EA045259B1 - PROVIDING A PHARMACOKINETIC DOSAGE SCHEME OF A MEDICINE - Google Patents

Description

State of the art

Coagulation factor VIII is a blood clotting protein that is activated in response to injury or bleeding. Individuals with relatively low levels of coagulation factor VIII are susceptible to episodes of internal or external prolonged bleeding resulting from injury and/or spontaneous bleeding without cause. Although skin bleeding is not dangerous, internal bleeding in joints, muscles, and organs can cause permanent damage, structural damage, or even death.

Patients with hemophilia A have a genetic deficiency that causes low levels of clotting factor VIII. The amount of coagulation factor VIII in a patient is expressed as a percentage of the normal level. Patients with 5-40% coagulation factor VIII are considered to have a mild form of hemophilia A, while patients with 1-5% coagulation factor VIII are considered to have moderate hemophilia A. Patients with less than 1% coagulation factor VIII are considered to have a mild form of hemophilia A. have a severe form of hemophilia A.

Treatment of patients with hemophilia A (or patients who otherwise have low levels of clotting factor VIII) involves providing these patients with periodic infusions of a clotting factor concentrate (eg, therapeutic plasma protein). The clotting factor concentrate functions as a replacement or replacement for the patient's naturally occurring clotting factor VIII. One example of such a therapeutic plasma protein is Baxter Healthcare's Advate. In some cases, patients receive therapeutic plasma protein in response to uncontrolled internal bleeding. Alternatively, patients may be prescribed a prophylactic treatment regimen with a therapeutic plasma protein to reduce the possibility of future bleeding. Often, this regimen requires the patient to visit a health care provider and/or self-administer infusions of therapeutic plasma protein three or more times per week in order to receive treatment.

The goal of the treatment regimen is to schedule patient visits so that coagulation factor VIII, as provided by therapeutic plasma protein, does not fall below a predetermined threshold, such as one percent (1%). However, the amount of therapeutic plasma protein required by a patient depends on the dosage amount and the patient's metabolism. Additionally, because there is wide variability in therapeutic plasma protein metabolism within the group, many patients may not be properly dosed to maintain the planned target deflection. Thus, it is necessary to determine the individual patient's plasma therapeutic protein metabolism or pharmacokinetic profile to ensure that the proper dose is infused within the selected time interval.

To identify a patient's pharmacokinetic profile in order to prescribe a treatment regimen, the healthcare provider currently determines how the patient metabolizes the administered dose of therapeutic plasma protein over the course of treatment. Often, determining a patient's pharmacokinetic profile requires five or more blood draws to determine the level or concentration of the therapeutic plasma protein in the patient at various time points from the initial dose of the therapeutic plasma protein (eg, to determine how the therapeutic plasma protein is metabolized over time ). These multiple blood draws require the patient to stay in the health care facility for a certain number of days or visit the health care facility multiple times. These multiple visits and/or multiple blood draws place stress on the patient and the health care facility.

In particular, WO 0223186 is known, which presents a method for measuring the effectiveness of at least one therapeutic agent, including a combination of data on a patient's response to therapy and resistance. For example, in one embodiment, this solution relates to a method for measuring the effectiveness of at least one therapeutic agent, comprising: determining a pharmacological effect using either a measured or a predicted population; a pharmacokinetic model for the at least one therapeutic agent; determining the resistance of the etiological agent to the specified at least one therapeutic agent; determining an inhibition coefficient for said at least one therapeutic agent based on said pharmacological effect and said resistance and using said inhibition coefficient to determine the effectiveness of said at least one therapeutic agent. In one embodiment, these solutions further include the use of a bioanalytical method to obtain the actual concentration of the at least one therapeutic agent in the patient.

The inhibition coefficient can also be, for example, normalized. In one embodiment, the population pharmacokinetic model for use in any of the embodiments of the invention may be an optimized population pharmacokinetic model.

US 2012232517 is also known, which discloses a dose display mechanism for a drug delivery device that allows the user to select multiple doses

- 1 045259 of an injectable medicinal product and for dispensing a prescribed dosage of the medicinal product and administering said medicinal product to the patient, preferably by injection. In particular, the present invention relates to such devices that are processed by patients themselves. The problem to be solved by this solution is to provide a dose display that displays in clear and large indices, i.e. numbers, symbols, letters, etc. The prescribed dose is suitable for use by users with limited vision, especially for use with hand-held drug delivery devices.

To avoid any possibility that a patient will decline below a predetermined threshold, many healthcare providers design treatment regimens that require patients to receive an infusion of therapeutic plasma protein every one, two, three, or more days. The once-a-day or once-every-bi-daily regimen places stress on patients by requiring them to receive infusions relatively frequently. Once-daily and once-every-bi-daily regimens may also be unnecessary for some patients. However, once-daily and once-every-bi-daily regimens make it easier and more practical for the healthcare provider to maintain higher therapeutic plasma protein levels in a patient relative to a predetermined peak therapeutic plasma protein level.

Summary of the essence

Disclosed is an exemplary system, method, and apparatus that defines a therapeutic plasma protein dosing regimen for a patient. An exemplary system, method, and apparatus determines a dosing regimen using a patient pharmacokinetic profile that is derived from a pharmacokinetic model of a previously sampled patient population and/or individual patient information. A patient's pharmacokinetic profile may be refined or modified based on the patient's previous treatment with a therapeutic plasma protein and/or patient-specific characteristics such as age, body weight, levels of other plasma proteins, physical activity level, gender, disease state, etc. The system, method, and apparatus provide a graphical patient pharmacokinetic profile interface that allows the user to adjust the dose, dosing interval, and minimum acceptable plasma therapeutic protein concentration in the patient to see how the dosing schedule changes. This configuration allows the healthcare provider to determine the optimal dosing regimen that reduces (or prevents) the patient's risk of bleeding as a result of the presence of low levels of clotting factor VIII.

In an exemplary embodiment, the method includes determining an estimated pharmacokinetic profile of a patient using a Bayesian model of the pharmacokinetic profiles of patients from whom samples were taken, the estimated pharmacokinetic profile based on at least one of the patient's body weight or age. The exemplary method also includes determining a first dosing regimen for a first predetermined dosing interval comprising (i) a first dose and (ii) a first therapeutic plasma protein level in a patient over a period of time, based on at least an estimated pharmacokinetic profile, and determining a second dosing regimen at during a second predetermined dosing interval comprising (i) a second dose and (ii) a second therapeutic plasma protein level in the patient over a period of time, based on at least a calculated pharmacokinetic profile. The method further includes displaying the first dosage schedule and the second dosage schedule on the client device such that the first dosage schedule is displayed in combination with the second dosage schedule.

In another exemplary embodiment, the apparatus comprises a model generator configured to generate a Bayesian model of the pharmacokinetic profiles of patients from whom samples are taken, the Bayesian model comprising (i) plasma therapeutic protein clearance and (ii) volume of distribution relationship for plasma therapeutic protein based on at least at least one of the patient's age or body weight. The exemplary apparatus also includes a pharmacokinetic server configured to determine an approximate pharmacokinetic profile of a patient based on a Bayesian model and at least one of the patient's age or the patient's weight and determine a therapeutic plasma protein dosing regimen comprising a dose and level of the therapeutic plasma protein over a period of time of based on the patient's approximate pharmacokinetic profile. The pharmacokinetic server is also configured to modify the therapeutic plasma protein dosing regimen in response to receiving a dosing interval for administering the dose to the patient and transmit the modified therapeutic plasma protein dosing regimen to the client device.

In yet another exemplary embodiment, the machine-readable device has instructions stored therein that are configured, when executed, to cause the machine to at least prompt the user to enter at least one of the patient's weight or age, and to use a Bayesian model of the patients' pharmacokinetic profiles, from whom samples were taken, in order to determine the approximate pharmacokinetic profile of the patient based on the Bayesian model and at least one of the administered weight or age of the patient,

- 2045259 the Bayesian model comprises (i) clearance of a therapeutic plasma protein and (ii) a volume of distribution relationship for a therapeutic plasma protein based on at least one of the administered weight or age of the patient. The exemplary instructions also direct the machine to determine a dosing regimen for a patient based on the patient's approximate pharmacokinetic profile, the dosing regimen comprising a dose and a dosage interval. The exemplary instructions further direct the machine to modify the dosing schedule in response to receiving a different dosing interval for applying the dose to the patient, and to enable the dosing schedule and the time-varying therapeutic plasma protein level based on the dosing schedule to be displayed to the user.

Aspects of the subject matter described herein may be used alone or in combination with one or more other aspects described herein. Without limiting the foregoing description, in a first aspect of the present invention, a method of providing a therapeutic plasma protein dosing regimen includes determining, by a processor, a calculated pharmacokinetic profile of a patient using a Bayesian model of the pharmacokinetic profiles of patients from whom samples were taken, the calculated pharmacokinetic profile based on at least one from the body weight or age of the patient, determining, by the processor, a first dosing regimen for a first predetermined dosing interval that contains (i) a first dose and (ii) a first therapeutic plasma protein level in the patient over a period of time, based on at least pharmacokinetic profile, determining, by the processor, a second dosing regimen for a second predetermined dosing interval that comprises (i) a second dose and (ii) a second therapeutic plasma protein level in a patient over a period of time, based on at least a pharmacokinetic profile, and displaying the first dosage regimen and the second dosage regimen on the client device such that the first dosage regimen is displayed in combination with the second dosage regimen.

In accordance with the second aspect of the present invention, which can be used in combination with the first aspect, the method further includes adjusting, by the processor, the calculated pharmacokinetic profile of the patient based on the patient's previous treatment.

In accordance with a third aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the second predetermined dosing interval is longer than the first predetermined dosing interval.

In accordance with a fourth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the first predetermined dosing interval is 48 hours and the second predetermined dosing interval is 72 hours.

According to a fifth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the minimum threshold level is less than 20%.

In accordance with a sixth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the first dose is determined such that the patient's first therapeutic plasma protein level does not fall below a minimum threshold level over a period of time.

In accordance with a seventh aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the patient's first therapeutic plasma protein level is based on at least one of a minimum threshold level, a first dose, or a first predetermined dosing interval, and the patient's second therapeutic plasma protein level is based on at least one of a minimum threshold level, a second dose, or a second predetermined dosing interval.

According to an eighth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the Bayesian model comprises a two-block model that has a first block corresponding to the time for plasma therapeutic protein to be metabolized, and a second block corresponding to the time for metabolizing the therapeutic plasma protein, appropriate dose to achieve a certain amount of therapeutic plasma protein in a patient.

In accordance with a ninth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, an apparatus for providing a therapeutic plasma protein dosing regimen to a client device comprises a model generator configured to generate a Bayesian model of the pharmacokinetic profiles of patients in whom samples were taken, the Bayesian model comprises (i) clearance of the therapeutic plasma protein and (ii) a volume of distribution relationship for the therapeutic plasma protein based on at least one of the age or body weight of the patient, and a pharmacokinetic server configured to determine the approximate pharmacokinetic profile of the patient on based on a Bayesian model and at least one of the patient's age or patient weight, determine a therapeutic plasma protein dosing regimen that contains the dose and level of the therapeutic plasma protein over a period of time, based on the approximate pharmacokinetic

- 3 045259 patient profile, modify the therapeutic plasma protein dosing regimen in response to receiving a dosing interval for applying the dose to the patient, and transmit the modified therapeutic plasma protein dosing regimen to the client device.

In accordance with a tenth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the dosing interval is a two-day dosing interval, and wherein the pharmacokinetic server is configured to further modify the therapeutic plasma protein dosing schedule in response to receiving three-day dosing interval instead of a two-day dosing interval.

In accordance with an eleventh aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the pharmacokinetic server is configured to transmit a drug dosing tool to a client device, the drug dosing tool is configured to determine a dosing regimen of a therapeutic plasma protein and a modified therapeutic plasma protein dosing regimen.

In accordance with a twelfth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the pharmacokinetic server is further configured to modify a therapeutic plasma protein dosing regimen based on a patient's daily activity.

In accordance with a thirteenth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the pharmacokinetic server is further configured to transmit a modified therapeutic plasma protein dosing regimen to an infusion pump for administering the therapeutic plasma protein to a patient.

In accordance with a fourteenth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the estimated pharmacokinetic profile is a first estimated pharmacokinetic profile determined for the first treatment of a patient with a therapeutic plasma protein, and wherein the pharmacokinetic server is further configured with the ability to determine a second approximate pharmacokinetic profile for a patient for a second treatment of the patient with a therapeutic plasma protein based on a modified dosing regimen of the therapeutic plasma protein.

In accordance with a fifteenth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the volume of distribution relationship for a therapeutic plasma protein is the relationship for at least one coagulation factor VIII and modified forms of coagulation factor VIII.

In accordance with a sixteenth aspect of the present invention, which may be used in combination with any one or more of the preceding aspects, a machine-readable device has instructions stored therein that are configured, when executed, to cause the machine to at least prompt the user to input at least one of the patient's weight or age, use a Bayesian model of the pharmacokinetic profiles of the patients sampled to determine an approximate patient pharmacokinetic profile based on the Bayesian model and at least one of the input patient's weight or age, the Bayesian model comprising (i) clearance therapeutic plasma protein and (ii) the volume of distribution relationship for the therapeutic plasma protein based on at least one of the administered weight or age of the patient, determine a dosing regimen for the patient based on the approximate pharmacokinetic profile of the patient, the dosing regimen contains a dose and dose interval, modify the dosing regimen in response to receiving a different dosing interval for applying the dose to the patient, and allowing the dosing schedule and the time-varying therapeutic plasma protein level based on the dosing schedule to be displayed to the user.

In accordance with a seventeenth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the machine-readable device further comprises instructions stored therein that are configured, when executed, to cause the machine to determine a first dosage schedule for a two-day dosing interval, define a second dosing schedule for a three-day dosing interval, and enable the first dosing schedule to be displayed in combination with the second dosing schedule.

In accordance with an eighteenth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the machine-readable device further includes instructions stored therein that are configured, when executed, to cause the machine to display a graphical representation of a time-varying the amount of therapeutic plasma protein in the patient, including at least one indication of the dose of therapeutic plasma protein provided to the patient.

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In accordance with a nineteenth aspect of the present invention, which may be used in combination with any one or more of the preceding aspects, the machine-readable device further includes instructions stored therein that are configured, when executed, to cause the machine to display a graphical feature that allows the user to change at least one of (i) the minimum concentration threshold, (ii) the dose range, or (iii) the dose of the therapeutic plasma protein.

In accordance with the twentieth aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the machine-readable device further includes instructions stored therein that are configured, when executed, to cause the machine to modify the dosage schedule in response to receipt of a change to any one of clauses (i), (ii) or (iii).

In accordance with the twenty-first aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the machine-readable device further includes instructions stored therein that are configured, when executed, to cause the machine to display a graphical representation of the change in quantity therapeutic plasma protein in a patient over time based on changes in any one of (i), (ii) or (iii).

In accordance with the twenty-second aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the machine-readable device further includes instructions stored therein that are configured, when executed, to cause the machine to accept a minimum concentration threshold and display the amount of time the therapeutic plasma protein level is below the minimum concentration threshold.

In accordance with the twenty-third aspect of the present invention, which can be used in combination with any one or more of the preceding aspects, the machine-readable device further includes instructions stored therein that are configured, when executed, to cause the machine to receive laboratory blood measurement data patient, which contain the concentration of therapeutic plasma protein in the patient, after a certain time when the therapeutic plasma protein was administered to the patient, and modify the approximate pharmacokinetic profile based on laboratory data from blood measurements of the patient.

In accordance with the twenty-fourth aspect of the present invention, any of the structure and functionality illustrated and described in connection with FIGS. 1 to 31 may be used in combination with any of the structure and functionality illustrated and described in connection with any other of FIGS. 1 to 31 and any one or more of the preceding aspects.

Brief description of the figures

In fig. 1 is a diagram of an exemplary pharmacokinetic dosing environment of a drug, according to an exemplary embodiment of the present invention.

In fig. 2 is a chart of patient sample data for a plurality of hemophilia A patients, according to an exemplary embodiment of the present invention.

Figures 3 through 13 are diagrams that contain exemplary user interfaces provided by the drug dispensing tool of FIG. 1 to determine dosing recommendations and an estimated pharmacokinetic profile for a particular patient according to an exemplary embodiment of the present invention.

Figures 14 to 18 are diagrams that include user interfaces provided by the drug dosing tool of FIG. 1, in an embodiment of a marketing tool according to an exemplary embodiment of the present invention.

In fig. 19 and 20 are diagrams that include a flowchart that illustrates an exemplary procedure for determining a dosage regimen, according to an exemplary embodiment of the present invention.

In fig. 21 and 22 are charts that contain an exemplary embodiment in which the pharmacokinetic profile for a particular patient is adjusted based on activity level.

Figures 23 to 30 provide charts of tables and graphs that correlate the concentration of administered therapeutic plasma protein with the risk of bleeding for various patients, according to an exemplary embodiment of the present invention.

In fig. 31 is a detailed block diagram of an example model generator, server, and/or client device from the pharmacokinetic drug dosing environment of FIG. 1, according to an exemplary embodiment of the present invention.

Detailed description

The present invention generally relates to a method, system and apparatus for providing circuit

- 5 045259 we dosage the drug and, in particular, to provide a pharmacokinetic dosing regimen for the drug based on a model of the pharmacokinetic profiles of the patients from whom samples were taken. The pharmacokinetic dosing regimen of the drug described herein provides a cost-effective use of therapeutic plasma protein that can be tailored to the individual patient. As such, the exemplary pharmacokinetic dosing regimen for a drug described herein provides healthcare providers with a tool that enables relatively rapid and accurate patient dosing recommendations without the need to determine a patient-specific pharmacokinetic profile based on (only) a blood test. The invention also provides FVIII clotting factor products that are modified to increase the patient's average retention time relative to native FVIII, for example, through the use of water-soluble proteins or FC-fusion technology, and dosing schedules/intervals longer than three days.

Currently, healthcare providers design a treatment regimen for a patient with low levels of naturally occurring coagulation factor VIII by determining a patient-specific pharmacokinetic profile to identify how the patient metabolizes the therapeutic plasma protein over time. To determine a patient's pharmacokinetic profile, the healthcare provider performs an initial baseline blood draw before the patient is administered the therapeutic plasma protein. This baseline blood draw is used to determine the amount of naturally occurring clotting factor VIII in the body. The healthcare provider then administers the therapeutic plasma protein and performs three or more blood draws within a 48-hour period after treatment. During this time, the patient metabolizes the therapeutic plasma protein such that the patient's factor VIII concentration returns to the patient's own naturally occurring level. The health care provider analyzes the patient's blood using laboratory analyzers to determine the patient's amount of clotting factor VIII each time the blood is drawn. This laboratory blood test data allows the healthcare provider to determine how quickly the patient metabolizes the therapeutic plasma protein.

As a general guideline, most healthcare providers set the target threshold so that the patient's clotting factor VIII does not fall below 1%. Patients with less than 1% clotting factor VIII are considered susceptible to uncontrolled or spontaneous bleeding. Although this approach works for some time, many patients have daily, weekly, or even monthly variations in their metabolism and/or bleeding tendencies, and may require different levels of clotting factor FVIII in order to remain bleeding-free. These variations are often related to the patient's weight, age, joint health, and physical activity level. The dosing regimen determined for the patient usually does not account for these variations, potentially leaving the patient susceptible to bleeding if clotting factor VIII falls below the generally accepted natural baseline threshold of 1% and/or is below what is needed to prevent bleeding during higher risk periods /physical activity.

The exemplary method, system and apparatus described herein takes into account patient pharmacokinetic variations by creating individual patient profiles based not only on intensive pharmacokinetic profiling of the patient itself, but also on a (Bayesian) model that uses the pharmacokinetic profiles of a set of patients with representative samples and/or limited number of patient blood sample data points coupled with minimal patient information. The exemplary method, system and apparatus described herein allow a healthcare provider to refine the model based on the patient's previous treatment and/or the patient's activity level. This configuration allows healthcare providers to create individualized dosing regimens based on knowledge of patient populations that have characteristics similar to the patient being treated, thereby reducing the effects of individual patient pharmacokinetic variations and reducing (or nullifying) the number of bleeding experienced by the patient during prophylaxis.

The exemplary invention includes two main embodiments. The first main embodiment comprises a drug dosing tool that uses pre-collected patient data to generate one or more pharmacokinetic models. An exemplary method, system, and apparatus uses this model to determine how a therapeutic plasma protein changes over time in a patient based on the patient's physical attributes (e.g., age, weight, sex, activity level, endogenous coagulation factor VIII level, etc. .d.) and previous dosing treatment. The health care provider can use the model to determine the drug dose and dosing interval for the patient.

The second main embodiment comprises a drug dosing tool, such as an application (App) running on a mobile computer (for example, a smartphone or

- 6 045259 tablet computer). The application is configured to allow a user (eg, a drug sales agent) to provide healthcare providers with a graphical interface that displays how a particular therapeutic plasma protein (eg, coagulation factor VIII, such as Baxter ADVATE) performs under various conditions. An exemplary pharmacokinetic tool for a drug of this second embodiment uses a pharmacokinetic model of the patients sampled to allow the user to isolate the effects of use, for example, a q-d dosing schedule, a q-d dosing schedule, dosing schedule once every five days, etc. in place of once-daily or once-every-bi-daily dosing regimens for therapeutic plasma protein. The drug tool uses relationships between therapeutic plasma protein concentrations, therapeutic plasma protein dose levels, therapeutic plasma protein dose times, and patient parameters to calculate how therapeutic plasma protein concentrations change over time for a theoretical patient.

As used herein, the term coagulation factor VIII, FVIII or rAHF refers to any FVIII molecule that has at least a portion of an intact B domain and that exhibits biological activity that is associated with native FVIII. In one embodiment of the invention, the FVIII molecule is full-length FVIII. The FVIII molecule is a protein that is encoded by DNA sequences capable of hybridizing with DNA encoding FVIII:C. Such a protein may contain amino acid deletions at various sites between or within the A1-A2-B-A3-C1-C2 domains. The FVIII molecule may also be an analogue of the native coagulation factor FVIII, where one or more amino acid residues are replaced by site-directed mutagenesis.

The term recombinant factor VIII (rFVIII) may include any rFVIII, heterologous or naturally occurring, produced by recombinant DNA technology, or a biologically active derivative thereof. As used herein, endogenous FVIII includes FVIII that originates from a mammal scheduled to receive treatment. The term also includes FVIII transcribed from a transgene or any other foreign DNA present in the mammal. As used herein, exogenous FVIII or therapeutic plasma protein includes the coagulation factor FVIII, which is not derived from a mammal.

The FVIII molecule exists in nature and in therapeutics as a heterogeneous distribution of polypeptides arising from a single gene product. The term coagulation factor VIII, as used herein, refers to all such polypeptides, whether derived from blood plasma or obtained through the use of recombinant DNA techniques, and includes, but is not limited to, FVIII mimetics, fc-FVIII conjugates, FVIII, chemically modified with water-soluble polymers, and other forms or derivatives of FVIII. Commercially available examples of therapeutic drugs containing FVIII include those sold under the trade names Advate, Hemofil M and Recombinate (available from Baxter Healthcare Corporation, Deerfield, Ill., U.S.A.). Other drugs contain primarily a single subpopulation of FVIII molecules that lack part of the B domain of the molecule.

FVIII molecules that can be used for the present invention include the full-length protein, protein precursors, biologically active or functional protein subunits or fragments and/or functional derivatives thereof, as well as variants thereof, as described later herein. Reference to coagulation factor FVIII means that all possible forms of such proteins are included, and wherein each of the forms of FVIII has at least partially or completely the native intact B domain sequence.

Dosing interval, as used herein, refers to the amount of time that elapses between multiple doses administered to a patient. The dosing interval for administering the therapeutic plasma protein containing coagulation factor VIII may be at least about every one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen days or more. . The dosing interval may be adjusted based on changes in patient conditions/characteristics, changes in the patient's minimum acceptable (eg, target trough) therapeutic plasma protein concentration, and/or changes in dose.

Pharmacokinetic drug dosing environment.

In fig. 1 is a diagram of an exemplary pharmacokinetic drug dosing environment 100 that may be implemented in any one or both of the embodiments described above. The environment 100 includes a model generator 102 that is configured to generate one or more patient pharmacokinetic models 106 based on the patient data 104 from which samples were taken. The environment 100 also includes a pharmacokinetic (PK) server 108 that is configured to provide patients, healthcare providers, and/or sales agents with a graphical pharmacokinetic drug dosing tool 110 based on one or more pharmacokinetic models 106.

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In the illustrated embodiment, the FC server 108 transmits the tool 110 to the client devices 112 via a network 114 (eg, the Internet). In other embodiments, on the FC server

108, a tool 110 is located that is accessible by client devices 112. In these other embodiments, the FC server 108 may comprise a single server or alternatively may be distributed on a cloud computing infrastructure.

An exemplary PK server 108 and/or model generator 102 may be in communication communication with a database 116 configured to store patient pharmacokinetic models 106 . Database 116 may comprise any type of computer-readable media, including RAM, ROM, flash memory, magnetic or optical disks, optical memory, or other storage media. The exemplary database 116 may also store information generated in response to the use of the tool 110 by users, which contains, for example, patient information, dosing regimens, etc. In some cases, the database 116 may be managed by a separate third party storage provider.

In some cases, the FC server 108 and/or model generator 102 may be provided by the same server and/or processor and/or driven by the same entity. In these cases, the functionality of the model generator 102 may operate in conjunction with the functionality of the PK server 108. For example, the model generator 102 may periodically update the pharmacokinetic models using therapeutic plasma protein dosing information and/or patient information obtained from the PK server 108 through the tool 110 .

Exemplary client devices 112a, 112b, and/or 112c may include any device capable of displaying or otherwise operating the tool 110. Exemplary client devices 112 include a smartphone, desktop computer, laptop computer, desktop computer, workstation, server, processor, smart glasses, smart watches, etc. In some cases, the tool 110 may be installed on the client device 112. In other cases, the tool 110 provides an interface (e.g., a web browser) to functionality configured to reside on the FC server 108. In these cases, the FC server 108 may contain one or more application programmable interfaces (APIs) configured to allow the tool 110 to access desired data and/or functionality.

Model generator.

In the embodiments described herein, a pharmacokinetic model is used to estimate or approximate the pharmacokinetic profiles of patients, since precise patient-specific pharmacokinetic profiles are relatively complex or difficult to determine. For example, existing methods for determining a patient-specific pharmacokinetic profile for hemophilia A involve performing a variety of blood tests. These blood tests involve performing an initial blood draw to determine the patient's baseline factor VIII level. Then, after the therapeutic plasma protein is administered, five or more blood draws are performed over a 48-hour period following the infusion. As can be understood, this procedure is particularly burdensome for the patient, healthcare provider, and laboratory due to the many separate blood draws. Accordingly, the exemplary model generator 102 is configured to generate relatively accurate pharmacokinetic models based on patient samples of varying ages, body weights, genders, and activity levels. These models are then used to determine or approximate a patient's pharmacokinetic profile without having to subject the patient to all the blood draws and subsequent analysis.

In one embodiment, pharmacokinetic models 106 are determined using patient samples 104 selected from one or more patient data sets. Patient samples 104, for example, can be selected from patients who are already prescribed a therapeutic dosing regimen using the blood collection procedure described above. Patient samples 104 may also include patients specifically selected to undergo blood collection procedures for the purpose of creating models. Patient samples 104 may include patients from a single hospital or medical system and/or patients associated with multiple hospitals, medical systems, geographic regions, etc.

The 104 patient samples contain data for patients with varying ages, body weights (or body mass indexes (BMIs), medical conditions, clinical laboratory data, gender, and/or activity levels. In the example described herein, the ages of patients who samples are taken ranging between 2 and 100 years. In some embodiments, the patient data may be divided into pediatric and adult age groups such that a separate model is generated for each group. The patient data may additionally or alternatively be subdivided based on weight, sex, and/or or activity level.

As noted, the exemplary 104 patient samples include determination of coagulation factor VIII before the therapeutic plasma protein is infused into the patients. Then, after the infusion, blood samples are collected from each patient after a certain duration of time. It will be appreciated that in other examples, blood samples may be collected at different time points and/or the number of blood samples collected may be fewer or more. For example, fewer blood samples can be collected from children.

In fig. 2 is a diagram of a graph 200 containing patient sample data 104 for one hundred fifty-two patients with hemophilia A. The sample data 104 is shown as coagulation factor VIII level in international units (IU) per deciliter (dL). Samples were collected before infusion (shown at time 0) and after infusion at intervals of 15 min, 30 min, 1 h, 3 h, 6 h, 9 h, 24 h, 28 h, 32 h, and 48 h. that the amount of coagulation factor VIII provided by the therapeutic plasma protein in a patient decreases over time as patients metabolize the infused therapeutic plasma protein.

An exemplary model generator 102 creates a pharmacokinetic model of a patient by performing a Bayesian analysis that uses previous knowledge of coagulation factor VIII in sampled patients over time after infusion of the therapeutic plasma protein. In some cases, model generator 102 is configured to analyze the dosing history of each patient sampled in conjunction with pre-infusion factor VIII levels so that washout data is not required to build pharmacokinetic models 106. In other embodiments, model generator 102 may use patient washout data in combination with post-infusion factor VIII levels to create one or more pharmacokinetic models 106. Patient washout data corresponds to a baseline where the patient does not have the therapeutic plasma protein in their system.

An exemplary model generator 102 creates one or more pharmacokinetic models 106 using, for example, patient sample data represented in graph 200. The model generator 102 may combine individual patient samples 104 into one or more group profiles (e.g., sets by age, sets by mass, activity level sets, endogenous factor VIII levels, etc.), which are then used as the basis for an appropriate pharmacokinetic model 106. For example, model generator 102 may group patient samples 104 for different ages, weights, and/or levels activities into different sets. The model generator 102 then performs covariance and statistical modeling on the grouped patient samples 104 from each set to generate a group pharmacokinetic model 106 for that set, as described in the white paper entitled Population pharmacokinetics of recombinant factor VIII - the relationships of pharmacokinetics to age and body weight, Bjorkman et al., which is incorporated herein by reference in its entirety. However, it should be appreciated that the model generator 102 may model the sample data 104 using other Bayesian analysis techniques (eg, a Naive Bayes classifier).

In the illustrated example, the covariance model used by model generator 102 determines the relationships between pharmacokinetic parameters (e.g., therapeutic plasma protein metabolic rate, endogenous coagulation factor VIII level, etc.) and patient characteristics (e.g., age, body weight, clinical laboratory data , gender, activity level, etc.). Model generator 102 uses a statistical model to determine the variance of pharmacokinetic parameters among patients sampled, in addition to residual variance resulting from between-patient biological variability, measurement errors, and errors in fitting sample data 104 to the pharmacokinetic model.

The exemplary model generator 102 is configured to perform covariance and statistical modeling using nonlinear mixed effects modeling using a first order integral approximation method as provided in SAS® software (NLMIXED routine). In the illustrated example, model generator 102 uses a two-block model. In other examples, model generator 102 may use a single block model or models with three or more blocks. In the illustrated two-block example, the first block includes the pharmacokinetic parameters of clearance (CL) and volume of distribution (V1).

CL refers to the amount of time for a patient to metabolize therapeutic plasma protein, in milliliters (ml) per hour per kilogram (kg). In other words, clearance is a measure of the efficiency and rate at which a therapeutic plasma protein is removed or eliminated from a patient. Model generator 102 uses the example equation (1) to determine CL, where BW denotes body weight, i denotes the particular patient from whom samples were taken, and η denotes statistical variability between patients.

CX(ml/h) = 193%^^) ⁰⁸⁰ *(1-0.0045* (age -22))*exp(;/ _; ^C£ ) (i) 56

V1 refers to the theoretical volume that a therapeutic plasma protein must occupy in order to provide the same concentration as is currently present in the patient's blood. This theoretical volume provides an estimate for a dose to achieve a given level of coagulation factor VIII. The model generator 102 uses the example equation (2) to determine V1.

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In the example described herein, V1 is approximately 0.04 L/kg.

Г1(.,) = 2.22П^/'=*схр( ^уп ) (2)

The second component of the illustrated model contains interunit clearance (Q) and a second volume of distribution (V2), which does not account for interpatient variability. Model generator 102 uses example equation (3) to determine Q and equation (4) to determine V2. Interblock clearance Q is used in combination with clearance CL to determine the scaling ratio of the second volume of distribution V2 and the first volume of distribution V1. In this example, interunit clearance Q is not significantly related to body weight, indicating that V1 and V2 are cumulative in determining the volume of distribution at steady state. In other words, the total volume of distribution is determined by summing V1 and V2. In one implementation, the average total volume of distribution of patient samples was found to be approximately 0.053 L/kg.

/h) = 147 (3) = 0.73-(¾ ⁰⁷¹⁵ (4)

After generating the model 106 as provided by the example equations (1) to (4) above, the example model generator 102 may verify the model by determining individual values for CL, Q, V1, V2, and V1+V2 for each patient sampled. samples, and comparison of results with the model. This comparison provides an indication of the accuracy of the model. In some examples, the model generator 102 may determine the statistical distribution of the data of the patient from whom the samples were taken in order to determine whether the model is accurate. In cases where the model does not appear to be accurate, model generator 102 may compile additional patient samples 104 and/or perform other modeling techniques.

In response to the creation of one or more pharmacokinetic models 106, the model generator 102 provides the pharmacokinetic model(s) 106 to the server 108. The transmission may occur through a private network, such as a local area network, or through a public network, such as the Internet. The model generator 102 may also store the models 106 in a database 116, which is also accessible to the FC server 108 through one or more interfaces. In other cases, the model generator 102 may be integrated with the FC server 108.

In addition to providing pharmacokinetic models 106 based on equations (1) to (4) above as applied to random patient samples, the exemplary model generator 102 may refine the models for each patient for whom therapeutic plasma protein dosing is calculated using the tool dosing of the drug. For example, PK server 108 may receive patient-specific information that includes weight, age, sex, endogenous coagulation factor VIII level, and dosage level for previous treatment. Model generator 102 uses previous treatment information (eg, dosage amounts, intervals, etc.) to refine or adjust the model so that dosing recommendations and pharmacokinetic profile are more tailored to the individual patient while still accounting for possible variations. at the patient. Model generator 102 transmits the patient-specific model to FC server 108.

Alternatively, the PK server 108 may be configured to generate patient-specific models using the pharmacokinetic model 106 provided by the model generator 102 to account for patient-specific pharmacokinetic variations. Thus, one or more base models 106 are refined or adjusted by the FC server 108 in response to prior treatment information for a particular patient. The FC server 108 may be configured to store a patient-specific model in a database 116 for later use by the same healthcare provider or other healthcare providers.

In other embodiments, the exemplary tool 110 may be configured to adjust or refine the pharmacokinetic model based on patient-specific treatment information. For example, tool 110 may include fields for the user to provide information about previous treatment. Exemplary tool 110 uses this prior treatment information in determining the pharmacokinetic profile and dosing recommendations for the patient. Additionally or alternatively, tool 110 may use treatment information from multiple patients to refine and/or adjust model 106.

An embodiment of a patient-specific instrument.

As discussed above, the PC server 108 may be configured to provide various embodiments of the drug dispensing tool 110. In fig. 3 to 13 are diagrams of exemplary user interfaces provided by the drug dosing tool 110 for determining dosing schedules and calculations.

- 10 045259 patient-specific pharmacokinetic profile using one or more pharmacokinetic models 106. It should be appreciated that the appearance and/or function of user interfaces can be modified based on the configuration of the drug dosing tool 110. For example, graphical elements of user interfaces can be modified based on the type of client device 112 (eg, smartphone display, tablet display, personal computer display).

In fig. 3 is a diagram of a user interface 300 that includes user registration fields to allow a healthcare provider to access the medication dosing tool 110. Interface 300 contains data fields for user information (eg, name, activity, address, contact information). In addition, the user interface 300 includes a field for a Drug Enforcement Administration (DEA) number, which the QC server 108 uses to validate that the user is an authorized healthcare professional. In cases where a healthcare professional does not have a DEA number, the professional can contact customer support to manually set up an account to use the 110 tool.

In response to receiving user-supplied information in FIG. 3 (including the correct DEA number), the exemplary FC server 108 is configured in the illustrated embodiment with the ability to create a user account that includes a user control panel. In fig. 4 is a diagram of a user interface 400 for the patient information portion of the control panel. The user interface 400 allows the user to control the patients under the user's supervision.

The user uses the user interface 400 to add a new patient, reactivate an existing patient, open a report providing details regarding a previous treatment (including a previously determined pharmacokinetic profile and dosing recommendation), or open a report with patient information. To add a patient, drug dispensing tool 110 may provide another user interface that prompts the user for patient information, including name, address, insurance information, age, gender, body weight (or BMI), medical conditions, clinical laboratory data etc.

For any given patient, the drug dosing tool 110 allows the user to determine a calculated/approximate pharmacokinetic profile and dosing recommendations. In fig. 5 is a diagram of a user interface 500 associated with a new patient visit. In this illustrated example, user interface 500 includes fields for patient information regarding a therapeutic plasma protein infusion. In cases where the patient has already been registered using the tool 110, at least some of the fields may be pre-populated. Additionally, the Dose for PK infusion field may be populated by tool 110 in response to the user's progression through the steps to determine an estimated pharmacokinetic profile and dosing recommendations for the patient.

The exemplary drug dispensing tool 110 may also be configured to alert the user if the information provided exceeds a predetermined threshold. For example, instrument 110 may be configured to provide a warning message if the pre-infusion level exceeds 20 IU/kg. This warning is intended to indicate to the user that the value entered is not typical for that field. However, the user may still continue to use the tool 110 with the information that caused the alert to be generated. Alternatively, the tool 110 may be configured to only receive information within a predetermined range.

After providing information about the patient's name, body weight, date of birth, infusion date, and pre-infusion washout or level, the exemplary drug dosing tool 110 prompts the user to advance to the next step. In fig. 6 is a diagram of the user interface 600 that is displayed after the user has provided information in the user interface 500 of FIG. 5.

An exemplary user interface 60 0 provides an overview of a patient's previous treatments and/or samples, including pre-infusion (or washout) and dose (ie, PK infusion) information. The user may choose to use data from one or more previous treatments and/or samples with instrument 110 in order to refine or adjust the pharmacokinetic model 106 for the patient. The user makes this selection by toggling the "On/Off" buttons on the right side of the interface 600. For example, the user can deactivate previous treatments and/or samples that occurred more than three years ago. As a result of this selection, the tool 110 only uses activated prior treatments and/or samples when refining the pharmacokinetic model 106. This configuration of the tool 110 thereby allows the user to refine the pharmacokinetic model, optionally using only the specified prior treatments

- 11 045259 and/or patient samples. In some cases, the user may choose to deactivate all previous treatments and/or samples, thereby instructing the tool 110 to use the pharmacokinetic model 106 as provided by the model generator 102.

In the illustrated embodiment, three patient samples are shown for treatment with a plasma protein therapeutic. Each of the samples corresponds to a patient's blood drawn at a specific time point from a therapeutic plasma protein infusion treatment. For example, the first sample was taken 6 hours after infusion, the second sample was taken 24 hours after infusion, and the third sample was taken 30 hours after infusion. The sample information contains a determination of the concentration of coagulation factor VIII in the patient's blood at the time of sample collection. It should be appreciated that the use of a pharmacokinetic model 106 in combination with certain selected patient samples can refine a patient's defined pharmacokinetic profile to be patient specific while also compensating for the patient for variations common within the sample group.

After selecting which treatments and/or samples are to be included in the pharmacokinetic model 106, the drug dosing tool 110 prompts the user to select a Next step button, which causes the exemplary tool 110 to display the user interface 700 of FIG. 7. An exemplary user interface 700 provides an overview of what previous treatments and/or samples should be included in determining the calculated pharmacokinetic profile and dosing recommendations for the patient. Selected previous treatments and/or samples can be used to provide a weight for the dosage regimen based on previous doses provided. User interface 700 prompts the user to select a Calculate button to instruct the drug dosing tool 110 (or PK server 108) to apply patient-specific information to the pharmacokinetic model 106 to determine a calculated or estimated pharmacokinetic profile and dosing recommendations for the patient. In some cases, tool 110 may not make the Calculate button available until the user has provided at least a predetermined number (e.g., three) of previous treatments and/or samples to ensure that the resulting determination is more patient specific . It should be appreciated that the tool 110 and/or the PK server 108 selects, from available pharmacokinetic models, that pharmacokinetic model that best matches the patient information provided in the user interface 500 and/or other user interfaces that prompt the user for specific patient information. For example, the pharmacokinetic model can be selected based on patient age, weight, gender, and/or activity level.

In fig. 8 is a diagram of the user interface 700 of FIG. 7, which now displays the determined pharmacokinetic profile of the patient after calculation by the tool 110 and/or PK server 108. The Theoretical fields correspond to data that is based only on the pharmacokinetic model 106 without previous treatments and/or patient samples. The Adjusted fields correspond to patient-specific pharmacokinetic profile data based on the pharmacokinetic model 106 that is adjusted using previous treatment and/or sample information. The Offset fields correspond to the difference between the corresponding Theoretical and Adjusted fields. In the illustrated example, the pharmacokinetic profile data comprises the therapeutic plasma protein clearance, volume of distribution (vdBeta), the maximum concentration that the therapeutic plasma protein can achieve after dosing (CMax/Peak), the half-life of the therapeutic plasma protein (FVTII half-life) and the time to trough ( or lower) of the patient's predetermined therapeutic plasma protein concentration threshold. It should be appreciated that in other embodiments, the user interface 700 may contain fewer fields or additional fields for the pharmacokinetic profile, including V1 and V2 and/or assay type.

In some cases, exemplary tool 110 may provide a warning and/or alarm if any pharmacokinetic profile data is outside a certain percentage of the sample population that was used to create the pharmacokinetic model 106. For example, tool 100 may display that the adjusted clearance value is outside 95% of the clearance values of patients sampled in the same cohort as the patient undergoing treatment. The user can use the warning and/or alarm as a trigger to verify entered patient information. The warning and/or alarm can also be used as an indication that the dosing schedule is abnormal or outside the dosing schedules for patients sampled with characteristics similar to the patient being treated.

In addition to providing the pharmacokinetic profile data presented in FIG. 8, example tool 110 also provides a graphical representation of the calculated pharmacokinetic profile and dosing recommendations. In fig. 9 and 10 are charts of user interfaces 900 and 1000 that display dosing and pharmacokinetic information (eg, a patient's plasma therapeutic protein level (eg, CL) over time) for a particular patient. The therapeutic plasma protein level is shown as a percentage of the concentration relative to the patient's normal factor VIII level. However, in other embodiments, the therapeutic plasma protein level may be indicated as a unit of measurement.

In fig. 9 is a user interface chart 900 that graphically displays the estimated or estimated pharmacokinetic profile of a patient 902. The exemplary pharmacokinetic profile 902 shows how a patient metabolizes a therapeutic plasma protein over time, starting from the time point at which the therapeutic plasma protein is administered. The pharmacokinetic profile of patient 902 is indicated by a solid line. The exemplary user interface 900 also includes a comparison of the pharmacokinetic profile of patient 902 with the pharmacokinetic profile of patients 904 from whom samples were taken and used to generate pharmacokinetic model 106, which is indicated by the dashed line. The user interface 900 also includes a shaded bar 906 that represents ±20% of the pharmacokinetic profile of the patients 904 from whom samples were taken.

In addition, exemplary user interface 900 includes a graphical representation of patient samples 908 and 910 in cases where the patient has had one or more blood tests following infusion of a therapeutic plasma protein. Patient sample 908 corresponds to a sample not selected for inclusion in the determination of the pharmacokinetic profile of patient 902, and patient samples 910 correspond to samples selected for inclusion in the determination of the pharmacokinetic profile of patient 902. Blood tests are performed to determine the amount of therapeutic plasma protein in the patient after an initial infusions, and may be performed to further refine the pharmacokinetic profile of patient 902. For example, instead of performing five or more blood draws after an infusion, the exemplary PK server 108 and/or instrument 110 may be used to create a pharmacokinetic profile of patient 902 with using data from a smaller number of blood draws in combination with the pharmacokinetic profile of the patients 904 from whom the samples were taken, based on a pharmacokinetic model 106.

An exemplary user interface 1000 in FIG. 10 allows the user to graphically see dosing changes based on a change in dosing interval and/or a minimum (lower) target therapeutic plasma protein concentration threshold (eg, target trough) based on the pharmacokinetic profile of patient 902 shown in FIG. 9. For example, in FIG. 10 is a dosing schedule graph that visually shows how the administered therapeutic plasma protein is metabolized based on the calculated pharmacokinetic profile of patient 902. The dosing schedule contains a dosing interval of 72 hours such that the therapeutic plasma protein concentration does not fall below the target trough of 30%. The exemplary drug dosing tool 110 uses this information to calculate an estimated dose (eg, 48.0 IU or 0.76 IU/kg) to be administered every 72 hours. Exemplary tool 110 also calculates the amount of time the therapeutic plasma protein level is above (eg, below) the target trough. In other cases, instrument 110 may provide an indication of the amount of time the therapeutic plasma protein level is below a target deflection, which corresponds to the amount of time the patient is unprotected by the therapeutic plasma protein and is bleeding.

The exemplary tool 110 is configured to allow the user to adjust the interval and target deflection through the interface 1000 and accordingly change the dosing schedule, including the dose and level of therapeutic plasma protein over time. It should be appreciated that changing either the interval or target sag does not change the calculated pharmacokinetic profile of the patient 902. However, the exemplary tool 110 applies the selected interval or target sag to the determined pharmacokinetic profile of the patient 902.

The configuration of the interface 1000 of the exemplary tool 100 allows the healthcare provider to determine how the dosage changes based on changes in the interval or target deflection. For example, a health care provider may compare dosing schedules for a bi-daily dosing interval and a once-every-three-day dosing interval (or additional intervals such as a once-daily dosing interval) to determine whether whether the dosing interval can be extended (or reduced) for the patient, thereby requiring fewer health care visits and/or fewer self-medications. Target deflection allows the healthcare provider to determine how the dosing regimen is affected by the patient's desired trough level of therapeutic plasma protein. For example, a healthcare provider may determine that a 10% target deflection is acceptable for a (relatively active) patient and accordingly sets a target deflection of 10% in the user interface 1000. In response to receiving a target deflection selection, exemplary tool 110 determines a target dose such that the factor VIII concentration does not fall below a 10% threshold while maintaining a once-every-tri-daily dosing interval.

- 13 045259

The health care provider accordingly uses tool 110 to determine whether the once-every-tri-daily dosing schedule is appropriate for the 10% target deflection such that the dose or Cmax does not exceed a safe threshold.

The exemplary drug dosing tool 110 also provides a graphical level of therapeutic plasma protein over time and dosage based on a plan (eg, week, month, year, etc.). For example, the user may select a Schedule button on the interface 1000, causing the tool 110 to display available days for dosing. The user selects on which day the dose should be provided to the patient by causing the instrument 110 to determine the dose and therapeutic plasma protein level over time such that the therapeutic plasma protein level does not fall below a target deflection. For example, in FIG. 11 is a diagram of an exemplary user interface 1100 that allows a user to select specific days (and/or time points) to provide a dose of therapeutic plasma protein. For example, the user may enter into the instrument 110 that a dose of therapeutic plasma protein 1753 IU is to be provided to the patient on Monday, Wednesday, Friday, and Sunday using a 48-hour dosing interval. The user may select anywhere on the concentration line 1102 to view the date/time and specific concentration of clotting factor VIII in the patient.

In fig. 12 is a diagram of a user interface 1200 that allows a user to see the amount of time that the amount of clotting factor VIII is above a given concentration and below a given concentration. For example, the user can select time below to be 3% and time above to be 10%. In response to this information, exemplary instrument 110 and/or PK server 108 determines the amount of time that the amount of coagulation factor VIII is above 10% and below 3%. The exemplary tool 110 also graphically displays this time on a graph of the user interface 1200. This information shows, for example, the amount of time below 3% that the patient may be unprotected and susceptible to bleeding, and the amount of time that the patient is fully protected.

The exemplary drug dosing tool 110 also allows the user to store in the database 116 (and/or local memory of the client device 112) patient pharmacokinetic profiles in combination with dosing data and therapeutic plasma protein levels. For example, the user may select a Save button on the interface 1000 in FIG. 10, causing the drug dispensing tool 110 to save the information described in relation to Figures 5 to 12 to the data storage device. The information can also be stored as a report. In fig. 13 is a diagram of a report 1300 of the stored information described with respect to Figures 5 to 12. A healthcare provider may view the report 1300 to determine how a therapeutic plasma protein dosing schedule for a patient was calculated.

In addition to providing dosing information to the patient, the exemplary instrument 110 may be configured, in conjunction with the PK server 108, to communicate dosing information to the hospital information system and/or to the infusion pump 120. For example, referring back to FIG. 1, a healthcare provider may use tool 110 on client device 112c to determine dosing information for a patient. Instrument 110 may be configured to transmit dosing information to PC server 108. The healthcare provider may also identify an infusion pump that will provide dosing. In response to receiving the dosing information, the PC server 108 transmits the dosing information to the infusion pump and/or to the hospital information system. Alternatively, PC server 108 may hold dosing information until requested by the infusion pump. In cases where the pump is not precisely identified, the hospital information system determines which pump is providing the patient's infusion and initiates transmission of dose information to the appropriate pump.

Alternatively, exemplary tool 110 on client device 112c may transmit dose information directly to infusion pump 120 (eg, via near-field communications, Bluetooth®, etc.). For example, tool 110 may be configured to control client device 112c to establish a communication session or determine the location of a nearby pump. After establishing communication with pump 120, instrument 110 transmits dosing information in order to program the infusion pump.

Additionally or alternatively, the patient may directly use the tool 110. For example, the exemplary tool 110 may be configured to communicate a plan to the patient after the health care provider has selected a dosing regimen. For example, the instrument 110 may transmit a dosing regimen or plan to the patient client device 112, which instructs the patient how much and when to infuse the therapeutic plasma protein. The dosing regimen or plan indicates (and may contain reminders) specific days (and/or times) of the week, month, year, etc., on which the patient should take a dose of the therapeutic plasma protein. In addition, the tool 110 may be accessible to the patient to allow the patient to see previous treatments and compare how the dosing schedule changes based on changes in the dosing interval.

Option for implementing a marketing tool.

In the previous embodiment, the healthcare provider uses the exemplary tool 110 to determine a dosing regimen for administering a therapeutic plasma protein to a patient. In a second embodiment, the exemplary instrument 110 may instead be configured to provide a generalized dosing regimen (eg, a dosing regimen for a theoretical patient) to demonstrate to a healthcare provider the capabilities of a plasma protein therapeutic as part of a sales or marketing presentation. For example, a sales agent may demonstrate how the drug Advate Therapeutic Plasma Protein works under once-every-two-day and once-every-three-day dosing regimens. The exemplary tool 110 may also compare how a first brand of therapeutic plasma protein performs in a theoretical patient compared to a second brand of therapeutic plasma protein.

Figures 14 to 18 illustrate the user interfaces provided by the drug dispensing tool 110 in this embodiment of the marketing tool. The user interfaces display theoretical patient data that the sales agent can use to demonstrate to the healthcare provider how a therapeutic plasma protein can be prescribed based on the theoretical patient's pharmacokinetic profile, taking into account the theoretical patient's weight and half-life. Half-life is the time it takes for a drug to reach half its original concentration in a patient.

In particular, exemplary tool 110 allows a sales agent to demonstrate to a healthcare provider how a therapeutic plasma protein performs when dosing is performed every two days versus every three days for a given theoretical patient. It should be appreciated that the user interfaces shown in FIGS. from 14 to 18, only represent exemplary embodiments. In other examples, the layout and/or functionality of the user interfaces may be modified based on the requirements of the sales agents.

In fig. 14 is a diagram of the user interface 1400 that is provided by the drug dispensing tool 110 on the client device 112 of FIG. 1. Interface 1400 is configured to prompt a user to provide a current dosing regimen that is accurately defined for an actual patient or a theoretical patient. In this illustrated embodiment, a theoretical patient has a precise weight of 60 kg and a drug half-life of 12 hours. In addition, the user specifies a dosing schedule of 2300 IU every 48 hours. In addition, the user selects a deflection threshold (e.g., a minimum or lower threshold ) 1% using the 1401 scroll bar. The deflection is shown in the user interface 1400 as a line 1402.

In response to providing patient and drug parameters, drug dosing tool 110 uses a pharmacokinetic model (eg, pharmacokinetic model 106 described above) to determine the pharmacokinetic profile of a theoretical patient. The drug dosing tool 110 uses this profile to determine a dosing schedule (eg, dose and interval). Instrument 110 graphically displays the dosing schedule as therapeutic plasma protein concentration in a theoretical patient over a period of time (shown as line 1404). For example, it is shown that at time 0, a theoretical patient would be given 2300 IU of drug, resulting in a therapeutic plasma protein concentration of 76.7% in the patient. The therapeutic plasma protein concentration decreases over the next 48 hours based on the determined pharmacokinetic profile of the theoretical patient.

In fig. 15 illustrates the user interface 1400 of FIG. 14 after the user has selected the 2 days button. Selecting this button causes the tool 110 to determine a bi-daily dosing schedule based on the pharmacokinetic profile of a theoretical patient. This chart contains a dose (eg, 600 IU) and a graphical display of therapeutic plasma protein concentration in a theoretical patient over a period of time (shown as line 1406). Exemplary instrument 110 determines the dose amount for a two-day dosing interval such that the plasma therapeutic protein concentration does not fall below a predetermined target deflection of 1%.

User interface 1400 in FIG. 15 also provides a comparison of the dosing schedule initially provided by the user and the dosing schedule determined by tool 110. In the illustrated example, tool 110 graphically indicates that the user should only prescribe 600 IU instead of 2300 IU every 48 hours. In other words, tool 110 indicates that the user has overestimated the dose required to keep the therapeutic plasma protein concentration from falling below the target deflection of 1%.

In fig. 16 illustrates the user interface 1400 of FIG. 14 after the user has selected the 3 days button. Selecting this button causes the tool 110 to determine a tri-daily dosing schedule based on the pharmacokinetic profile of a theoretical patient. This chart contains a dose (eg, 2600 IU) and graphically displays the therapeutic plasma protein concentration over time in a theoretical patient (shown as line 1408). Tool

110 defines a scheme so that the concentration does not fall below a given target deflection of 1%.

User interface 1400 in FIG. 16 also displays a comparison of the dosing schedule originally provided by the user and the dosing schedule that was determined using tool 110. In the illustrated example, tool 110 graphically indicates that the healthcare provider should prescribe 2600 IU every 72 hours so that the concentration does not drop below 1% at any time between doses. The sales agent can use this graphical comparison to indicate to the healthcare provider that the dose should be increased only slightly from the current dose given every 48 hours to achieve the same bleeding protection while increasing the amount of time between doses. It should be appreciated that increasing the dosing interval creates less stress for the patient (eg, fewer trips to the healthcare provider) and the healthcare provider (eg, fewer doses to administer).

The sales agent uses the charts shown in FIG. 15 and 16 to graphically illustrate to a healthcare provider how the dosing schedule changes for the same theoretical patient when using a bi-daily dosing interval and a once-every-three-day dosing interval. The sales agent can also use the tool to graphically highlight the effects of using the every-three-day interval, showing that the therapeutic plasma protein can be administered to a patient every three days without violating the 1% threshold. The sales agent may concurrently display a tri-day interval and a bi-day interval by selecting a Both button included in the user interface 1400.

In addition to providing a graphical display of the differences between once-every-bi-daily and once-every-three-day dosing regimens, the exemplary drug dosing tool 110 also graphically shows how long a theoretical patient remains unprotected based on given parameters. For example, user interface 1400 in FIG. 17 shows an indication 1410 displayed by the instrument 110 in response to a determination that the time-varying therapeutic plasma protein concentration of a theoretical patient (eg, line 1404) falls below the target deflection line 1402. In this embodiment, the user raises the scroll bar 1401 so that the target sag increases to 13%. Exemplary instrument 110 determines the length of time that the plasma therapeutic protein concentration is below 13% and indicates this duration in display 1410. Exemplary instrument 110 may also determine a new dosing schedule (e.g., interval and/or dose) so that the therapeutic concentration plasma protein did not fall below the target deflection of 13%.

In fig. 18 is a diagram of a user interface 1800 that displays an indication 1802 of how long a theoretical patient has remained unprotected with a plasma protein therapeutic. Indication 1802 is based on the length of time that the therapeutic plasma protein concentration remains below the 13% target deflection, as determined in conjunction with FIG. 17. Exemplary tool 110 also predicts the number of bleeding events per year based on the length of time the therapeutic plasma protein concentration remains below the target deflection. In the illustrated example, indication 1802 contains a graph indicating that a theoretical patient would remain unprotected for 39 hours per week, which could lead to 2.3 bleeds per year. The sales agent may use the information presented in FIG. 17 and 18 to show healthcare providers how the once-every-tri-daily dosing regimen reduces (or eliminates) the time a patient is not protected by the effects of a therapeutic plasma protein.

Flowchart of an embodiment of an exemplary drug dispensing tool

In fig. 19 and 20 are a flow chart that illustrates an exemplary procedure 1900 for determining a dosage regimen for a patient (or theoretical patient), according to an exemplary embodiment of the present invention. The exemplary procedure 190 0 can be performed using, for example, the FC server 108 and/or the drug dispensing tool 110 described in conjunction with Figures 1 through 18. Although the procedure 1900 is described with reference to the flowchart illustrated in FIG. . 19 and 20, it should be appreciated that many other ways of performing the functions associated with procedure 1900 may be used. For example, the order of many blocks may be changed, certain blocks may be combined with other blocks, and many of the described blocks are optional.

Routine 1900 begins when drug dispensing tool 110 receives an indication that a user (eg, healthcare provider, sales agent, patient, etc.) wishes to determine a dosage regimen (block 1902). The indication may coincide with the operation of the drug dispensing tool 110 on the client device 112 and/or implement

- 16 045259 access to the drug dosing tool on the FC server 108. In response to receiving a request for a dosing schedule, the drug dosing tool provides a request for patient information (for example, body weight, gender, age, activity level, etc.) (block 1904). Patient information may correspond to an actual or theoretical patient.

The exemplary drug dosing tool 110 also provides a request for previous therapeutic plasma protein treatment for the patient (block 1908). In some embodiments, the drug dosing tool 110 may access previous treatment information from a stored data structure (eg, database 116). An exemplary drug dosing tool 110 accesses and refines a pharmacokinetic model (eg, pharmacokinetic model 106) based on previous treatments and/or samples (block 1910). It should be appreciated that information about previous treatment may not be available or provided to the drug dosing tool 110. In these embodiments, the drug dosing tool 110 uses the pharmacokinetic model 106 without modification. It should also be appreciated that in this procedure 1900, the pharmacokinetic model 106 has already been created and provided to the PK server 108 and/or instrument 110. In other examples, the pharmacokinetic model 106 can be created from patient samples 104 at any time during and/or before the steps , which are specified in blocks from 1902 to 1910).

An exemplary drug dosing tool 110 uses a (refined or modified) pharmacokinetic model and patient information to determine a (calculated or estimated) pharmacokinetic profile for the patient (block 1912). The drug dispensing tool 110 then provides a request for the dosing interval and/or target deflection (block 1914). In some cases, the metering tool 110 may use a default target sag (eg, 1%) when the user does not provide or does not accurately specify the sag. The drug dosing tool 110 then determines the therapeutic plasma protein dose and an estimate of the therapeutic plasma protein concentration in the patient over a predetermined period of time (block 1916). The drug dosing tool 110 graphically provides the user with a dosing schedule that includes a detectable dosage and concentration over time (block 1918).

After providing a dosing schedule, the drug dosing tool 110 in the illustrated embodiment determines if the user has selected a different dosing interval (block 1920). For example, the user can choose to view the dosing interval once-every-two-days and once-every-three-days. If the user provides a different interval, the exemplary drug dosing tool 110 returns to block 1916 and determines a new dosing schedule based on the selected interval.

However, if the user does not select a different interval, the exemplary drug dispensing tool 110 determines whether the user has selected a different target sag (block 1922). If the user selects a different sag, exemplary drug dispensing tool 110 determines the length of time during which the plasma therapeutic protein concentration is less than the sag level (block 1924). The drug dispensing tool 110 then provides the user with a graphical indication of this duration (block 1926). The drug dispensing tool 110 then determines if the user selects the dispensing tool 110 to determine a dosing schedule based on the newly provided target deflection (block 1928). If the user desires a dosage regimen based on the new deflection, exemplary routine 1900 returns to block 1916 and drug dispensing tool 110 determines the new regimen.

However, if the user does not wish to see the new dosage schedule, the exemplary drug dosing tool 110 provides a prompt to save the current dosage schedule (block 1930). In response to storing the dosing regimen, exemplary routine 1900 is completed. Alternatively, (eg, as selected by the user), exemplary routine 1900 returns to block 1902 to determine a dosing regimen for another patient and/or a dosing regimen for the same patient for another visit. to your healthcare provider.

An exemplary embodiment of a patient's activity level.

In fig. 21 and 22 are diagrams that demonstrate an exemplary embodiment in which the pharmacokinetic profile for a particular patient is adjusted based on activity level. In fig. 21 shows a data structure 2100 that contains the normal dosing regimen in the first column (ie, prophylactic (IU)), the activity level for the patient in the second column, and the dosing regimen adjustment in the third column. Each row in the data structure 2100 corresponds to a day of the week.

An estimated or approximate pharmacokinetic profile and corresponding normal dosing schedule is determined for a particular patient (eg, Hem A) using the procedures discussed above in conjunction with Figures 3 through 13. In this embodiment, the exemplary PK server 108 of FIG. 1 is designed with the ability to adjust the normal dosage regimen by

- 17 045259 based on the patient’s activities. This adjustment compensates for the increased risk of bleeding resulting from the increased activity level, which increases the need to maintain the patient's therapeutic plasma protein level above a higher threshold. As discussed above, the amount or concentration of therapeutic plasma protein in a patient depends on the patient's metabolism.

To compensate for these temporary increases in risk, the exemplary FC server 108 may request a weekly activity plan from the patient or health care provider. In other cases, the FC server 108 may receive the plan through an electronic calendar or activity log maintained by the patient. In this embodiment, activities are classified by intensity such that activities with lower intensities are separated from activities with relatively higher intensities. Intensity can also be based on the duration of the activity. FC server 108 may contain a data structure that associates various activities with an appropriate intensity level (with adjustments made for duration).

An exemplary PK server 108 uses the activities and associated intensities to adjust the patient's normal pharmacokinetic profile to determine a modified pharmacokinetic profile based on time periods of increased bleeding risk. PK server 108 then compares the modified pharmacokinetic profile to determine whether there is a period of time in which the calculated therapeutic plasma protein concentration falls below the target trough. If a period of time is determined in which the concentration falls below the target trough, then the PK server 108 determines when and how much additional dose of therapeutic plasma protein should be provided to the patient. In other cases, PK server 108 and/or instrument 110 may use a pharmacokinetic model 106 that includes sampled patients with an active lifestyle similar to the patient being managed.

In the example in FIG. 21 and 22, FC server 108 determines that the activity scheduled for Monday (eg, mountain biking) is relatively intense, increasing the need to maintain therapeutic plasma protein concentration above the target trough level (eg, 3%). Accordingly, PK server 108 determines that an additional dose of 1000 IU should be administered to the patient on Monday so that the therapeutic plasma protein concentration does not fall below 3%.

In fig. 22 is a plot 2200 of a modified pharmacokinetic profile based on temporal changes in bleeding risk associated with activity. Graph 2200 shows that before the first Tuesday (before administration of the additional dose), the patient's plasma therapeutic protein concentration falls below 3%. Schedule 2200 also shows that on the Monday before the second Tuesday, 1000 IU is provided to the patient. This additional dose causes the therapeutic plasma protein concentration to be maintained above the target trough of 3%. Thus, the exemplary PK server 108 reduces the chance of bleeding for relatively active patients.

An embodiment for comparing therapeutic plasma proteins.

An exemplary model generator 102, PK server 108, and drug dosing tool 110 are described in conjunction with defining a dosing regimen for one particular type of therapeutic plasma protein. However, in some examples, the model generator 102 may generate pharmacokinetic models for multiple types or brands of therapeutic plasma proteins. This allows, for example, a user (eg, a sales agent) to compare how concentrations of different therapeutic plasma proteins vary for the same patient for the same or different dosing intervals.

For example, the user may provide the tool 110 with patient information. Patient information is incorporated by tool 110 into a first pharmacokinetic model for a first brand of therapeutic plasma protein and a second pharmacokinetic model for a second brand of therapeutic plasma protein. The user may then enter into the instrument 110 a prescribed dosing regimen for the first therapeutic plasma protein and a prescribed dosing regimen for the second therapeutic plasma protein, which causes the instrument 110 to simultaneously display in the user interface the concentration of the first therapeutic plasma protein and the second therapeutic plasma protein over a period of time for the patient. . The exemplary tool 110 may also allow dosing intervals and/or doses to be modified (to the extent permitted or recommended by the manufacturer of the therapeutic plasma protein) to show how changes affect concentration.

In particular, the user may use the tool 110 to demonstrate that the first brand therapeutic plasma protein can be provided at three-day dosing intervals at a dose of 2600 IU while remaining above the target 3% deflection between doses. When compared, tool 110 indicates that a second brand of therapeutic plasma protein should be provided every two days at a dose of 2000 IU to remain above the same 3% target deflection. In this case, the first brand of therapeutic plasma protein may represent a better alternative to administer to the patient to reduce the required number of infusions per week while still keeping the patient safe from bleeding.

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Treatment option.

As discussed above, the exemplary drug dosing tool 110 and/or PK server 108 determines the amount of therapeutic plasma protein (eg, coagulation factor VIII) to administer to a patient. To administer a therapeutic plasma protein to a patient, in one aspect, the therapeutic plasma protein comprises one or more pharmaceutically acceptable carriers. The phrase pharmaceutically or pharmacologically acceptable refers to molecular entities and compositions that are stable, inhibit protein degradation such as aggregation and degradation products, and, in addition, do not cause allergic or other adverse reactions when administered using routes well known in the art . Pharmaceutically acceptable carriers include any and all clinically useful solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.

Pharmaceutical formulations are administered orally, topically, transdermally, parenterally, by inhalation spray, vaginally, rectally or by intracranial injection. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intracisternal injection or infusion routes. Administration by intravenous, intradermal, intramuscular, intramammary, intraperitoneal, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a specific site is also contemplated. In general, the compositions are substantially free of pyrogens as well as other impurities that may be harmful to the recipient.

Single or multiple administrations of the therapeutic plasma protein are administered using dose levels and patterns selected by the healthcare provider. As discussed, the dosing regimen for a therapeutic plasma protein is based on various patient characteristics, including age, sex, body weight, condition, activity level, diet, etc. The dosage regimen may also be based on the type of disease being treated, the severity and course of the disease, the preventive or therapeutic purposes of administering the therapeutic plasma protein, previous therapy, the patient's clinical history and response to the therapeutic plasma protein, and at the discretion of the healthcare provider. As an example, a typical dose of recombinant therapeutic plasma protein coagulation factor FVIII is approximately 30 IU/kg to 50 IU/kg.

In one embodiment, the therapeutic plasma protein coagulation factor FVIII can be administered via an initial bolus followed by a continuous infusion to maintain therapeutic levels of the therapeutic plasma protein in the circulation. In another embodiment, the inventive compound may be administered as a single dose. Those of ordinary skill in the art will readily optimize effective dosages and schedules of administration as determined by good medical practice and the clinical condition of the individual patient in conjunction with the results provided by example tool 110. Dosing frequency may depend on the pharmacokinetic parameters of the agents and the route of administration. The final dosing regimen is determined by the health care provider, taking into account various factors that modify the effect of drugs, for example, the specific activity of the drug, the severity of the lesion and the susceptibility of the patient, the age, condition, body weight, sex and diet of the patient, the severity of any infection, time administration and other clinical factors.

Preferably, the effective dose of therapeutic plasma protein is 15-85 IU/kg (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,

47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 62, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,

77, 78, 79, 80, 81, 82, 83, 84 or 85 IU/kg) and the dosing interval is once every 1-5, 2-5, 35, 3-6, 3, 4, 5, 6. 7 or 8 or more days or three times a week or no more than three times a week.

Additional therapeutic doses that can be used are from about 10 to about 150 IU/kg, more specifically about 100-110, 110-120, 120-130, 130-140, 140-150 IU/kg, and more specifically about 110 , 115, 120, 125, 130, 135, 140, 145 or 150 IU/kg. The dose should be high enough to feel effective, but not too high to avoid severe side effects. This therapeutic window is different for each patient, taking into account environmental and genetic factors.

Relationship between patient and treatment-related variables, including mean Cmax, time below target deflection, and time spent above a given threshold, such as 5, 10, 20, 30, and 40% of the patient's therapeutic plasma protein concentration, and the risk of bleeding during prophylaxis represent indicators that can be used to optimize the dosing regimen. Thus, individualized regimens with hemostatically effective non-hemophilic FVIII ranges and increased prophylactic efficacy are created and implemented. In various embodiments, annual bleeding rates (ABR) are reduced by at least 50, 60, 70, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 , 95, 96, 97, 98 or 99%, for example, when following a PK-targeted dosing regimen as described above, compared to an on-demand dosing regimen.

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Increased time with therapeutic plasma protein concentrations below 1 IU/dL is associated with increased total hemorrhage and hemarthrosis in patients with severe hemophilia A treated with conventional prophylactic regimens. Target deflection levels at >1% above baseline using PK-guided dosing at 72-hour intervals have been demonstrated to be an effective treatment strategy. Although targeting FVIII deflection at >1% above baseline is generally effective, this strategy alone may not be appropriate for all patients, particularly those who have recently had episodes of high ABR on on-demand therapy. Such patients may require alternative dosing regimens that contain higher doses and/or shorter dosing intervals to achieve higher troughs and/or more frequent peaks in therapeutic plasma protein concentrations.

In one embodiment, patients using a PK-guided dosing regimen have a median ABR of 2.0 (range 0-17.1), representing a 96% reduction in ABR relative to on-demand therapy. Individual half-life of therapeutic plasma FVIII protein (median: 11.7 hours; range: 7.3-30.7; IQR: 10.1-13.6; 5-95% percentiles: 7.7-21.4), and consequently, therapeutic plasma protein FVIII dose/infusion (median 41.3 (IU/kg), range 18.9–84.9) varied widely in the study cohort. This makes it possible to study the role of treatment-related and patient-related variables other than therapeutic plasma protein FVIII deflections in achieving low ABRs in patients using individualized regimens.

Data from patients prescribed PK-guided dosing given every third day (n=34) were studied. The mean Cmax for these patients was estimated using each patient's individual IVR values and their mean dose per prophylactic infusion. Therapeutic plasma protein concentration and time spent above 5, 10, 20, 30, or 40% therapeutic plasma FVIII protein levels (i.e., in the hemostatically effective non-hemophilic range) in each patient were extrapolated using parameters from individual PK profiles and actual infusion records . A negative binomial multivariate regression model was used for analysis using age and BMI as covariates.

Estimates of mean Cmax ranged from 24.3 to 167.5% (median 70.9%) in patients with PK-guided dosing using a QD infusion plan. As shown in graph 2300 in FIG. 23 observed a significant relationship between lower Cmax and increased risk of bleeding. In fig. 24 is a table 2400 that provides the average Cmax and bleeding risk. Time spent above 20% therapeutic plasma protein FVIII concentration (joint bleeding only), time spent above 30% therapeutic plasma protein FVIII concentration, and time spent above 40% therapeutic plasma protein concentration showed a significant relationship with lower ABR. In fig. 25 is a plot of the 2500 percent of total time spent above 30% therapeutic plasma FVIII protein concentration as a function of bleeding risk. In fig. 26 presents a table of 2600 time spent in the non-hemophilic range, depending on the risk of bleeding.

Similar significant relationships were found for all tested plasma therapeutic protein concentration variables (eg, above 5, 10 and 20%). However, the coefficient variables decreased with increasing mean therapeutic plasma protein concentrations over the course of a week. In fig. 27 is a graph plotting 2700 mean therapeutic plasma protein concentrations over a period of one week (AUC) versus bleeding rates over a period of one year. In fig. 28 is a table 2800 that shows average therapeutic plasma protein concentrations over a week in relation to the patient's bleeding risk. As shown in FIG. 29, all variables mean Cmax, time above % and weekly AUC were strongly correlated.

A significant reduction in ABR during prophylaxis was observed in every patient. However, many patients with higher ABRs on prophylaxis appeared to have more bleeding episodes during the previous on-demand period and had a lower % reduction in ABR on prophylaxis, as shown in plot 3000 of FIG. 30. These results demonstrate a relationship between higher Cmax values and/or time spent in the hemostatically effective non-hemophilic FVIII range and better prophylactic efficacy in patients with PK-guided dosing given every third day. Conversely, increasing time spent in the lower therapeutic plasma protein FVIII range increased the risk of bleeding. Although targeting therapeutic plasma FVIII protein trough >1% above baseline is generally effective, this strategy alone may not be appropriate for all patients, particularly those who have recently experienced high ABRs on on-demand therapy. These patients may require alternative dosing regimens involving higher doses and/or shorter dosing intervals to achieve higher troughs and/or more frequent peaks. CPU

A detailed block diagram of the electrical systems of an exemplary computing device (eg, model generator 102, PC server 108, and/or client device 112) is illustrated in FIG. 31. In this example, devices 102, 108 and/or 112 include a main unit 3102, which preferably contains one or more processors 3104 in communication communication with the

- 20 045259 address/data bus 3106 with one or more memory devices 3108, other computer circuitry 3110, and one or more interface circuitry 3112. Processor 3104 may be any suitable processor, such as a microprocessor from the INTEL PENTIUM® or CORE™ family of microprocessors . Memory 3108 preferably includes volatile memory and non-volatile memory. Preferably, memory 3108 stores a software program that interacts with other devices in environment 100, as described above. This program may be executed by the processor 3104 in any suitable manner. In an exemplary embodiment, memory 3108 may be part of a cloud such that cloud computing may be used on devices 102, 108 and/or 112. Memory 3108 may also store digital data reflecting documents, files, programs, web pages, patient samples, pharmacokinetic models, patient pharmacokinetic profiles, etc., extracted from (or downloaded through) devices 102, 108 and/or 112.

Exemplary memory devices 3108 store software instructions 3123, patient samples/pharmacokinetic models 3124, application interfaces 3126, user interface features, permissions, protocols, identification codes, content information, registration information, event and/or configuration information. Memory devices 3108 may also store information 3128 about network or system interface attributes, permissions, protocols, configurations, and/or preferences for use on devices 102, 108, and/or 112. It should be appreciated that many other data fields and records may be stored in the memory device 3108 in order to facilitate the implementation of the methods and apparatus described herein. Additionally, it should be appreciated that any type of suitable data structure (e.g., flat file data structure, relational database, tree data structure, etc.) may be used to facilitate the implementation of the methods and apparatus described herein. document.

Interface circuit 3112 may be implemented using any suitable interface standard, such as an Ethernet interface and/or a Universal Serial Bus (USB) interface. One or more input devices 3114 may be coupled to interface circuitry 3112 to input data and commands to the main unit 3102. For example, input device 3114 may be a keyboard, mouse, touch screen, trackpad, trackball, isopoint, image sensor, pattern recognition , bar code scanner, microphone and/or speech or voice recognition system.

One or more displays, printers, speakers, and/or other output devices 3116 may also be coupled to the main unit 3102 via interface circuitry 3112. The display may be a cathode ray tube (CRT), liquid crystal display (LCD), or some other display type. The display generates a visual display generated during operation of the device 102, 108 and/or 112. For example, the display may provide a user interface and may display one or more web pages received from the device 102, 108 and/or 112. The user interface may include request human input from the user of devices 102, 108 and/or 112, including links, buttons, bookmarks, check-in buttons, thumbnails, text fields, drop-down boxes, etc., and may provide various outputs in response to user input, such such as text, static images, video, audio and animation.

One or more storage devices 3118 may also be coupled to the main unit 3102 via interface circuitry 3112. For example, a hard drive, CD drive, DVD drive, and/or other storage devices may be coupled to the main unit 3102. The storage devices 3118 may store any type of data such as identifiers, identification codes, registration information, patient samples, patient information, pharmacokinetic models, patient pharmacokinetic profiles, treatment regimens, statistical data, safety data, etc., which can be used on devices 102, 108 and/or 112.

The computing device 102, 108 and/or 112 may also communicate with other network devices 3120 through a connection over a network 3121 (e.g., the Internet) or a wireless transceiver 3122 connected to the network 3121. Network devices 3120 may include one or more servers that can used to store certain types of data and, in particular, large volumes of data that can be stored in one or more data repositories. The server can process or manage any type of data, including databases, programs, files, libraries, identifiers, identification codes, registration information, content information, patient samples, patient information, pharmacokinetic models, patient pharmacokinetic profiles, treatment regimens, statistics data, security data, etc. The server can store and execute various applications related to receiving, transmitting, processing and storing large amounts of data. It should be appreciated that various configurations of one or more servers may be used to support, operate, or enable devices 102, 108, and/or 112 of environment 100. For example, various entities, including FC server 108 operators, hospital systems, patients, drug manufacturers, service providers, etc., can power the servers. Also defined

Claims (17)

This data may be stored on one of the devices 102, 108 and/or 112, which are also stored on a server, either temporarily or permanently, such as in memory 3108 or storage device 3118. A network connection can refer to any type of network connection, such as an Ethernet connection , digital subscriber line (DSL), telephone line, coaxial cable, wireless connection, etc. Access to devices 102, 108 and/or 112 can be controlled using suitable security software or security measures. Individual third party client or consumer access may be determined by device 102, 108 and/or 112 and limited to certain data and/or activities. Accordingly, users of environment 100 may be required to register using one or more computing devices 102, 108 and/or 112. Conclusion. It should be appreciated that all disclosed methods and procedures described herein may be implemented using one or more computer programs or components. These components may be provided as a series of computer instructions in any standard computer-readable medium, including RAM, ROM, flash memory, magnetic or optical disks, optical memory, or other storage media. The instructions may be executable by a processor that, when executing a series of computer instructions, performs or assists in the execution of all or a portion of the disclosed methods and procedures. It should be understood that various changes and modifications to the exemplary embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its intended advantages. Therefore, the appended claims are intended to cover such changes and modifications. CLAIM 1. A method of providing a therapeutic plasma protein dosing regimen, which includes: determining, by the processor, an estimated pharmacokinetic profile of the patient using a Bayesian model of the pharmacokinetic profiles of the patients from whom the samples were taken; determining, by the processor, a first dosing regimen for a first predetermined dosing interval comprising (i) a first dose and (ii) a first therapeutic plasma protein level in a patient as it changes over time, based on at least a calculated pharmacokinetic profile; displaying a first dosing schedule on the client device, wherein upon receiving a selection indicating a first dosing interval, the processor determines a first dose of therapeutic plasma protein and a first level of therapeutic plasma protein over time such that the therapeutic plasma protein level of the patient does not fall over the period of time below the target deflection. 2. The method according to claim 1, wherein the method additionally contains: obtaining a selection of a first predetermined concentration level above the target deflection; obtaining a selection of a second predetermined concentration level above the target deflection and below the first predetermined concentration level; determining a first duration of time during which a first therapeutic plasma protein level in the patient is above a first predetermined concentration level; and determining a second duration of time during which the patient's first therapeutic plasma protein level is below a second predetermined concentration level; and displaying a graphical representation of the first time duration and the second time duration together with the display of the first dosage regimen. 3. The method of claim 2, wherein the selection of the first predetermined concentration level and the second predetermined concentration level is obtained using a scroll bar displayed in a graphical user interface that displays the first dosage mode. 4. The method of claim 1, wherein said calculated pharmacokinetic profile is based on at least one of the patient's body weight or age. 5. The method of claim 1, further comprising adjusting, by the processor, the patient's calculated pharmacokinetic profile following the patient's previous treatment. 6. The method of claim 1, further comprising determining, by the processor, a second dosing regimen for a second predetermined dosing interval comprising (i) a second dose and (ii) a second therapeutic plasma protein level in the patient, over a period of time, based on at least the extent of the calculated pharmacokinetic profile; and in response to administration, changing at least one of a first therapeutic plasma protein level, a first dose, or a predetermined target deflection. 7. The method of claim 6, further comprising displaying the first dosage schedule and the second - 22 045259 dosage schedules on the client device such that the first dosage schedule is displayed in combination with the second dosage schedule. 8. The method according to claim 6, characterized in that the first specified dosing interval is 48 hours, and the second specified dosing interval is 72 hours. 9. The method according to claim 1, in which the specified target deflection is less than 20%. 10. The method of claim 1, wherein the Bayesian model comprises a two-compartment model that has a first compartment corresponding to the time to metabolize the therapeutic plasma protein, and a second compartment corresponding to the dose to achieve a certain amount of therapeutic plasma protein in the patient. 11. A machine-readable device that has instructions stored therein that are capable, when executed, of causing the machine to at least: prompt the user to enter at least one of the patient's weight or age; use a Bayesian model of the pharmacokinetic profiles of patients sampled to determine an approximate pharmacokinetic profile of the patient based on the Bayesian model, and at least one of the input values for the patient's weight or age, wherein the Bayesian model includes (i) plasma therapeutic protein clearance and (ii) a volume of distribution relationship for a therapeutic plasma protein based on at least one of the age or body weight of the patient; adjust the patient's approximate pharmacokinetic profile based on one or more of the patient's prior treatments; determine a dosing regimen for a patient based on the patient's approximate pharmacokinetic profile, the dosing regimen including a dose and a dosing interval; modify the dosing regimen in response to receiving a different dosing interval for dosing to the patient to create a modified dosing regimen; provide the user with a time-varying therapeutic plasma protein level based on the dosing schedule and the modified dosing schedule; and determine, based on the specified dosing regimen or a modified dosing regimen, a target dose and therapeutic plasma protein level over time such that the therapeutic plasma protein level does not fall below a predetermined target deflection. 12. The machine-readable device of claim 11, which has instructions stored therein that are configured, when executed, to cause the machine to at least: determine a first dosing schedule for a two-day dosing interval; determine a second dosing schedule for a three-day dosing interval; cause the first dosage schedule to be displayed in conjunction with the second dosage schedule. 13. The machine-readable device of claim 11, which further comprises instructions stored therein that are configured, when executed, to cause the machine to: display a graphical representation of a time-varying amount of therapeutic plasma protein in a patient, including at least one of indicating a dose therapeutic plasma protein provided to the patient. 14. The machine-readable device of claim 11, which has instructions stored therein that are configured, when executed, to cause the machine to at least: display a graphical feature that allows the user to change at least one of: (i) minimum level of therapeutic plasma protein; (ii) the dosing interval; or (iii) the dose of therapeutic plasma protein. 15. The machine-readable device of claim 14, which has instructions stored therein that are configured, when executed, to cause the machine to modify the dosage regimen in response to receiving a change in any one of the indicators (i); (ii) or (iii). 16. The machine-readable device of claim 15, which has instructions stored therein that are configured, when executed, to cause the machine to: display a graphical representation of a change in the amount of therapeutic plasma protein in a patient over time based on a change in any one of the indicators ( i); (ii) or (iii). 17. The machine-readable device of claim 15, which further has instructions stored therein that are configured, when executed, to instruct the machine to: accept a minimum level of therapeutic plasma protein and display the time during which the level of therapeutic plasma protein remains below the minimum level therapeutic plasma protein. -