prevention interval can be based on user input of the expected dose. In the second case, the system output can be a table of doses and associated troughs (e.g., x IU / kg, 10% trough, y IU / kg, 20% trough, etc.), and in the third case, the system output can be a table of intervals and associated troughs (e.g., x days, 10% trough, y IU / kg, 20% trough, etc.).

[0158] In some embodiments, the user may wish to use the system without inputting any individualized PK data. In some embodiments, the dosage output will be based on a population mean or median, rather than the individualization of a particular subject. In some embodiments, the user inputs, for example, body weight and / or self-reported race, and (i) after the dosage, the expected plasma FVIII activity level rises, (ii) the expected dosage interval for prevention, or (iii) the expected dosage for prevention. In the first case, the system can output the dosage. In the second case, the system can output the dosage and the associated trough value. In the third case, the system can output the interval and the associated trough value.

[0159] The system can comply with patient privacy laws. In some embodiments, the system is encrypted, for example, with SSL encryption. In some embodiments, input subject information is anonymous.

[0160] In some embodiments, the system includes a user instructions function.

[0161] In some embodiments, the methods can be performed by, for example, a subject, a physician, a nurse, or other medical practitioner. In some embodiments, the methods are performed by a subject.

[0162] Some embodiments include a computer-readable storage medium having stored thereon instructions that, when executed by a processor, cause the processor to perform one or more of the steps of the above-described methods.

[0163] Some embodiments include a system comprising a processor and a memory having stored thereon instructions which, when executed by the processor, cause the processor to perform any of the above methods.

[0164] A user of the system or computer-readable storage medium may be, for example, a subject or a caregiver or a physician, nurse or other medical practitioner.

[0165] In certain embodiments, the subject information input into the system includes body weight. In certain embodiments, the subject information input into the system is self-reported race. In certain embodiments, the expected treatment outcome information is the expected plasma FVIII activity level rise after the dosage, and the output information is the dosage for acute treatment. In certain embodiments, the expected treatment outcome information is the expected dosage interval, and the output information is the dosage for prevention. In certain embodiments, the expected treatment outcome information is the expected dosage, and the output information is the prevention interval.

[0166] In some embodiments, the individual avermitog alpha PK information includes 2-3 PK sampling time points. In some embodiments, the individual avermitog alpha PK information includes one or more of the subject's weight, diagnosed (baseline) factor level, dosage history (if the PK sample is taken from multiple doses), actual dose, actual time of PK sampling, factor activity level, subject weight, and / or subject self-reported race.

[0167] In some embodiments, the output individualized subject PK includes a PK curve or a PK parameter selected from incremental recovery (Cmax / dose), mean retention time, terminal t1 / 2, clearance, Vss, and AUC / dose. In some embodiments, the expected treatment outcome information based on the PK of the individual subject is the expected increase in plasma FVIII activity level after administration, and the output information is the dose for acute treatment.

[0168] In some embodiments, the method disclosed herein includes an electronic device. The electronic device may include, but is not limited to, a device having a processor for executing instructions and a memory for storing instructions. The electronic device may also include a display and one or more computer input devices (such as a keyboard, mouse, pad, touch screen, microphone and / or joystick). In some embodiments, the electronic device is a general-purpose computing and data communication device (such as a digital pen, smart phone, smart watch, tablet computer, personal digital assistant, handheld computer, laptop computer, point-of-sale transaction device, scanner, camera and fax machine). The electronic device may also have multiple processors and multiple shared or separate memory components. For example, the electronic device may be a cluster computing environment or a server farm.

[0169] Alternatively, the electronic device can be a special data collection, calculation and communication device, such as, can receive the real-time nursing (POC) device of subject demographic information (including age, including the vital signs of weight and / or the blood characteristic values ​​of the race of self-report). The blood characteristic values ​​can be received by the electronic device via the data communication channel, the manual input and / or by the diagnostic process performed by the electronic device. The diagnostic process performed on the subject's blood sample in the device can include ultrasonic measurement, impedance measurement, conductivity measurement and / or optical measurement. The electronic device can be further configured to receive, detect, record and / or communicate the subject information of (baseline) FVIII level, PK determination, PK sampling time, dosage history (if PK sample is taken from multiple doses), actual dose, FVIII activity level of other including diagnosis. The electronic device communicates with one or more network-based (for example, based on web) applications through one or more networks (such as the Internet). Similar to the electronic device, network-based (for example, based on web) applications can be realized using general-purpose computers, servers or other devices that can provide data to the electronic device. The electronic device can receive individualized subject avermitogen alpha PK information from a network-based (eg, web-based) server and program. In some embodiments, the electronic device can assist in selecting a dosing regimen based on outputting the calculated subject PK information.

[0170] The methods and systems described herein can be implemented in or via a mobile device. Mobile devices include navigation devices, mobile phones, smart phones, smart watches, tablet computers, mobile personal digital information processing terminals, laptop computers, palmtop computers, netbooks, pagers, electronic book terminals, music players, etc. In addition to other components, these devices may include storage media (such as flash memory, buffers, RAM, ROM, and one or more computing devices). The computing device associated with the mobile device may be suitable for executing program codes, methods, and instructions stored thereon. As another example, the mobile device may be configured to collaborate with other devices to execute instructions. The mobile device may communicate with a base station connected to a server and configured to execute program codes. The mobile device may also communicate through a peer-to-peer network, a mesh network, or other communication networks. The program code may be stored in a storage medium associated with a server and executed by a computing device embedded in the server. The base station may include a computing device and a storage medium. The storage medium may store program codes and instructions executed by a computing device associated with the base station. In some embodiments, the methods and systems described herein relate to a test kit for collecting subject information. Although different embodiments of the test kit may include different components, an exemplary test kit includes a diagnostic device (e.g., a processing component and / or a computing component for obtaining information from a subject, and a transmission component for transmitting the subject information to a computer device via a wired or wireless connection). When the device is in use, the transmission component in the test kit may be configured to transmit the subject information in real time, or to transmit diagnostic information upon receipt of an instruction from a user or provider. Any component of the test kit (e.g., a main body) may be configured as a hands-free unit or a handheld unit during use.

[0171] Exemplary computing environment for the disclosed methods and systems

[0172] The various modeling techniques, dose calculations and estimates described herein may be implemented in software, firmware, hardware, or a combination thereof. Figure 1 An example computer system 1900 is shown in which embodiments or portions thereof may be implemented as computer readable code. In another embodiment, the modeling disclosed in the examples herein may be implemented in the system 1900 for avermitog alpha.

[0173] Computer system 1900 includes one or more processors such as processor 1904. Processor 1904 is connected to a communication infrastructure 1906 (eg, a bus or network).

[0174] The computer system 1900 also includes a main memory 1908, preferably a random access memory (RAM), and may also include a secondary memory 1910. Depending on the implementation, user interface data may be stored in, for example, but not limited to, the main memory 1908. The main memory 1908 may include, for example, a cache and / or static and / or dynamic RAM. The secondary memory 1910 may include, for example, a hard drive and / or a removable storage drive. The removable storage drive 1914 may include a floppy disk drive, a tape drive, an optical drive, a flash memory, etc. The removable storage drive 1914 reads from and / or writes to a removable storage unit 1916 in a well-known manner. The removable storage unit 1916 may include a floppy disk, a tape, an optical disk, etc., which is read and written by the removable storage drive 1914. As will be appreciated by those skilled in the relevant art, the removable storage unit 1916 includes a computer-readable storage medium having computer software and / or data stored therein.

[0175] The computer system 1900 may also include a display interface 1902. The display interface 1902 may be adapted to communicate with a display unit 1930. The display unit 1930 may include a computer monitor or similar device for displaying graphics, text, and other data received from the main memory 1908 via the communication infrastructure 1906. In alternative implementations, the secondary memory 1910 may include other similar devices for allowing computer programs or other instructions to be loaded into the computer system 1900. Such devices may include, for example, a removable storage unit 1922 and an interface 1920. Examples of such devices may include a program cartridge and cartridge interface, a removable memory chip (such as an EPROM or PROM) and associated sockets, and other removable storage units 1922 and interfaces 1920 that allow software and data to be transferred from the removable storage unit 1922 to the computer system 1900.

[0176] The computer system 1900 may also include a communication interface 1924. The communication interface 1924 allows software and data to be transferred between the computer system 1900 and external devices. The communication interface 1924 may include a modem, a network interface (such as an Ethernet card or WiFi), a communication port, a PCMCIA slot and card, etc. The software and data transferred via the communication interface 1924 are in the form of signals, which may be electronic, electromagnetic, optical, or other signals that can be received by the communication interface 1924. These signals are provided to the communication interface 1924 via a communication path 1926. The communication path 1926 carries the signals and may be implemented using wires or cables, optical fibers, telephone lines, mobile phone links, WiFi, Bluetooth, RF links, or other communication channels.

[0177] In this document, the term "computer-readable storage medium" is generally used to refer to non-transitory storage media (such as removable storage unit 1916, removable storage unit 1922, and a hard disk installed in hard disk drive 1912). Computer-readable storage media can also refer to one or more memories (such as main memory 1908 and auxiliary memory 1910), which can be memory semiconductors (e.g., DRAMs, etc.). These computer program products are means for providing software to computer system 1900.

[0178] Computer programs (also referred to as computer control logic) are stored in the main memory 1908 and / or the secondary memory 1910. The computer programs may also be received via the communication interface 1924 and stored on the main memory 1908 and / or the secondary memory 1910. Such computer programs, when executed, enable the computer system 1900 to implement the embodiments as discussed herein. In particular, the computer programs, when executed, enable the processor 1904 to implement the processes of the present disclosure (such as certain methods discussed above). Therefore, such computer programs represent the controller of the computer system 1900. When the embodiments use software, the software may be stored in a computer program product and loaded into the computer system 1900 using the removable storage drive 1914, the interface 1920, or the hard disk drive 1912.

[0179] Embodiments may relate to computer program products including software stored on any computer-readable medium. Such software, when executed in one or more processing devices, causes the processing devices to operate as described herein. Embodiments may utilize any computer-usable or readable medium. Examples of computer-readable storage media include, but are not limited to, non-transitory primary storage devices (e.g., any type of random access memory) and non-transitory secondary storage devices (e.g., hard drives, floppy disks, CD ROMS, ZIP disks, magnetic tapes, magnetic storage devices and optical storage devices, MEMS, nanotechnology storage devices, etc.). Other computer-readable media include communication media (e.g., wired and wireless communication networks, local area networks, wide area networks, intranets, etc.).

[0180] Non-limiting examples of software-based systems include network-based systems and web-based systems.

[0181] Figure 3An example of a computing device 400 and an example of a mobile computing device that can be used to implement the techniques described herein are shown. Computing device 400 is intended to represent various forms of digital computers (such as laptop computers, desktop computers, workstations, personal digital assistants, servers, blade servers, mainframes, and other appropriate computers). Mobile computing devices are intended to represent various forms of mobile devices (such as personal digital assistants, mobile phones, smart phones, and other similar computing devices). The components shown herein, their connections and relationships, and their functions are intended to be exemplary only and are not intended to limit implementations of the inventions described and / or claimed in this document.

[0182] The computing device 400 includes a processor 402, a memory 404, a storage device 406, a high-speed interface 408 connected to the memory 404 and a plurality of high-speed expansion ports 410, and a low-speed interface 412 connected to a low-speed expansion port 414 and the storage device 406. Each of the processor 402, the memory 404, the storage device 406, the high-speed interface 408, the high-speed expansion port 410, and the low-speed interface 412 is interconnected using a variety of buses and can be installed on a shared motherboard or installed in other ways as appropriate. The processor 402 can process instructions executed within the computing device 400 (including instructions stored in the memory 404 or on the storage device 406) to display graphical information for a GUI on an external input / output device (such as a display 416 coupled to the high-speed interface 408). In other implementations, multiple processors and / or multiple buses, as well as multiple memories and multiple memory types, can be used as appropriate. In addition, multiple computing devices can be connected, each device providing a portion that must be operated (for example, as a server library, a blade server group, or a multiple processor system).

[0183] Memory 404 stores information within computing device 400. In some implementations, memory 404 is one or more volatile memory units. In some implementations, memory 404 is one or more non-volatile memory units. Memory 404 may also be another form of computer-readable medium (such as a magnetic disk or optical disk).

[0184] Storage device 406 can provide mass storage for computing device 400. In some implementations, storage device 406 can be or contain a computer-readable medium, such as a floppy disk device, a hard disk device, an optical disk device, or a magnetic tape device, a flash memory or other similar solid-state memory device or device array (including a storage area network or other configured device). A computer program product can be tangibly embodied in an information carrier. A computer program product can also include instructions that, when executed, perform one or more methods, such as those described above. A computer program product can also be tangibly embodied in a computer-readable medium or a machine-readable medium (such as memory 404, storage device 406, or memory on processor 402).

[0185] The high-speed interface 408 manages bandwidth-intensive operations of the computing device 400, while the low-speed interface 412 manages less bandwidth-intensive operations. Such functional allocation is exemplary only. In some implementations, the high-speed interface 408 is coupled to the memory 404, the display 416 (e.g., through a graphics processor or accelerator), and the high-speed expansion port 410, which can accept a variety of expansion cards (not shown). In an implementation, the low-speed interface 412 is coupled to the storage device 406 and the low-speed expansion port 414. The low-speed expansion port 414, which can include a variety of communication ports (e.g., USB, Bluetooth, Ethernet, wireless Ethernet), can be coupled to one or more input / output devices (such as a keyboard, a pointing device, a scanner, or a networking device (such as a switch or router)), for example, through a network adapter.

[0186] Computing device 400 can be implemented in a number of different forms, as shown in the figure. For example, it can be implemented as a standard server 420, or multiple times as a group of such servers. In addition, it can be implemented in a personal computer such as a laptop computer 422. It can also be implemented as part of a rack server system 424. Alternatively, components from computing device 400 can be combined with other components in a mobile device (not shown) such as mobile computing device 450. Each such device can contain one or more of computing device 400 and mobile computing device 450, and the entire system can be composed of multiple computing devices that communicate with each other.

[0187] The mobile computing device 450 includes a processor 452, a memory 464, an input / output device (such as a display 454), a communication interface 466, and a transceiver 468, among other components. The mobile computing device 450 may also provide a storage device (such as a microdrive or other device) to provide additional storage. Each of the processor 452, the memory 464, the display 454, the communication interface 466, and the transceiver 468 are interconnected using a variety of buses, and several components may be mounted on a shared motherboard or otherwise as appropriate.

[0188] The processor 452 may execute instructions within the mobile computing device 450 (including instructions stored in the memory 464). The processor 452 may be implemented as a chipset including single or multiple analog processors and digital processors. The processor 452 may provide, for example, coordination of other components of the mobile computing device 450 (such as control of a user interface, applications executed by the mobile computing device 450, and wireless communications performed by the mobile computing device 450).

[0189] The processor 452 can communicate with the user through the control interface 458 and the display interface 456 coupled to the display 454. The display 454 can be, for example, a TFT (thin film transistor liquid crystal display) display or an OLED (organic light emitting diode) display, or other appropriate display technology. The display interface 456 can include appropriate circuits for driving the display 454 to present graphics and other information to the user. The control interface 458 can receive commands from the user and convert them to submit to the processor 452. In addition, the external interface 462 can provide communication with the processor 452 so that the mobile computing device 450 can communicate with other devices in a near area. The external interface 462 can provide, for example, wired communication in some implementations, or wireless communication in other implementations, and multiple interfaces can also be used.

[0190] The memory 464 stores information within the mobile computing device 450. The memory 464 may be implemented as one or more of one or more computer-readable media, one or more volatile memory units, or one or more non-volatile memory units. An expansion memory 474 may also be provided and connected to the mobile computing device 450 via an expansion interface 472, which may include, for example, a SIMM (Single In-line Memory Module) card interface. The expansion memory 474 may provide additional storage space for the mobile computing device 450, or may also store applications or other information for the mobile computing device 450. In particular, the expansion memory 474 may include instructions for executing or supplementing the processes described above, and may also include security information. Thus, for example, the expansion memory 474 may be provided as a security module for the mobile computing device 450, and may be programmed with instructions that allow the secure use of the mobile computing device 450. In addition, security applications and additional information (such as placing identification information on the SIMM card in an unbreakable manner) may be provided via a SIMM card.

[0191] The memory may include, for example, flash memory and / or NVRAM memory (non-volatile random access memory), as discussed below. In some implementations, the computer program product is tangibly embodied in an information carrier. The computer program product contains instructions that, when executed, perform one or more methods, such as those described above. The computer program product may be a computer-readable medium or a machine-readable medium (such as memory 464, expansion memory 474, or memory on processor 452). In some implementations, the computer program product may be received, for example, by transceiver 468 or external interface 462 as a propagated signal.

[0192] The mobile computing device 450 can communicate wirelessly through the communication interface 466, which may include digital signal processing circuits when necessary. The communication interface 466 can provide communications in multiple modes or protocols (such as GSM voice calls (Global System for Mobile Communications), SMS (Short Message Service), EMS (Enhanced Message Service) or MMS information transceiver (Multimedia Message Service), CDMA (Code Division Multiple Access), TDMA (Time Division Multiple Access), PDC (Personal Digital Cellular), WCDMA (Wideband Code Division Multiple Access), CDMA2000 or GPRS (General Packet Radio Service) and the like). Such communications can be performed, for example, by using a radio frequency transceiver 468. In addition, short-range communications can be performed using Bluetooth, WiFi or other such transceivers (not shown). In addition, the GPS (Global Positioning System) receiver module 470 can provide additional navigation-related and positioning-related wireless data to the mobile computing device 450, which can be used as appropriate by applications running on the mobile computing device 450.

[0193] Mobile computing device 450 may also communicate audibly using audio codec 460, which may receive voice information from a user and convert it into usable digital information. Audio codec 460 may also generate audible sounds for the user, such as through a speaker (e.g., in the handheld portion of mobile computing device 450). Such sounds may include sounds from voice phone calls, may include recorded sounds (e.g., voice messages, music files, etc.), and may also include sounds generated by applications operating on mobile computing device 450.

[0194] Mobile computing device 450 can be implemented in a number of different forms, as shown in the figure. For example, it can be implemented as a mobile phone 480. It can also be implemented as part of a smart phone 482, a personal digital assistant or other similar mobile device.

[0195] Various implementations of the systems and techniques described herein can be realized in digital electronic circuitry, integrated circuitry, specially designed ASICs (application specific integrated circuits), computer hardware, firmware, software, and / or combinations thereof. These various implementations can include implementations in one or more computer programs executable and / or interpretable on a programmable system including at least one programmable processor that can be coupled for special or general purposes to receive data and instructions from and transmit data and instructions to a storage system, at least one input device, and at least one output device.

[0196] These computer programs (also referred to as programs, software, software applications, or code) include machine instructions for a programmable processor and can be implemented in high-level procedural and / or object-oriented programming languages, and / or in assembly / machine language. As used herein, the terms machine-readable medium and computer-readable medium refer to any computer program product, device, and / or apparatus (e.g., disk, optical disk, memory, programmable logic device (PLD)) for providing machine instructions and / or data to a programmable processor, including a machine-readable medium that receives machine instructions as a machine-readable signal. The term machine-readable signal refers to any signal for providing machine instructions and / or data to a programmable processor.

[0197] To provide interaction with a user, the systems and techniques described herein may be implemented on a computer having a display device (e.g., a CRT (cathode ray tube) or LCD (liquid crystal display) monitor) for displaying information to the user and a keyboard and pointing device (e.g., a mouse or trackball) through which the user can provide input to the computer. Other kinds of devices may also be used to provide interaction with the user; for example, the feedback provided to the user may be any form of sensory feedback (e.g., visual feedback, auditory feedback, or tactile feedback); and the input from the user may be received in any form, including auditory, voice, or tactile input.

[0198] The systems and techniques described herein can be implemented in a computing system that includes a back-end component (e.g., as a data server), or includes a middleware component (e.g., an application server), or includes a front-end component (e.g., a client computer with a graphical user interface or a web browser through which a user can interact with an implementation of the systems and techniques described herein), or any combination of such back-end, middleware, or front-end components. The components of the system can be interconnected by any digital data communication form or medium (e.g., a communication network). Examples of communication networks include a local area network (LAN), a wide area network (WAN), and the Internet.

[0199] A computing system may include clients and servers. Clients and servers are generally remote from each other and typically interact via a communication network. The relationship of client and server arises from computer programs running on the respective computers and having a client-server relationship to each other.

[0200] Having now described the disclosure in detail, the disclosure will be more clearly understood by reference to the following examples, which are included herein for illustrative purposes only and are not intended to limit the disclosure. All patents and publications cited herein are expressly incorporated herein by reference.

[0201] Examples

[0202] Example 1. Characterization of Factor VIII (FVIII) Activity Levels in Ivancholine Alpha in Patients with Severe Hemophilia A Population Pharmacokinetics (PopPK) Model

[0203] Once-weekly ivampicin alfa provides high sustained FVIII activity in the normal to near-normal range for most of the week and demonstrates improved protection against bleeding compared with previous FVIII prophylaxis. FVIII activity data were collected from 5 clinical studies (Phase 1 / 2a single-dose and repeated-dose studies in adults [NCT03205163 and EudraCT2018-001535-51, respectively], Phase 3 studies in adults and adolescents ≥12 years [XTEND-1, NCT04161495], and Phase 3 studies in children ≥1 to <12 years [XTEND-Kids, NCT04759131], as well as a Phase 3 long-term extension study [XTEND-ed, NCT04644575]). A popPK model was developed to characterize FVIII activity after ivampicin alfa dosing, identify intrinsic and extrinsic factors that affect pharmacokinetics (PK), and assess PK variability.

[0204] The FVIII activity levels used to develop the popPK model were measured by a phase I coagulation assay from 3054 blood samples from 199 adults and adolescents and 61 children who received ivampicin alpha in the aforementioned study. Body weight and VWF levels ranged from 12.5kg-133kg and 40IU / dL-339IU / dL, respectively. A one-compartment model with linear elimination was used to characterize FVIII activity, and the allometric weight effects of clearance (CL) and central compartment volume (V) were estimated to account for the dependence of CL and V on body size. The ivampicin alpha popPK model is shown in equation [A] above.

[0205] Baseline VWF, baseline race, ethnicity (white and Asian), baseline hematocrit, hepatitis C virus and human immunodeficiency virus status, and blood type (A, B, O) were tested for statistical significance in the covariate analysis. Baseline descriptive statistics for continuous covariates for subjects in the final data set are shown in Table 1. The final popPK model was used to simulate multiple dose regimens in a virtual population of adult and adolescent patients generated using the baseline weight distribution of the Phase 1 / 2a study and XTEND-1.

[0206] Table 1. Baseline descriptive statistics of continuous covariates for subjects in the final dataset

[0207]

[0208] In Table 1, the abbreviations are SD, standard deviation; VWF, von Willebrand factor; VWF:RCo, VWF ristocetin cofactor.

[0209] result:

[0210] Table 2 shows the C values ​​of adults and adolescents at week 26 of ivampicin alfa prophylaxis. maxss and C trough PopPK model estimates of the parameters and C at week 26 from a phase 3 clinical trial maxss and C trough (Observed values ​​or non-compartmental analysis). As shown in the comparison in Table 2, the PK parameter estimates from the PopPK model were consistent with the clinical trial data.

[0211] Table 2. PopPK parameter estimates at week 26 of ivampicin alfa prophylaxis in adults and adolescents

[0212]

[0213] In Table 2, the abbreviations are Cmax, maximum concentration; Ctrough, trough concentration; PopPK, population pharmacokinetics; SD, standard deviation; ss, steady state.

[0214] Table 3. Parameter estimates for the final popPK model for ivampicin alpha

[0215]

[0216] Table 3 Abbreviations: CL, central compartment clearance; CV, coefficient of variation; popPK, population pharmacokinetics; RSE (%), relative standard error (SE) (100% x SE / estimate); V, central compartment volume; θ is the population estimate of the PK parameter.

[0217] The final popPK model describes the curve of FVIII activity over time, captures the inter-individual variability of FVIII activity, and accurately estimates the moderate inter-individual variability of CL and V (Table 3). The weight-effect allometric index shows that CL and V increase with increasing body weight and are generally eliminated faster with decreasing body weight. Asian race was identified as a statistically significant covariate for CL (P<0.001); CL was 10.4% lower in Asians than in non-Asians. In the final popPK model, baseline VWF level was not identified as a statistically significant covariate, which is consistent with previous studies demonstrating that the PK of ivampicin alpha is independent of VWF. For example, Figure 4 The independence of ivenclav alfa clearance on baseline VWF levels in adult and adolescent patients was shown. Blood type was not identified as a statistically significant covariate in the final PopPK model. In the final PopPK model, simulated steady-state FVIII activity of ivenclav alfa over time and population-predicted and individual-predicted compared to observed FVIIII activity were compared in the Figure 5 , which demonstrated FVIII activity >40 IU / dL 3 to 4 days after dosing.

[0218] The final popPK model showed that a once-weekly prophylactic regimen of ivampicin alfa (50 IU / kg) achieved a steady-state C >10 IU / dL in most adult and adolescent patients. trough And the time that FVIII activity reaches 40IU / dL is 3 to 4 days, regardless of body weight and race.The simulation of perioperative management during major surgery and the treatment of massive hemorrhage shows that the loading dose of 50IU / kg then meets the guidelines of the peak FVIII activity of the World Federation of Hemophilia (World Federation of Hemophilia) for most adults and adolescents every 2-3 days in the postoperative period.Similarly, for the treatment of minor surgery and moderate to mild bleeding, the single dose of 50IU / kg Avancog α realizes the peak FVIII activity (>50IU / dL to 80IU / dL) that meets these guidelines.

[0219] in conclusion: In patients with severe hemophilia A, a linear one-compartment popPK model was able to adequately characterize FVIII activity. Although CL and V depended on body weight and Asian race was identified as a covariate for CL, the limited effects of body weight and Asian race on FVIII exposure were considered to be not clinically significant. PopPK simulations demonstrated that once-weekly 50 IU / kg ivampicin alfa achieved sustained FVIII activity within the normal to near-normal range (>40 IU / dL) for 3-4 days in most adults and adolescents, and reached >10 IU / dL on day 7. PopPK simulations also supported the selection of a Phase 3 dosing regimen for regular prophylaxis, treatment of bleeding, and perioperative management. In adults and adolescents, individual clearance of ivampicin alfa was independent of baseline VWF.

[0220] Additional details on the development of the popPK model

[0221] Available data from the Phase 3 avermitog alfa studies in adults, adolescents, and children were incorporated into the development of the population pharmacokinetic (PopPK) model. Complete data from the adult and adolescent studies and partial data from the pediatric and long-term safety studies were also included.

[0222] Table 4 : Description of studies used in the PopPK analysis.

[0223]

[0224] a Number of patients exposed to BIVV001 in each study for PopPK model development; total N = 260, including 199 adult / adolescent patients and 61 pediatric patients from EFC15295. One patient from EFC16295 did not have dosing information and was excluded.

[0225] b In EFC16293, there were 17 patients in the sequential group in whom patients skipped doses at Week 1 Day 7 and Week 26 Day 7 to allow estimation of terminal half-life by collecting FVIII activity samples until Day 15 after dosing at Day 1 and Week 26.

[0226] c Three patients (2 from Group A and 1 from Group B) who had surgery in the LTS16294 study were included in the PopPK model development. Two of the 3 patients continued with EFC16293.

[0227] Table 4 Definitions: a) Number of exposures to avermectin alfa in each study for PopPK model development; Total N=260, with 199 adult and adolescent patients and 61 pediatric patients from EFC15295; b) Only patients who had surgery in the LTS16294 study were included in PopPK model development (3 patients); c) In EFC16293, there were 17 patients in the sequential group, in which patients skipped doses at Week 1 Day 7 and Week 26 Day 7 to allow estimation of terminal half-life by collecting primary coagulation (OSC) FVIII activity samples until Day 15 after dosing at Day 1 and Week 26.

[0228] The phase 1 PopPK analysis described the OSC FVIII activity data using the 1-CMT model, with body weight as a covariate for CL, V, and hematocrit level as a covariate for V. In the final PopPK analysis, the 1-CMT model was selected as the structural model to describe the OSC FVIII activity curve, and the base model included the WT effect. Further covariate screening was performed on the base POP PK model.

[0229] Body weight (WT) in kg or other continuous covariates were scaled to the median baseline WT for adults and adolescents (median baseline value) (78.3 kg) to assess covariate effects in adults or allometric effects in children.

[0230] For example, for adult covariate effects and child allometric effects, CL = TVCL*(WT 时变的 / 78.3) CLexp *(exp(ETA1)). For volume, a similar approach is used.

[0231] Dataset : A popPK dataset for observed data is based on the adult / adolescent study EFC16293. Fig. 6A and Figure 6B Baseline-corrected FVIII activity time curves are shown. All patients ( Fig. 6A ). The sequential group patients at day 1 (baseline) and at week 26 are shown ( Figure 6B ). The FVIII activity time curve follows the general one-compartment (logarithmic scale linear decline) type kinetics. FVIII activity shows that the average half-life of ivagin alpha is 47.8 hours.

[0232] The correlations among the four continuous covariates at baseline were Figure 7The median value of baseline weight (WTKGB) was 78.3, which does not include the EFC16295 study. The median value of baseline race (BH) was 43 (also not including the EFC16295 study). Baseline VWF (BVWF) showed a median of 112 (also not including the EFC16295 study). Age appeared to be associated with WT, so age was not tested as a covariate. Race and VWF were tested as covariates and found to be non-significant.

[0233] The distribution of categorical covariates (such as blood type, race, HIV status, and HCV status) is shown in Table 5. The data in Table 5 include all studies (n=260). Blacks (1.92%) and other races (3.08%) were present in approximately 5% of the patients. For blood type, there were more patients with blood types A and O, 29.62% and 36.15%, respectively. Blood type B was present in <10% (9.23%) of patients. Blood type AB was present in <5% (3.85%) of patients. HCV and HIV positive patients were older, and no pediatric patients were HCV or HIV positive. There were 2 patients aged <2 years. Among the categorical factors shown, only HCV status, HIV status, blood type (A, B, and O), and race (Caucasian and Asian) were tested as covariates.

[0234] Table 5 : Descriptive statistics for categorical covariates

[0235]

[0236] OSC activity is the concentration in the central compartment (C). All parameters of the base and final covariate models were estimated with acceptable precision. Increasing the body weight effect reduced the instrumental variable estimates (IIV) of CL and V, while increasing the Asian race effect on CL reduced the IIV of CL. When compared with simple allometric indices, the WT effect indices on CL and V were acceptable. An Asian race effect on CL was identified, and the clearance rate of Asians was 10.4% lower than that of non-Asians of the same body weight.

[0237] Fig. 8A and Figure 8B The population prediction (PRED) and individual prediction (IPRED) are shown compared to the DV, respectively. This demonstrates that both the population model and the individual model are able to describe the PK data across age categories.

[0238] Fig. 9 Visual Prediction Check (VPC) of the final PopPK model is shown. The VPC for each study showed that most of the observed FVIII activity data were within the predicted range [5th-95th percentile]. For the purpose of VPC, one unique patient from LTS16294 was considered in EFC16293.

[0239] Fig. 10A and Fig. 10B The population prediction (PRED) and individual prediction (IPRED) for surgery are shown separately compared to DV. In the surgical time range, data from 19 patients from EFC16293, EFC16295 and LTS16294 are included. The model performs reasonably well in describing the PK data collected during surgery and after specific surgical agents.

[0240] Fig.11 The steady-state C values ​​across all groups are shown according to baseline body weight (kg). trough , C maxss and the distribution of the time when FVIII activity reached 40 IU / dL. Fig.12 The steady-state C between non-Asian and Asian groups is shown for all age groups. trough , C maxss The distribution of steady-state FVIII activity C max , C trough The time to reach 40 IU / dL of FVIII activity and FVIII activity increased with increasing body weight and was higher in Asians compared with non-Asians. However, the 50 IU / kg QW prophylaxis regimen showed that steady-state C trough >10 IU / dL and the time to reach FVIII activity of 40 IU / dL was 3 to 4 days. The 50 IU / kg QW prophylaxis regimen also showed that for most children (age <12 years), steady-state C trough >5 IU / dL, and the time for FVIII activity to reach 40 IU / dL is 2 to 3 days.

[0241] Major surgery and bleeding : The model was analyzed with respect to major surgery and major bleeding. Major surgery and major bleeding were classified based on the criteria listed in Table 6.

[0242] Table 6:

[0243] Number of days Major surgery Heavy bleeding Before surgery (bleeding day) Peak >80 IU-100 IU / dL Peak >80 IU-100 IU / dL Day 1 to Day 3 Peak >60 IU-80 IU / dL Peak >50 IU / dL (Day 3) Day 4 to Day 7 Peak >40 IU-60 IU / dL Peak > 50 IU / dL Day 7 to Day 14 Peak >30 IU-50 IU / dL Peak > 50 IU / dL

[0244] For major surgery and hemorrhage, simulation is based on a single dose regimen of 50 IU / kg, and if necessary, the other dosage of 30 or 50 IU / kg is used every 2 to 3 days. Therefore, after the preoperative dose of 50 IU / kg, 50 IU / kg Q2D, 50 IU / kg Q3D, 30 IU / kg Q2D and 30 IU / kg Q3D are possible dosage regimen combinations (QXD is every X days). These same simulations can be applied to both major surgery and massive hemorrhage, because both comprise the same dosage combination.

[0245] Fig.13 Simulated OSC FVIII activity for major bleeding and major surgery over time in subjects under six years of age is shown. Over 95% of patients 6 years of age and older met major surgery criteria throughout the surgical period, and over 80% of patients younger than 6 years of age met surgical criteria throughout the surgical period.

[0246] Fig.14 Simulated FVIII activity using avermectin alfa at a dose of 50 IU / kg followed by 30 IU / kg every 3 days until day 14 in a hypothetical adult and adolescent population is shown. The simulations demonstrate that an initial dose of 50 IU / kg followed by 30 IU / kg every 3 days until day 14 should be sufficient for perioperative management during major surgery ( Fig.15 ) and treatment of major bleeding. It is predicted that >95% of adult and adolescent patients meet the World Federation of Hemophilia (WFH) guidelines for peak FVIII activity (>80-100 IU / dL before surgery or on the day of major bleeding) (Srivastava A et al. Haemophilia [blood disease]. 2020; 26 Supplement 6: 1-158). In addition, other dosage regimens (such as an initial dose of 50 IU / kg, then 50 or 30 IU / kg every 2 or 3 days) were simulated, and it is predicted that these other dosage regimens also meet the WFH peak FVIII guidelines. Therefore, the simulation shows that an initial dose of 50 IU / kg and then 50 IU / kg or 30 IU / kg every 2 or 3 days will meet the WFH peak FVIII guidelines for most (>95%) adult and adolescent patients to be managed during the treatment of major surgery and major bleeding.

[0247] Minor surgery and mild or moderate bleeding : Fig.15The OSC FVIII activity of simulations over time in all age groups is shown. In all age groups, more than 95% of patients meet the standard of peak FVIII>50IU / dL after the preoperative dose of minor surgery. Similarly, more than 95% of patients meet the standard of peak FVIII>40IU / dL required for mild / moderate bleeding management in all age groups. When using the other dosage of 30 or 50IU / kg every 2 or 3 days, more than 95% of patients meet the standard of peak FVIII>50IU / dL in all age groups.

[0248] in conclusion :Based on this data, one-compartment (1-CMT) model describes adult, adolescent and children OSCFVIII activity data quite well.Include weight effect (to CL and V) in basic model, and Asian race effect (to CL) is identified as statistically significant covariate.Simulation for a series of body weights shows that the fixed scheme of 50IU / kg QW provides high FVIII activity in adult, adolescent and children's population, regardless of body weight and race.Simulation using this model can also support and illustrate the possible ivantrin alpha dosage scheme for surgery and bleeding situations.

[0249] Embodiments of the present disclosure

[0250] The present disclosure includes (and is not limited to) the following exemplary embodiments:

[0251] Example 1. A method for determining ivenclav alfa dosage information for an individual subject, the method comprising:

[0252] receiving information specific to the subject and calculating the ivenomiclotin alfa dosing information using a software-based system,

[0253] The system was programmed to implement a one-compartment ivampicin α popPK model,

[0254] wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0255] Embodiment 2. The method as described in embodiment 1 further comprises outputting the subject's dosage information through the software-based system.

[0256] Embodiment 3. The method of embodiment 2 further comprises outputting a recommended dosage regimen by the software-based system.

[0257] Embodiment 4. The method of any one of embodiments 1-3, wherein expected treatment outcome information is also received.

[0258] Example 5. A method for estimating personalized ivenclav alfa dosage information for a subject, the method comprising:

[0259] (a) receiving, by a processing device via an application programmed to operate with the avermitigin alpha popPK model, subject information and / or expected treatment outcome information, wherein the received information is transmitted via one or more electronic devices,

[0260] (b) calculating, using at least one software-based system, individualized avermitog alpha dosing information using the avermitog alpha popPK model and the received information, and

[0261] (c) transmitting the individualized avermitigin alpha dosage information calculated in (b) to one or more electronic devices to output the information,

[0262] wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0263] Example 6. A method for estimating personalized ivenclav alfa dosage information for a subject, the method comprising:

[0264] (a) receiving subject information and / or expected treatment outcome information via one or more electronic devices,

[0265] (b) transmitting, by a processing device, the subject information and / or the expected treatment outcome information to an application program, wherein the application program is programmed to implement an avermitigin alpha popPK model,

[0266] (c) receiving from the application personalized ivenclavulanate alpha dosage information calculated using the ivenclavulanate alpha popPK model and the information transmitted in (b), and

[0267] (d) outputting the individualized ivenomic alpha dosage information via the one or more electronic devices,

[0268] wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0269] Example 7. A method for providing an avermitog alpha dosage regimen based on a median popPK, the method comprising:

[0270] (a) receiving subject information and / or desired treatment outcome information via a software-based system comprising an ivenomic alpha popPK model,

[0271] (b) calculating, by the software-based system, median PK information using the ivenomic alpha pop PK model and the received information, and

[0272] (c) outputting the median PK information by the software-based system,

[0273] wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0274] Example 8. A method for providing an avermitog alpha dosage regimen based on a median avermitog alpha popPK, the method comprising:

[0275] (a) receiving subject information and / or expected treatment outcome information via one or more electronic devices,

[0276] (b) transmitting, by a processing device, the subject information and / or the expected treatment outcome information to an application program, wherein the application program is programmed to implement an avermitigin alpha popPK model,

[0277] (c) receiving from the application median avermitog alpha PK dosage information calculated using the avermitog alpha popPK model and the received information, and

[0278] (d) outputting the median PK information via the one or more electronic devices,

[0279] wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0280] Example 9. A method for providing a dosage regimen of ivenclavulanate alpha, the method comprising:

[0281] (a) receiving, by a processing device via an application programmed to implement an avermitog alpha population pharmacokinetic (popPK) model, subject information and / or desired treatment outcome information, wherein the received information is transmitted via one or more electronic devices,

[0282] (b) calculating, by the application, individualized avermitog alpha dosage information using the avermitog alpha popPK model and the received information, and

[0283] (c) transmitting the dosage information calculated from the individualized avermitigin alpha dosage regimen of (b) to one or more electronic devices through a processing device to output the information,

[0284] wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0285] Example 10. A method for estimating PK information of avermitogen alpha for an individualized subject, the method comprising:

[0286] (a) receiving subject information via a software-based system comprising an avermitogen alpha popPK model,

[0287] (b) estimating, by the software-based system, individualized subject avermitogen alpha PK information using the avermitogen alpha popPK model and the received information, and

[0288] (c) outputting the individualized subject ivampicin alpha PK information by the software-based system,

[0289] wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0290] Example 11. A method for estimating PK information of avermitogen alpha for an individualized subject, the method comprising:

[0291] (a) receiving subject information via one or more electronic devices,

[0292] (b) transmitting, by a processing device, the subject information to an application, wherein the application is programmed to implement an avermitog alpha pop PK model, and wherein the application generates individualized subject avermitog alpha PK information using the avermitog alpha pop PK model and the transmitted information,

[0293] (c) receiving the individualized subject ivenomic alpha PK information from the application, and

[0294] (d) outputting the individualized subject PK information via the one or more electronic devices,

[0295] wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0296] Example 12. A method for estimating PK information of avermitogen alpha for an individualized subject, the method comprising:

[0297] (a) receiving subject information via an application programmed to implement the avermitoglucagon alpha popPK model, wherein the received information is transmitted via one or more electronic devices,

[0298] (b) calculating, by the application, ivampicin alpha PK information for ivampicin alpha for the individualized subject using the ivampicin alpha popPK model and the received information, and

[0299] (c) transmitting the individualized subject ivampicin alpha PK information calculated in (b) to one or more electronic devices to output the information by means of a processing device,

[0300] wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0301] Example 13. A method for estimating PK information of avermitogen alpha for an individualized subject, the method comprising:

[0302] (a) receiving, via one or more electronic devices, information about the individual's body weight and (i) an expected increase in plasma factor activity level following administration or (ii) an expected dose or an expected dose interval,

[0303] (b) transmitting the information of (a) to an application program by a processing device, wherein the application program is programmed to implement the avermitigin alpha popPK model,

[0304] (c) receiving from the web-based server and program individualized subject ivampicin alpha PK information calculated using the ivampicin alpha popPK model and the transmitted information of (b), and

[0305] (d) outputting the calculated individualized subject ivampicin alpha PK information by the one or more electronic devices,

[0306] wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0307] Embodiment 14. The method of any one of embodiments 5-13, wherein the subject information comprises the subject's weight.

[0308] Embodiment 15. The method of any one of embodiments 5-14, wherein the subject information comprises the subject's baseline FVIII activity level.

[0309] Embodiment 16. The method of any one of embodiments 5-15, wherein the subject information comprises the subject's self-reported race.

[0310] Embodiment 17. The method of any one of embodiments 5-16, wherein the subject information includes whether the subject self-identifies as Asian.

[0311] Embodiment 18. The method of any one of embodiments 5-17, wherein the subject provides the subject information.

[0312] Embodiment 19. The method of any one of embodiments 5-17, wherein a healthcare professional provides the subject information.

[0313] Embodiment 20. The method of any one of embodiments 5-19, wherein the subject information does not include the level of VWF or hematocrit of the subject.

[0314] Embodiment 21. A method as described in any of embodiments 1-20, wherein the system is programmed to implement a one-compartment avermitogen alpha popPK model for calculating the dosage information that includes body weight as a covariate, and wherein the avermitogen alpha popPK model does not include the level of VWF or hematocrit as a covariate.

[0315] Embodiment 22. The method of any one of embodiments 1-6, 8-9 or 14-21, further comprising selecting a dosing regimen based on the dosing information.

[0316] Embodiment 23. The method of any one of embodiments 7-8 or 10-21, further comprising selecting a dosage regimen based on the PK information.

[0317] Embodiment 24. The method of embodiment 22 or 23, further comprising administering the ivenomiclotin alfa to the subject according to the selected dosing regimen.

[0318] Embodiment 25. The method of any one of embodiments 1-6, 8-9, 14-22 or 24, wherein the dosage information comprises an estimated or predicted FVIII activity level over time following administration of the avermitog alfa.

[0319] Embodiment 26. The method of any one of embodiments 7-9 or 14-25, wherein the dosage regimen is a prophylactic regimen.

[0320] Embodiment 27. The method of any one of embodiments 7-9 or 14-25, wherein the dosing regimen is an on-demand regimen.

[0321] Embodiment 28. The method of any one of embodiments 7-9 or 14-25, wherein the dosing regimen is for perioperative bleeding management.

[0322] Embodiment 29. The method of any one of embodiments 4-5, wherein the desired treatment outcome information comprises a desired FVIII activity level.

[0323] Embodiment 30. The method of embodiment 29, wherein the desired FVIII activity level comprises a minimum FVIII activity level between doses.

[0324] Embodiment 31. The method of embodiment 29, wherein the desired FVIII activity level comprises a minimum FVIII activity level at a time point.

[0325] Embodiment 32. The method of embodiment 31, wherein the time point is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after administration of ivenclavulanate alpha.

[0326] Embodiment 33. The method of any one of embodiments 1-32, wherein the avermitigin alpha popPK model comprises self-reported race as a covariate.

[0327] Embodiment 34. The method of any one of embodiments 1-32, wherein the avermitigin alpha popPK model comprises whether the subject self-reports being of Asian descent as a covariate.

[0328] Embodiment 35. The method of embodiment 33 or 34, wherein the subject does not self-report being of Asian descent.

[0329] Embodiment 36. The method of embodiment 33 or 34, wherein the subject self-reports being of Asian descent.

[0330] Embodiment 37. The method of any one of embodiments 1-38, wherein the avermitogen alpha pop PK model is the avermitogen alpha pop PK model [A].

[0331] Embodiment 38. A method of treating hemophilia A in a subject in need thereof, the method comprising administering to the subject a dosage regimen selected according to any one of Embodiments 1-37.

[0332] Embodiment 39. A device or system comprising a processor configured to provide dosage or PK information according to any of the methods of embodiments 1-38.

[0333] Embodiment 40. A data processing device, apparatus or system comprising a processor configured to implement a one-compartment avermitogen alpha pop PK model, wherein the avermitogen alpha pop PK model comprises body weight as a covariate, and wherein the avermitogen alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0334] Embodiment 41. A data processing apparatus, device or system as described in Embodiment 40, wherein the avermitigin alpha popPK model includes self-reported race as a covariate.

[0335] Embodiment 42. A data processing apparatus, device or system as described in Embodiment 40, wherein the avermitigin alpha popPK model includes whether the subject self-reports being of Asian descent as a covariate.

[0336] Embodiment 43. A data processing device, apparatus or system as described in any one of Embodiments 40-42, comprising a smart phone, a tablet computer, a personal digital assistant, a palm computer, a laptop computer or a smart watch.

[0337] Embodiment 44. A data processing device, apparatus or system as described in any one of Embodiments 40-42, comprising a smart phone.

[0338] Embodiment 45. A data processing device, apparatus or system as described in any one of Embodiments 40-42, comprising a smart watch.

[0339] Embodiment 46. A data processing device, apparatus or system as described in any one of embodiments 40-45, wherein the processor is configured to implement the avermitigin α popPK model [A].

[0340] Embodiment 47. A computer program comprising instructions, which, when executed by a computer, cause the computer to perform a method as described in any one of embodiments 1-38.

[0341] Embodiment 48. A computer program comprising instructions which, when executed by a computer, cause the computer to implement a one-compartment avermitogen alpha pop PK model, wherein the avermitogen alpha pop PK model comprises body weight as a covariate, and wherein the avermitogen alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0342] Embodiment 49. The computer program of embodiment 48, wherein the ivenomiclotin alpha popPK model comprises self-reported race as a covariate.

[0343] Embodiment 50. The computer program of embodiment 48, wherein the avermitigin alpha popPK model comprises whether the subject self-reports being of Asian descent as a covariate.

[0344] Embodiment 51. The computer program of Embodiment 48, wherein the Avancoagulation αpopPK model is the Avancoagulation αpopPK model [A].

[0345] Embodiment 52. A computer-readable medium comprising instructions which, when executed by a computer, cause the computer to provide for performing a method as described in any one of embodiments 1-38.

[0346] Embodiment 53. A computer-readable medium comprising instructions which, when executed by a computer, cause the computer to implement a one-compartment avermitogen alpha pop PK model, wherein the avermitogen alpha pop PK model comprises body weight as a covariate, and wherein the avermitogen alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

[0347] Embodiment 54. The computer-readable medium of Embodiment 53, wherein the avermitigin alpha popPK model comprises self-reported race as a covariate.

[0348] Embodiment 55. The computer-readable medium of Embodiment 53, wherein the ivenomic alpha popPK model comprises whether the subject self-reports being of Asian descent as a covariate.

[0349] Embodiment 56. The computer-readable medium of Embodiment 53, wherein the avermitogen alpha pop PK model is the avermitogen alpha pop PK model [A].

[0350] Embodiment 57. The method of embodiment 37, wherein the estimated value of typical clearance (TVCL) in the avermitigin alpha popPK model [A] is 0.433 dL / h.

[0351] Embodiment 58. The method of embodiment 37 or 57, wherein the estimated value of the typical volume (TVV) in the ivenomic alpha popPK model [A] is 30.2 dL.

[0352] Embodiment 59. The method of any one of embodiments 37, 57 or 58, wherein the central compartment clearance variability (η1) in the avermitoglucagon α popPK model [A] is 0.0354.

[0353] Embodiment 60. The method of any one of embodiments 37 or 57-59, wherein the central compartment volume variability (η2) in the avermitoglucagon α popPK model [A] is 0.0209.

[0354] Embodiment 61. A data processing apparatus, device or system as described in Embodiment 46, wherein the estimated value of typical clearance (TVCL) in the avermitigin alpha popPK model [A] is 0.433 dL / h.

[0355] Embodiment 62. A data processing apparatus, device or system as described in any of Embodiments 46 or 61, wherein the estimated value of the typical volume (TVV) in the avermitigin alpha popPK model [A] is 30.2 dL.

[0356] Embodiment 63. A data processing apparatus, device or system as described in any one of Embodiments 46, 61 or 62, wherein the central compartment clearance variability (η1) in the avermitigin α popPK model [A] is 0.0354.

[0357] Embodiment 64. A data processing apparatus, device or system as described in any one of Embodiments 46 or 61-63, wherein the central compartment volume variability (η2) in the avermitigin α popPK model [A] is 0.0209.

[0358] Embodiment 65. The computer program of embodiment 51, wherein the estimate of typical clearance (TVCL) in the avermitigin alpha popPK model [A] is 0.433 dL / h.

[0359] Embodiment 66. The computer program of embodiment 51 or 65, wherein the estimated value of the typical volume (TVV) in the avermitigin alpha popPK model [A] is 30.2 dL.

[0360] Embodiment 67. The computer program of any one of embodiments 51, 65 or 66, wherein the central compartment clearance variability (η1) in the avermitigin α popPK model [A] is 0.0354.

[0361] Embodiment 68. A computer program as described in any of embodiments 51 or 65-67, wherein the central compartment volume variability (η2) in the avermitigin α popPK model [A] is 0.0209.

[0362] Embodiment 69. The computer readable medium of any one of Embodiment 56, wherein the estimate of typical clearance (TVCL) in the avermitigin alpha popPK model [A] is 0.433 dL / h.

[0363] Embodiment 70. The computer readable medium of any one of Embodiments 56 or 69, wherein the estimated value of the typical volume (TVV) in the avermitigin alpha popPK model [A] is 30.2 dL.

[0364] Embodiment 71. The computer-readable medium of any one of embodiments 56, 69 or 70, wherein the central compartment clearance variability (η1) in the avermitigin α popPK model [A] is 0.0354.

[0365] Embodiment 72. The computer-readable medium of any one of embodiments 56 or 69-71, wherein the central compartment volume variability (η2) in the avermitoglucagon α popPK model [A] is 0.0209.

[0366] Table 7. Ivancholine α sequence information

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

Claims

1. A method for determining ivenclav alfa dosage information for an individual subject, the method comprising: receiving information specific to the subject and calculating the ivenomiclotin alfa dosing information using a software-based system, The system was programmed to implement a one-compartment ivampicin α popPK model, wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

2. The method of claim 1, further comprising outputting, by the software-based system, the subject's dosing information.

3. The method of claim 2, further comprising outputting, by the software-based system, a recommended dosage regimen.

4. A method for estimating ipamectin alpha PK information for an individualized subject, the method comprising: (a) receiving subject information via a software-based system comprising an ivenomic alpha popPK model, (b) estimating, by the software-based system, individualized subject avermitogen alpha PK information using the avermitogen alpha popPK model and the received information, and (c) outputting the individualized subject ivampicin alpha PK information by the software-based system, wherein the ivenomic alpha pop PK model comprises body weight as a covariate, and wherein the ivenomic alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

5. The method of claim 4, wherein the subject information comprises the subject's baseline FVIII activity level. The method of claim 4 , wherein the subject provides the subject information.

7. The method of any one of claims 1-6, wherein the system is programmed to implement a one-compartment Avancog αpopPK model comprising body weight as a covariate for calculating the dosing information, and wherein the Avancog αpopPK model does not comprise the level of VWF or hematocrit as covariates.

8. The method of claim 4, further comprising selecting a dosing regimen based on the PK information.

9. The method of claim 8, further comprising administering the ivenomiclotin alfa to the subject according to the selected dosing regimen.

10. The method of any one of claims 1-3, wherein the dosage information comprises estimated or predicted FVIII activity levels over time following administration of the avermitigin alfa.

11. The method of any one of claims 8-10, wherein the dosing regimen is a prophylactic regimen, an on-demand regimen, or for perioperative bleeding management.

12. The method of any one of claims 1-11, wherein the avermitigin alpha popPK model comprises whether the subject self-reports being of Asian descent as a covariate.

13. The method of any one of claims 1-12, wherein the avermitogen alpha pop PK model is the avermitogen alpha pop PK model [A].

14. The method of claim 13, wherein the estimated value of typical clearance (TVCL) in the avacoag αpopPK model [A] is 0.433 dL / h, the estimated value of typical volume (TVV) in the avacoag αpopPK model [A] is 30.2 dL, the central compartment clearance variability (η1) in the avacoag αpopPK model [A] is 0.0354, and the central compartment volume variability (η2) in the avacoag αpopPK model [A] is 0.0209.

15. A method of treating hemophilia A in a subject in need thereof, the method comprising administering to the subject a dosage regimen selected according to any one of claims 1-14.

16. A device or system comprising a processor configured to provide dosage or PK information according to any one of claims 1-14.

17. A data processing device, apparatus or system comprising a processor configured to implement a one-compartment avermitogen alpha pop PK model, wherein the avermitogen alpha pop PK model comprises body weight as a covariate, and wherein the avermitogen alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

18. The data processing device, apparatus or system of claim 17, wherein the processor is configured to implement the avermitigin alpha popPK model [A].

19. A computer program comprising instructions which, when executed by a computer, cause the computer to perform the method as claimed in any one of claims 1 to 14.

20. A computer program comprising instructions which, when executed by a computer, cause the computer to implement a one-compartment avermitogen alpha pop PK model, wherein the avermitogen alpha pop PK model comprises body weight as a covariate, and wherein the avermitogen alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

21. The computer program of claim 20, wherein the Avancog αpop PK model is Avancog αpop PK model [A].

22. A computer readable medium comprising instructions which, when executed by a computer, cause the computer to provide for performing the method of any one of claims 1-14.

23. A computer-readable medium comprising instructions which, when executed by a computer, cause the computer to implement a one-compartment avermitogen alpha pop PK model, wherein the avermitogen alpha pop PK model comprises body weight as a covariate, and wherein the avermitogen alpha pop PK model does not comprise the level of VWF or the level of hematocrit as a covariate.

24. The computer-readable medium of claim 23, wherein the avermitogen alpha pop PK model is the avermitogen alpha pop PK model [A].

Images