Drug Dosage Determination Device and Method

Abstract

This application relates to devices and methods for determining a dosage regimen for a drug in a subject. Determining a dosage regimen for a subject includes calculating the amount of drug to be administered to the subject for each base period, determining combinations of at least two dosage forms that can be used to administer the amount of drug, and evaluating the combinations against at least two different criteria. The methods of the invention find use in selecting dosage regimens for drugs available in multiple dosage forms, particularly drugs that are administered routinely over an extended period of time, such as in the routine prophylaxis of hemophilia.

Description

[Technical field]

[0001] The present invention relates to a computer-implemented method for determining a dosing regimen for a drug in a subject, and to a computing device for carrying out said method. The method and device of the present invention are applied to determining a dosing regimen for a drug that is available in multiple dosage forms with different amounts and / or concentrations of the drug, particularly for a drug that is to be administered periodically over an extended period of time for prophylactic and / or therapeutic purposes. [Background technology]

[0002] Many illnesses and diseases require regular administration of drugs for therapeutic and / or preventive purposes. Usually, through clinical trials, a safe and efficient loading of the drug is determined, along with the drug amount and administration interval that can be used to achieve the drug loading. These may further depend on one or more parameters related to the patient, such as the patient's weight, age, sex, etc. There may be various combinations of drug amount and administration interval that may meet the conditions set by the clinical trial. Furthermore, the drug may be made available in several different dosage forms to increase the flexibility of administration.

[0003] It is usually left to the medical practitioner to select a dosage regimen that meets the conditions set in the clinical trial and is suitable for a particular patient. This selection can be a complicated task, and therefore the selection of a particular regimen may cause avoidable inconvenience and / or cost to the patient. These may be particularly problematic for expensive products that are administered over a long period of time and / or when the administration is relatively complicated (e.g., by injection). Thus, there is an unmet need for a means to determine a dosage regimen for a patient where it is not easy to choose between multiple possibilities. Simple tools exist to calculate the amount of drug to be administered to a patient based on the patient's weight and the relationship between weight and the amount of drug to be administered. These tools reduce the risk of errors in calculating the amount of drug to be administered. Nevertheless, considering the large practical impact of selecting a dosage regimen for a patient, there is still a need in the art for more efficient and accurate means to determine a patient's dosage regimen. Summary of the Invention

[0004] The inventors have developed a new device and method for determining a drug dosage regimen for a subject, where the drug is available in at least two different dosage forms and the choice of dosage regimen affects at least two different criteria. The method and device originates from the discovery that suboptimal dosage regimens may be regularly chosen by medical professionals in such situations, and the complexity of the problem of choosing an appropriate dosage regimen may far exceed the intelligence of the medical professionals tasked with this choice. The inventors have determined that this discovery can be at least partially explained by the observation that there may be an exponential explosion in the number of possible dosage regimens that fall within the limits set by clinical trials, and that the choice of combinations may produce results that are not intuitive for a set of criteria of relevance to patients.

[0005] Accordingly, a first aspect of the present invention provides a computing device including a processor and a memory, the computing device being configured to receive a value of at least one parameter associated with a subject, and to determine an amount (A) of a drug to be administered to the subject per base period (t) based at least in part on the value of the at least one parameter associated with the subject. t determining the amount of drug to be administered to the subject (A), wherein the drug is available in at least two different dosage forms (D1, D2) that differ in total amount of drug and / or drug concentration in the dose of the dosage form; t All the minimum combinations of at least two different dosage forms that can be used to achieve the t [D1, D2, D1D2]), where the minimum combination is the amount of drug (A [D1, D2, D1D2]) by using the minimum number of doses of each dosage form in the dosage form combination (D1, D2, D1D2). t ) or the amount of drug (A t ), calculating the smallest combination that satisfies at least the first criterion and the second criterion (A t The present invention provides a computing device configured to determine a drug dosing regimen for a subject by selecting a subset of combinations [D1, D2, D1D2] and outputting the selected subset of combinations as an optimal dosing regimen for the subject.

[0006] The inventors have determined that multiple combinations of at least two dosage forms may often be used to administer a certain amount of drug, and that not all such combinations are considered according to the prior art.The inventors have further determined that calculating all possible combinations useful for evaluation can be achieved by defining the concept of a minimal combination and calculating all such minimal combinations for automatic formula evaluation and selection.

[0007] The amount of drug to be administered to the subject (A t All the minimum combinations of at least two different dosage forms that can be used to achieve the tCalculating [D1, D2, D1D2]) involves (a) calculating the amount of drug (A t (b) starting with each dosage form, calculate the amount of drug (A) to be administered to the subject in combination with an increment number of doses of the starting dosage form that is less than the number obtained in (a) for the starting dosage form. t If more than two dosage forms can be used, calculating all the minimum combinations may include (c) calculating the amount of drug (A) to be administered to the subject starting with each dosage form and combining it in sequence with the dose increment of the starting dosage form and the dose increment of each of the other dosage forms. t The method may further include calculating the minimum number of doses of each of the other dosage forms required to achieve the total dose.

[0008] Also provided herein is a computer-implemented method for determining a dosing regimen for a drug to a subject, the method comprising receiving a value of at least one parameter associated with the subject, and determining an amount (A) of the drug to be administered to the subject per base period (t) based at least in part on the value of the at least one parameter associated with the subject. t ), wherein the drug is available in at least two different dosage forms (D1, D2) that differ in total amount of drug and / or drug concentration in the dose of the dosage form; and determining the amount of drug to be administered to the subject (A t All the minimum combinations of at least two different dosage forms that can be used to achieve the t [D1, D2, D1D2]), where the minimum combination is the amount of drug (A) to be administered to the subject by using the minimum number of doses of each dosage form in the dosage form combination (D1, D2, D1D2). t ) or the amount of drug (A t ) and calculating the smallest combination that satisfies at least the first criterion and the second criterion (A t[D1, D2, D1D2]) and outputting the selected subset of combinations as an optimal dosing regimen for the subject.

[0009] Any features of the methods described herein are equally applicable to computing devices configured to perform those methods. Similarly, any features described herein in relation to a computing device may be applied to the methods described herein that a computing device is configured to perform.

[0010] In the context of this disclosure, a drug is one or more active ingredients that are administered to a subject for therapeutic or prophylactic purposes. A dosage form is a pharmaceutical formulation of a drug, and each dose of the dosage form contains a certain amount of the drug and, optionally, an excipient. When an excipient is included, the dosage form may vary by the concentration of the drug in the dosage form. Whether or not an excipient is included in the dosage form, the dosage form may vary by the total amount of the drug in each dose of the dosage form. The dose of the dosage form may be a single pill, tablet, capsule, vial of solution, or any other individual dose that is prescribed according to the dosage form.

[0011] The devices and methods of the present disclosure may be particularly advantageous when at least one of the dosage forms is a single-use dosage form. A single-use dosage form is a dosage form in which each dose can only be used for a single administration. When a dose of a single-use dosage form is at least partially consumed as part of a single administration, the remaining dose is discarded and cannot be used for a subsequent administration. For example, a dose of a single-use dosage form may be a vial of solution containing a sterile solution, or any other dosage form that is sterilized prior to consumption, where consumption of a portion of the dose compromises the sterility of the remaining dose. Similarly, a single-use dosage form may be any dosage form in which consumption of a portion of the dosage form compromises a property of the remaining dose. The property may relate to safety (e.g., contamination, creation of derivative forms of the drug, etc.) or efficacy (e.g., degradation of the drug). For example, the dosage form may contain components that oxidize or decompose upon exposure to air, and the remaining portion of the dose may be exposed to air during or after consumption of the portion of the dose. If at least one of the dosage forms is a single-use dosage form, selecting which combination of dosage forms to use can be particularly important since different combinations can be associated with different waste volumes (the residual portion of the dose remaining after partial consumption).

[0012] The agent may be a biopharmaceutical. In an embodiment, the agent is a polypeptide or protein. For example, the agent may consist of or include an antibody. In an embodiment, the agent is an antibody as described in EP2644698B1, which is incorporated herein by reference. In an embodiment, the agent is emicizumab (commercially available as HEMLIBRA®). The devices and methods of the present disclosure may be particularly advantageous in the context of biopharmaceuticals, as biopharmaceuticals may be expensive and difficult to manufacture. Furthermore, biopharmaceuticals may have a relatively short shelf life and / or may only be available as single-use dosage forms. As such, optimization of administration parameters may be particularly important for these types of products.

[0013] The device and method of the present disclosure are particularly advantageous when the drug is available in at least two different dosage forms (D1, D2) that differ in the drug concentration in the dose of the dosage forms. Indeed, in such cases, it may be particularly difficult to select the appropriate combination of dosage forms without the use of the present invention. Furthermore, the device and method of the present disclosure may be particularly advantageous when the drug is administered at regular intervals over an extended period of time. Indeed, when the drug is administered over an extended period of time, it is particularly important to reduce as much as possible the inconvenience and disadvantages associated with the administration of the drug. Extended period of time may refer to a period during which multiple administrations of the drug are required to achieve a therapeutic or prophylactic effect associated with the drug. For example, the treatment of a prophylactic effect associated with the drug may require a minimum concentration of the drug to be maintained in the patient (e.g., on the plasma) for a predetermined period of time, necessitating multiple separate administrations of the drug over said period of time. In some cases, the period of time may be the subject's lifetime. In an embodiment, the drug is administered for the routine prevention of a disease or disorder. In an embodiment, the disease is hemophilia and / or a bleeding disorder. Furthermore, the subject may be a human or animal subject. Typically, the subject may be a human subject.

[0014] The disclosed method and device is not limited with respect to the number of different dosage forms considered in the steps described herein, provided that multiple dosage forms (i.e., at least two dosage forms) are used. Specifically, the drug may be available in three dosage forms (D1, D2, D3), four dosage forms (D1, D2, D3, D), five dosage forms (D1, D2, D3, D4, D5), or six dosage forms (D1, D2, D3, D4, D5, D6). At least two of the two, three, four, five, or six dosage forms may differ from each other by the drug concentration in the dosage form dose.

[0015] In the context of this disclosure, a subset may not be a strict (true) subset, but instead may include all combinations in the set, for example, this may occur when all combinations in the set are equivalent when evaluated against the criteria used for selection.

[0016] A combination that satisfies at least the first and second criteria (A t Selecting a subset of the combination (A [D1, D2, D1D2]) according to the first criterion t [D1, D2, D1D2]) and selecting a second subset of combinations from the first subset according to a second criterion different from the first criterion. Thus, outputting the selected subset of combinations as the optimal dosing regimen for the subject may include outputting the last selected subset of combinations as the optimal dosing regimen for the subject. Furthermore, selecting the subset of combinations according to a criterion may include ranking the combinations according to the criterion and selecting all combinations with the highest rank. An embodiment based on successive selection of subsets (i.e., hierarchical or nested application of criteria) is particularly simple and efficient. Furthermore, in an embodiment using ranking to select a subset of combinations, it may be possible to track combinations that have not been selected, since the ranked list of combinations created in the first selection can be used as a starting point for the second selection, for example by ranking the combinations according to the second criterion within the rank according to the first criterion.

[0017] The methods and devices of the present disclosure are not limited with respect to the number of additional criteria used in selecting a successive subset of combinations. Thus, combinations that satisfy at least the first and second criteria (A tThe selection of the subset of [D1, D2, D1D2]) may include the selection of a subset of combinations that satisfy the first, second, and third criteria, the first, second, third, and fourth criteria, etc. Specifically, the computing device may be further configured to select a third (fourth, fifth, etc.) subset of combinations from the second (third, fourth, etc.) subset according to a third (fourth, fifth, etc.) criterion. In such a case, the last selected subset output will be the third (fourth, fifth, etc., respectively) subset. Similarly, the method of the present disclosure may include the further step of selecting a subset from the previously selected subsets according to a further criterion and outputting the last subset of those successively selected subsets. In the context of the present disclosure, the second criterion is a criterion different from the first criterion, the third criterion is a criterion different from the first criterion and the second criterion, and so on.

[0018] In an embodiment, the amount of drug to be administered per basic period (t) as a function of one or more parameters related to the subject is provided as an input to the method described herein. This input may be stored in memory prior to initiation of the method and retrieved or received by the processor as a value of at least one parameter related to the subject. Furthermore, this input may be provided as one or more mathematical relations linking the one or more parameters related to the subject to the amount of drug to be administered per basic period (t). The at least one parameter may include the subject's body weight, and the amount of drug to be administered to the subject per basic period (t) (A tDetermining the amount of drug (A) to be administered to a subject per basic period (t) based at least in part on a value received for the subject's body weight. Relationships between the amount of drug to be administered per basic period (e.g., per day, week, or month) and the subject's body weight may be provided as an output of a clinical trial, and these relationships may be used by the method to automatically determine the amount of drug to be administered to a subject. For example, the amount of drug per kg (patient's body weight) per basic period may be provided as an input to the method described herein. Thus, the amount of drug (A) to be administered to a subject per basic period (t) based at least in part on the subject's body weight may be determined. t Determining t may include multiplying the subject's weight by a preset (i.e., predetermined) amount of drug per basic period (t). Furthermore, multiple such preset amounts of drug per kg per basic period may be provided as input to the method, with the selection of such amount depending on the value of another parameter related to the patient (e.g., gender, age, severity / stage of disease, etc.). In an embodiment, at least one parameter is the subject's weight, and one or more parameters related to the subject are further received. These may be selected from the group including the subject's age, the subject's gender, a disease-related parameter, and a treatment-related parameter. The disease-related parameter may be an indication of disease severity, identification, stage of disease, co-occurrence of another disease or disorder, etc. The treatment-related parameter may be an indication of another treatment that the subject is or has been receiving. Thus, the computing device may be configured to select a relationship (e.g., from a set of relationships stored in memory) between the subject's weight and the amount of drug to be administered per basic period based on the received value of at least one parameter, and to use the received value of the subject's weight to calculate the amount of drug to be administered per basic period (t) according to the selected relationship. For example, the computing device may be configured to calculate the amount of drug (A tDetermining the amount (t) of the drug per selected basic period (t) may include the processor retrieving from a memory a pre-set amount of the drug per selected basic period (t) in response to a value of at least one further parameter associated with the subject, and multiplying the subject's body weight by the pre-set amount of the drug per selected basic period (t).

[0019] The inventors further recognized that in some situations, the appropriate dosing regimen may be based on one of a number of time intervals between administrations. In these situations, further consideration must be given to the possibility of further increasing the complexity of the problem, as well as further increasing the possibility of identifying a particularly advantageous dosing regimen. To accommodate and exploit this possibility, the computing device may determine the amount of drug (A) to be administered to the subject for one or more multiples (n) of a base period (t). n1t , A n2t ) is calculated, and the amount of drug (A n1t , A n2t The method may be further configured to calculate all minimal combinations of at least two different dosage forms that may be used to achieve the desired dosage.

[0020] In an embodiment, one or more suitable intervals between administrations (such as, for example, a maximum suitable interval between administrations) are provided as input to the method described herein. This input may be stored in memory prior to the start of the method and retrieved or received by the processor as a value of at least one parameter related to the subject. The one or more suitable intervals may be used to define another multiple (n) of the basic period (t) suitable for use in the method disclosed herein. For example, one or more amounts of the drug to be administered per kg per week may be provided in combination with a maximum suitable interval of 4 weeks. In an embodiment, the computing device is further configured to determine a multiple (n) of the basic period (t) that is a submultiple of the specific multiple (n) of the basic period (t), the specific multiple corresponding to a preset maximum interval between administrations. Advantageously, this means that the computing device may be able to automatically identify alternative dosage regimens that are within preset limits (such as, for example, limits that may have been previously set by clinical trials).

[0021] In an embodiment, the computing device is further configured to obtain one or more multiples (n) of the base period (t) by receiving the multiple (n) as a further parameter associated with the subject or by retrieving the multiple (n) from a memory. Similarly, the method described herein may further include obtaining one or more multiples (n) of the base period (t) by receiving the multiple (n) as a further parameter associated with the subject or by using one or more predefined multiples (n) of the base period (t). This may be particularly useful when for some reason (e.g., safety, regulatory, practical considerations related to administration, such as the availability of trained staff, etc.), strict adherence to the administration interval determined, for example, from a clinical trial, is recommended.

[0022] In some cases, a drug is administered to a subject in multiple phases that together form a treatment course, and the dosage regimen may differ between the multiple phases. In such cases, two potentially different dosage regimens need to be determined for each subject, which may further complicate the work of the medical practitioner and increase the risk of error or selection of a suboptimal dosage regimen. The devices and methods of the present disclosure may be able to advantageously handle these cases. For example, the drug may be administered according to a first dosage regimen during a first phase, which may be called a "loading phase". Following the loading phase, the drug may be administered according to a second dosage regimen, which may be called a "maintenance phase". A preset amount (A) of the drug to be administered to the subject per base period (t) may be determined by the patient's dosage regimen. t ) and / or one or more suitable intervals between administrations may vary between different phases. In embodiments, a computing device may be configured to perform each step of the method described herein for one or more of the phases that together form a course of treatment. For example, the computing device may determine the amount of drug (A) to be administered to a subject per base period (t). t ) and define another multiple (n) of the base period (t) to be used based on a pre-set value for the first phase (e.g., loading phase) and based on a pre-set value for the second phase (e.g., maintenance phase). The computer may be further configured to calculate all minimal combinations for the base period and any multiples (if applicable) and select a subset of combinations separately for each of the first phase and the second phase. The selected subsets may be output together or separately for each of the first phase and the second phase. Alternatively, the selection of the phase of treatment may be determined as an amount (A t ) and / or a value for an appropriate interval between doses may be received as input based on which a pre-set value for the appropriate interval between doses may be selected.

[0023] Some steps of the methods of the present disclosure (and corresponding steps that the devices of the present disclosure are configured to perform) may be performed prior to receiving a value of at least one parameter associated with the subject. For example, the amount of drug (A t , A nt ), and optionally the minimum combinations that can be used to achieve these amounts, may be pre-calculated (e.g., by a processor) (stored in memory) for a set of pre-defined values ​​of parameters associated with the subject. In some such embodiments, the computing device calculates the amount of drug (A) to be administered to the subject. t , A nt The computing device may be configured to calculate all minimal combinations of at least two different dosage forms that may be used to achieve each of the predetermined sets of doses (t) of the at least one parameter associated with the subject. Upon receiving a value for at least one parameter associated with the subject, the computing device may calculate an amount of drug (A) to be administered to the subject per base period (t) based at least in part on the received value. t ) and the amount of drug to be administered (A t , A nt ) the closest total amount of drug in the pre-calculated set (A t , A nt ) and the amount of the closest drug identified (A t , A nt Alternatively, the computing device may be further configured to select a subset of combinations from pre-calculated combinations that may be used to achieve the desired dose (A) of the drug to be administered to the subject per base period (t) based at least in part on a predetermined set of values ​​of at least one parameter (e.g., the subject's body weight, etc.). t ) and determining the amount of drug (A) determined from a predetermined set of values ​​for the at least one parameter. t , A ntThe computing device may be configured to calculate all minimal combinations of at least two different dosage forms that may be used to achieve each of the following: (A) The computing device may be configured to, upon receiving a value for at least one parameter associated with the subject, identify a closest value among a predetermined set of values ​​for the at least one parameter, and calculate an amount of drug (A) corresponding to the closest identified value. t Similarly, upon receiving a value for at least one parameter associated with the subject, the computing device may be further configured to select a subset of combinations from the pre-calculated combinations that may be used to achieve the total amount of drug to be administered (A t , A nt ) and calculate the amount of drug to be administered (A t , A nt ) in the pre-calculated set of t , A nt ) and the amount of the closest identified drug (A t , A nt The method may further be configured to select a subset of combinations from pre-computed combinations that may be used to achieve a recommendation for a user. Pre-computing combinations may allow for extensive automated and / or manual validation of combinations before using the combinations to generate recommendations for a user. Additionally, pre-computing combinations may increase the speed at which output is provided to a user upon receiving a request that includes a value for at least one parameter associated with the subject.

[0024] The term "user" as used herein refers to a user of the methods and devices of the present disclosure. The user may be the subject himself or herself, or may be a person who uses the methods and devices of the present disclosure to determine a dosage regimen for a subject. In the latter case, the user may be a medical professional.

[0025] In an alternative embodiment, upon receiving a value for at least one parameter associated with the subject, an amount of drug (A) to be administered to the subject per base period (t) is calculated. t ) and the amount of drug to be administered (At ) is performed. Calculating the combinations when information about the subject is received may not require making any assumptions about the value of the at least one parameter used, and may therefore provide greater flexibility and accuracy. For example, in an embodiment in which the at least one parameter includes the subject's weight, the exact weight may be used rather than the closest weight value in the set used to pre-calculate the combinations.

[0026] The selection of the subset of combinations may be performed separately for each of the base period (t) and the multiples (n) of the base period (t), or may be performed jointly for all of the base period (t) and the multiples (n) of the base period (t). If the selection is performed separately, outputting the (final) selected subset of combinations may include outputting the (final) selected subset of combinations for each of the base period (t) and the multiples (n) of the base period (t). In other words, a separate optimal dosing regimen may be provided for each of the different dosing intervals (t, and each of the multiples n of t) that have been considered. This may advantageously present the user with an optimal solution for each of the possible dosing intervals that the user may wish to use, and the user may then select the most convenient dosing interval with the knowledge that he or she is using the optimal regimen for that particular dosing interval. In some such embodiments, the computing device is configured to output an indication of which of the selected dosing regimens is optimal according to one of the criteria, preferably the first criterion, over the selected subset for each of the base periods (t) and multiples of the base periods (n). This may advantageously allow the user to select a convenient dosing interval based on his / her preferences, combined with knowledge of whether some dosing intervals may allow the user to select a more advantageous dosing regimen. For example, if multiple dosing intervals are possible, it may not be immediately obvious that some of these dosing intervals cannot be selected without compromising performance for one of the criteria that the user may be interested in. The method and device of the present disclosure may be able to address such situations by outputting the optimal dosing regimen for each dosing interval and flagging whether these "individually optimal" (i.e., individually optimal across the regimens for each dosing interval) dosing regimens are "globally optimal" (i.e., optimal across all regimens considered).

[0027] The selection result of the criterion used for any of the first, second, third, etc. selections may each be received as a value of one or more further parameters associated with the subject. For example, a criterion used as a first criterion may be received from a user. The second criterion and optionally subsequent criteria may be selected by the user in a similar manner, or a default value (such as a default criterion stored in memory) may be used. Furthermore, the default value used for each of the second criterion and subsequent criteria may be automatically selected based on the selection result received for the first criterion. Furthermore, the selection of the criterion may be from a set of predefined criteria. For example, the method may include providing a set of predefined criteria to a user, and receiving the selection result of one or more criteria from the predefined set as a value of a further parameter associated with the subject.

[0028] Selecting a subset of combinations that meet the first / second / third etc. criteria may include calculating a value of a parameter associated with each combination and selecting a combination that minimizes or maximizes the calculated parameter value. The combination that minimizes / maximizes the calculated parameter value may be a combination associated with the minimum / maximum value of the calculated parameter in the set of combinations from which the subset is selected. This selection may include some tolerance such that combinations associated with a parameter value that is within a predetermined range from the minimum / maximum value of the parameter in the set of combinations may be selected to be included in the subset that minimizes / maximizes the parameter value. For example, the parameter value associated with the combination may include a waste amount associated with the combination, a number of physical administration steps required to administer the combination, a number of physical preparation steps associated with administering the combination, or any combination or derivative of the above.

[0029] In an embodiment, the method further comprises determining the waste volume (W t [D1, D2, D1D2], W n1t [D1, D2, D1D2], W n2t[D1, D2, D1D2]) is the total amount of the drug in the combination of dosage forms and the amount of the drug to be administered to the subject (A t , A n1t , A n2t ) as the difference between the waste amount and the waste amount per period. The method may further include calculating the total waste amount as the waste amount per period. Calculating the total waste amount (waste amount per period) may include calculating the waste amount per base period t. This may be accomplished by dividing the waste amount of each combination by its corresponding multiple (n), where n=1 for the combination corresponding to the base period (t). In other embodiments, calculating the total waste amount (waste amount per period) includes calculating the total waste amount over the period corresponding to the least common multiple of the multiples (n). The waste amount associated with a dosage regimen may be a particularly useful parameter for calculations when a drug is expensive, difficult to obtain, and / or difficult to dispose of residuals. Furthermore, if some of the dosage forms differ by their concentrations, it may be particularly advantageous to track the waste amount with respect to the amount of drug. Indeed, in such cases, even if it were possible to determine the amount of dosage form being used according to each dosage regimen, it may not be immediately clear which dosage regimen is associated with the lowest waste amount. Furthermore, calculating the total waste (whether the base period or a common multiple of the different multiples n considered, the equivalent waste per period) can be particularly advantageous, since it allows the determination of the optimal dosing regimen for multiple administrations. This can be particularly advantageous for drugs that are administered over an extended period of time, which may not be immediately apparent from the parameters of a single administration. Thus, in an embodiment, one of the criteria used to select the subsets is applied to the value of the total waste (waste per period) associated with each combination, and the combination selected is the combination that minimizes this parameter.

[0030] Instead of or in addition to calculating the waste amount, the total number of physical dosing steps required for the administration of the combination may be calculated, which may be used as one of the criteria used to select a subset of combinations. Calculating the total number of physical dosing steps required for the administration of the combination may include calculating the minimum number of physical dosing steps that may be used to administer the combination and that satisfy one or more rules selected from a preset maximum amount of drug for each physical dosing step, a preset maximum amount of dosage form for each physical dosing step, and a restriction on combinations of dosage forms with different concentrations in a single physical dosing step. Furthermore, the rules regarding the preset amount of drug / dosage form for each physical dosing step may be applied in different ways depending on the accuracy required to administer a specific amount. For example, an amount specified with a specific accuracy may be associated with a preset maximum amount of drug / dosage form that is different from an amount specified with another lower specific accuracy. Each of these rules may be predetermined (e.g., stored in memory) or may be received as a further parameter associated with the subject. Furthermore, the selection of one or more such predefined rules may be based on the value of one or more parameters associated with the subject. For example, two or more predetermined maximum amounts of dosage forms for each physical administration step may be available, and the selection of one of these amounts may depend on parameters such as the subject's weight, the subject's age, disease-related parameters, etc. The number of physical administration steps required for the administration of a combination may be a particularly useful parameter to consider when the administration of the drug is difficult, painful, or inconvenient. Furthermore, the total number of physical administration steps required for the administration of a combination may not be immediately apparent from the combination, especially when multiple rules must be considered when determining the number of individual physical administration steps required for the administration of the combination. In such cases, the automated calculation of the total number of steps required for administration, and the comparison of combinations based thereon, may advantageously allow the selection of a combination that may have seemed intuitively unfavorable due to the complexity of factors that should be considered when administering the combination.Thus, in an embodiment, one of the criteria used to select the subset is applied to the value of the total number of physical administration steps associated with each combination, and the combination selected is the combination that minimizes this parameter.

[0031] The preset maximum amount of drug for each physical administration step may be specified as a weight of drug or a number of units of drug. The preset maximum amount of dosage form for each physical administration step may be specified as a weight of dosage form or a volume of dosage form. In embodiments, the dosage form is a liquid formulation. For example, the dosage form may be a solution, a suspension, or any other type of liquid formulation. A single physical administration step of a liquid formulation may be a single injection of a volume of the dosage form. In some embodiments, each single injection is a single injection of two preset maximum volumes (V 1 , V 2 In some embodiments, each single injection has a preset maximum volume selected from the group consisting of three preset maximum volumes (V 1 , V 2 , V 3 ), in some embodiments, the computing device is further configured to prioritize dosing regimens that do not combine single injections at different maximum volumes. For example, when calculating the number of physical administration steps associated with a combination, the computing device can associate with the combination the smallest possible number that does not use different maximum volumes. This can be useful to reduce the number of different syringes used. In embodiments, the single physical administration step can be a single ingestion of a volume of a dosage form that is a liquid formulation. In embodiments, the single physical administration step can be a unit of time required to administer a volume of a dosage form as a liquid formulation by intravenous means, for example using an infusion. In embodiments, the dosage form is a solid (e.g., tablet, powder, etc.) or encapsulated formulation. In some such embodiments, the single physical administration step can be the weight or volume of a dosage form, or a single ingestion of one or more capsules or tablets.

[0032] Instead of or in addition to calculating the amount of waste and / or the total number of physical dosing steps required for the administration of the combination, the total number of physical preparation steps required for the administration of the combination can be calculated. This can also be used as one of the criteria applied to select a subset of the combination. Calculating the total number of physical preparation steps required for the administration of the combination can include calculating the number of doses of each dosage form that constitutes the combination. The number of physical preparation steps can be proportional to the number of doses of each dosage form for each administration, where each dose must be extracted from its package and, optionally, placed in a form suitable for administration (e.g., drawn into a syringe for injection, poured into a container for ingestion, etc.). The total number of physical dosing steps required for the administration of the combination can be particularly useful in considering cases where administration requires preparation steps that are complex, error-prone, and / or waste-prone. For example, if the doses of the dosage form must be placed in a form suitable for administration by heating, injection, dilution, dissolution, etc., each such step can be associated with a risk of error, waste, contamination, etc. Furthermore, the number of preparation steps may not be identical to the number of administrations, since multiple doses of the dosage form may be suitable for administration in a combined form. As with the number of administration steps, the number of preparation steps and how they are compared between combinations may not be intuitive.Therefore, it may be of particular value to take into account either or both parameters.Therefore, in an embodiment, one of the criteria used to select subsets is applied to the value of the total number of physical preparation steps associated with each combination, and the combination that is selected is the combination that minimizes this parameter.

[0033] In addition to the parameters used to evaluate the combinations against the criteria used to select the subset of combinations, advantageously further information about each combination can be calculated and optionally output to the user. This information can include one or more of the following: waste amount associated with the combination (as the amount of drug and / or amount of dosage form combined across the dosage forms of the combination and / or separately for each dosage form of the combination), total waste amount associated with the combination (as the amount of drug and / or amount of dosage form combined across the dosage forms of the combination and / or separately for each dosage form of the combination), number of doses of each dosage form, total number of doses across the dosage forms, amount used from each dosage form (as the amount of drug and / or amount of dosage form) and / or from each dose of each dosage form, amount of each dosage form and / or each dose of each dosage form used for each physical administration step, number of physical administration steps, any parameters of the materials required for administration, for example, if the dosage form is a liquid formulation for injection, the volume of the injection device used for each physical administration step, and / or the number of syringes used.

[0034] Furthermore, at least one of the above parameters may be calculated in at least two ways, and the results of these calculations may be compared to identify discrepancies. For example, the computing device may be configured to calculate the total amount and total waste amount of each dosage form used, and compare the total waste amount with the total amount of each dosage form to ensure that the amount matches the multiple of the dosage form used. If a discrepancy is detected, a warning or error may further be generated.

[0035] In an embodiment, a user interface may be provided that allows a user to input information including a value of at least one parameter associated with the subject. Similarly, outputting one or more optimal dosing regimens may include providing information identifying one or more optimal dosing regimens to the user via the user interface. The user interface may form part of a computing device configured to perform the methods described herein, or may form part of a second computing device configured to be in communication with a computing device configured to perform the methods described herein. For example, a computing device according to the present disclosure may be configured to communicate with a second computing device such that receiving a value of at least one parameter associated with the subject by the computing device includes the computing device receiving information from the second computing device (which information may have been entered by a user via a user interface of the second computing device), and outputting one or more optimal dosing regimens by the computing device includes communicating information identifying one or more optimal dosing regimens to the second computing device (which information may be available for the second computing device to provide to the user via a user interface of the second computing device). An embodiment in which the same computing device performs the methods described herein and receives input / provides output via a user interface of the computing device may advantageously perform all calculations locally. As such, those embodiments may not require, for example, a connection to a network to provide results, and may not require sharing of data across public networks. Conversely, embodiments in which the computing device performing the method is separate from the computing device associated with the user interface may advantageously enable the tools of the present disclosure to be provided by a centrally maintained computing system (e.g., a server, etc.).The ability to centrally maintain the computing systems implementing the methods can ensure that the methods use up-to-date information and that adequate computing power is provided to perform the necessary calculations. Furthermore, such implementations can be provided as, for example, web applications rather than platform-specific applications, and thus can easily be provided as cross-platform implementations.

[0036] Also provided is a device for automatically determining a dosing regimen of a drug to a subject, the device comprising a processor and a memory, the memory storing instructions that, when executed by the processor, cause the processor to perform steps of the methods described herein. Specifically, the instructions include receiving a value of at least one parameter associated with the subject; determining an amount (A) of the drug to be administered to the subject per base period (t) based at least in part on the value of the at least one parameter associated with the subject; t determining the amount of drug to be administered to the subject (A), wherein the drug is available in at least two different dosage forms (D1, D2) that differ in total amount of drug and / or drug concentration in the dose of the dosage form; t All the minimum combinations of at least two different dosage forms that can be used to achieve the t [D1, D2, D1D2]), where the minimum combination is the amount of drug (A) to be administered to the subject by using the minimum number of doses of each dosage form in each combination of dosage forms (D1, D2, D1D2). t ) or the amount of drug (A t ), calculating the smallest combination that satisfies at least the first criterion and the second criterion (A t The processor may select a subset of combinations of [D1, D2, D1D2], and output the selected subset of combinations as an optimal dosing regimen for the subject. The device may have any of the above functions.

[0037] The device of the present invention may include a server or a personal computing device, which may be a mobile device such as a mobile phone or a tablet.

[0038] According to a further aspect, a computer readable medium is provided having instructions recorded thereon that, when executed by a processor, cause the processor to perform steps of the methods described herein. Specifically, the instructions include receiving a value of at least one parameter associated with a subject; determining an amount (A) of drug to be administered to the subject per base period (t) based at least in part on the value of the at least one parameter associated with the subject; t determining the amount of drug to be administered to the subject (A), wherein the drug is available in at least two different dosage forms (D1, D2) that differ in total amount of drug and / or drug concentration in the dose of the dosage form; t All the minimum combinations of at least two different dosage forms that can be used to achieve the t [D1, D2, D1D2]), where the minimum combination is the amount of drug (A) to be administered to the subject by using the minimum number of individual doses of each dosage form for each combination of dosage forms (D1, D2, D1D2). t ) or the amount of drug (A t ), calculating the smallest combination that satisfies at least the first criterion and the second criterion (A t [D1, D2, D1D2]) and outputting the selected subset of combinations as an optimal dosing regimen for the subject.

[0039] Also provided herein is a method for determining an amount of drug (A) to be administered to the subject per base period (t) based at least in part on the value of at least one parameter associated with the subject. t), wherein the drug is available in at least two different dosage forms (D1, D2) that differ in total amount of drug and / or drug concentration in the dose of the dosage form; and determining the amount of drug to be administered to the subject (A t All the minimum combinations of at least two different dosage forms that can be used to achieve the t [D1, D2, D1D2]), where the minimum combination is the amount of drug (A) to be administered to the subject by using the minimum number of doses of each dosage form in the dosage form combination (D1, D2, D1D2). t ) or the amount of drug (A t ) and calculating the smallest combination that satisfies at least the first criterion and the second criterion (A t Also provided is a method of treating a subject with a drug, comprising automatically determining (e.g., by a processor) a dosing regimen for the drug to the subject by selecting a subset of combinations [D1, D2, D1D2], outputting the selected subset of combinations as an optimal dosing regimen for the subject, and treating the subject with the optimal dosing regimen (or one of the optimal dosing regimens) for the subject. Embodiments of this aspect may include any of the features described in connection with any other aspect.

[0040] The present invention further provides a method for determining an amount of drug (A) to be administered to the subject per base period (t) based at least in part on the value of at least one parameter associated with the subject. t ), wherein the drug is available in at least two different dosage forms (D1, D2) that differ in total amount of drug and / or drug concentration in the dose of the dosage form; and determining the amount of drug to be administered to the subject (A t All the minimum combinations of at least two different dosage forms that can be used to achieve the t[D1, D2, D1D2]), where the minimum combination is the amount of drug (A) to be administered to the subject by using the minimum number of individual doses of each dosage form in the dosage form combination (D1, D2, D1D2). t ) or the amount of drug (A t ) and calculating the smallest combination that satisfies at least the first criterion and the second criterion (A t The present invention provides a computer program stored on a medium for operating in conjunction with hardware to select a subset of combinations of the agonist, agonist, and antagonist, agonist, and antagonist, agonist, and antagonist, [D1, D2, D1D2], and outputting the selected subset of combinations as an optimal dosing regimen for the subject. [Brief description of the drawings]

[0041] [Figure 1] FIG. 1 illustrates an exemplary computing system in which embodiments of the present invention may be used. [Diagram 2] 1 is a flow chart illustrating a method for determining a drug administration regimen for a subject. [Diagram 3] FIG. 1 illustrates a home screen of an exemplary embodiment of a user interface for a method of determining a drug dosing regimen for a subject. [Figure 4] FIG. 13 illustrates a result screen of an exemplary embodiment of a user interface for a method of determining a drug dosing regimen for a subject. [Diagram 5] FIG. 1 illustrates a dose details interface of an exemplary embodiment of a user interface for a method of determining a dosing regimen for a drug in a subject. [Figure 6] FIG. 13 illustrates an injection details interface of an exemplary embodiment of a user interface for a method of determining a drug dosing regimen for a subject. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] While the figures presented herein illustrate embodiments of the present invention, these figures should not be construed as limiting the scope of the present invention. Similar reference numbers are used in different figures as necessary to relate to the same structural features of the illustrated embodiments.

[0043] Specific embodiments of the invention are described below with reference to the figures.

[0044] FIG. 1 illustrates an exemplary computing system in which embodiments of the present invention may be used.

[0045] In Fig. 1, a first computing device 1 is shown. The first computing device 1 may for example form part of a service provider computing system and is therefore also referred to herein as a "service provider computing device". The first computing device 1 comprises one or more processors 101 (e.g. servers) and one or more memories 102. The first computing device may further comprise a number of switches (not shown). A user (not shown) is provided with a user computing device (also referred to herein as a "second computing device") 2. The user computing device 2 may be a mobile computing device such as a mobile phone, a personal computer, etc. The computing device 2 has at least one processor 202 and at least one memory 201 that together provide at least one execution environment. Typically, a mobile device has firmware and applications that run in at least one regular execution environment (REE) with an operating system such as iOS, Android, Windows, etc. The computing device 2 may also be equipped with means 203 for communicating with other elements of a computing infrastructure, for example via the public Internet 3. The means may include, for example, a wireless communication device for communication with a wireless communication network, a local wireless communication device for communication with the public Internet 3, for example using Wi-Fi technology, and / or a wired communication interface for connecting to the public Internet 3. The second computing device 2 comprises a user interface 204, typically including a display. The display 204 may be a touch screen. Other types of user interfaces may be provided, such as a speaker, a keyboard, one or more buttons (not shown). The second (user) computing device 2 may be connected to the first (service provider) computing device 1 by a network connection, such as via the public Internet 3.

[0046] In an embodiment, the first computing device 1 is configured to determine a drug dosage regimen for a subject. In such an embodiment, the memory 101 may store instructions that, when executed by the processor 102, cause the processor to perform steps of a method for determining a drug dosage regimen for a subject as described herein. In such an embodiment, the first computing device 1 may be configured to receive information from a user computing device 2, for example, via the public Internet 3. The first computing device 1 may further be configured to output information to the user computing device 2, for example, via the public Internet 3. The information may then be displayed by the user computing device 2, for example, using the display 204. For example, the processor 101 may comprise one or more servers, and the method may be implemented as a web page, a web application, or a progressive web application. In an embodiment, the method is implemented as a progressive web application that runs on the first computing device 1 and is distributed to the second computing device 2 via the public Internet 3.

[0047] In other embodiments, the second computing device 2 is configured to determine a drug dosage regimen for a subject. In such embodiments, the memory 201 may store instructions that, when executed by the processor 202, cause the processor to perform steps of a method for determining a drug dosage regimen for a subject as described herein. In such embodiments, the second computing device 1 may be configured to receive information upon input from a user via its user interface 204. The second computing device 2 may further be configured to output information to a user, for example via the user interface 204. In such embodiments, the method may be implemented as an application running locally on the processor 202.

[0048] Those skilled in the art will appreciate that alternative implementations are possible. For example, the processor 102 may be configured to execute the steps of a method for determining a drug dosing regimen for a subject as described herein, which may be accessed via a native application running locally on the second computing device 2 and sending queries to the first computing device 1.

[0049] Figure 2 shows a general embodiment of a method for determining a dosing regimen for a drug to a subject. The methods and devices of the present invention find use in situations where a drug is available in at least two different dosage forms (D1, D2) that differ in the total amount of drug and / or in the drug concentration in the dosage form dose.

[0050] In step 200, a value of at least one parameter related to the subject is received (e.g., by processor 102 or processor 202). The at least one parameter may be the subject's body weight. In step 200, values ​​of one or more additional parameters may also be received. These values ​​may include one or more user preferences. The user preferences may include, for example, a selection of one or more criteria used to determine the most appropriate drug regimen for the subject, as described further below. The user preferences may include a selection of one or more dosing frequencies (multiples of the base period of dosing, as described further below). The one or more further parameters related to the subject may alternatively or additionally be selected from a group including the subject's age, the subject's sex, a disease-related parameter, and a treatment-related parameter. The disease-related parameter may be an indication of disease severity, identification, disease stage, co-occurrence of another disease or disorder, etc. The treatment-related parameter may be an indication of another treatment that the subject is or has been undergoing. The value of the one or more parameters may be entered by a user at the user interface 204 and communicated to the processor 102 / 202.

[0051] In step 210, the amount of drug (A) to be administered to the subject per base period (t) is calculated. t ) is determined based at least in part on the value of at least one parameter associated with the subject. The amount of drug to be administered per basic period (t) and one or more administration frequencies suitable for achieving the desired prophylactic or therapeutic effect of the drug may be predefined, for example, through clinical trials, as known in the art. In an embodiment, a suitable (e.g., safe and effective) amount of drug to be administered per basic period (t) as a function of one or more parameters associated with the subject is provided as an input to the method described herein. For example, these may be stored in memory 101 / 201. These may be provided as one or more mathematical relationships linking one or more parameters associated with the subject to a safe and effective amount of drug to be administered per basic period (t). For example, the amount of drug per kg (patient's weight) per basic period may be provided as an input to the method described herein. Furthermore, multiple such amounts of drug per kg per basic period may be provided, and the selection of such amount may depend on the value of another parameter associated with the patient (e.g., gender, age, disease severity / stage, etc.). Thus, step 210 may include the processor 102 / 202 retrieving from the memory 101 / 201 a relationship linking one or more parameters related to the subject to an (e.g., safe and effective) amount of drug to be administered per basic period (t). Furthermore, the selection of the relationship to be retrieved when multiple such relationships are stored in the memory 101 / 201 may depend on the value of the at least one parameter received in step 200. Step 210 may further include the processor 102 / 202 applying the mathematical relationship to the value of the at least one parameter (e.g., the subject's body weight) received in step 200. Preferably, the at least one parameter includes the subject's body weight, and the processor 102 / 202 retrieves an amount (A) of drug to be administered to the subject per basic period (t) based at least in part on the subject's body weight. tDetermining n may include the processor 102 / 202 multiplying the subject's body weight by a preset amount of drug per base period (t). The base period t used may depend on the particular drug used, such as the minimum interval between doses evaluated in clinical trials. In an embodiment, the base time t is selected from 1 day, 1 week, and 1 month. In an embodiment, n is 2 and 4, and the base period is 1 week.

[0052] The amount of drug (A) to be administered to a subject for one or more multiples (n) of a base period (t). n1t , A n2t A further optional step 220 may be performed in which n is calculated. One or more multiples (n) may be received in step 200 as further parameters related to the subject (i.e., as user preferences). In an embodiment, one or more multiples (n) values ​​may be stored in memory 101 / 201. One or more multiples (n) values ​​may be retrieved by processor 102 / 202 and used in step 220 (as default values), or one or more multiples (n) values ​​may be used to verify that one or more values ​​n received in step 200 are compatible with the method of the present invention. For example, a maximum value of n may be stored in memory, and processor 102 / 202 may verify in step 220 that any value n received in step 200 is a divisor of the maximum value stored in memory. Since dosing schedules counted in whole days, weeks or months are more common, the multiple n is usually a multiple of an integer. However, the method of the present invention is not limited in principle to this. Additionally, the amount of drug (A) to be administered to the subject for one or more multiples (n) of the base period (t) is n1t , A n2t ) is the base period A t Alternatively, the amount of drug (A) to be administered to a subject for one or more multiples (n) of a base period (t) may be calculated by multiplying the amount of drug per unit time by each value n. n1t , A n2t) may be calculated by retrieving from memory 101 / 201 a mathematical relationship between the value of at least one parameter associated with the subject and the amount of drug to be administered per period n*t. For example, one or more amounts of drug to be administered per kg per week may be stored in memory in combination with a maximum suitable interval of 4 weeks. These may be used to calculate the amount of drug to be administered to the subject every week, every two weeks, or every four weeks depending on the subject's weight. As will be appreciated by those skilled in the art, the mathematical relationship between the amount of drug and the value of at least one parameter associated with the subject may also be provided by a user prior to the performance of step 210 and stored in memory 101 / 201 for use in steps 210, 220.

[0053] In step 230, the amount of drug to be administered to the subject (A t ) (and, if applicable, amount A n1t , A n2t All minimal combinations of at least two dosage forms of the drug that can be used to achieve the amount of drug (A) are calculated. For example, the processor 102 / 202 may calculate all possible minimal combinations and store these in the memory 101 / 201. A minimal combination is one that can achieve the amount of drug (A) by using the minimum number of individual doses of each dosage form for each combination of dosage forms (D1, D2, D1D2). t ) or the amount of drug (A t ). For example, for a drug available in two dosage forms D1 and D2, any dose can be achieved with three types of combinations: D1 only, D2 only, and D1 and D2. If D2 contains half the amount of drug in D1 and a total dose of 2*D1 is required, the minimum combinations are 2*D1 (i.e., 2 doses in dosage form D1), 4*D2 (i.e., 4 doses in dosage form D2), and 1*D1+2*D2 (i.e., 1 dose in dosage form D1 and 2 doses in dosage form D2). In other words, for each of the three types of combinations, the minimum combination is the combination that contains the minimum number of doses that achieves that amount while having a dosage form in the set. In the case of D1 only, this is A tFor D2 alone, this is the minimum number of doses of D1 that achieves A t In the case of D1+D2, these include both D1 and D2 (i.e., at least one D1 and one D2 must be used) and t The minimum combination of doses that achieves some amount A t and for some dosage forms D1, D2 (e.g., using 1*D1+2*D2 or 2*D1+1*D2, some amount A t (Because it is possible to achieve the above), there may be multiple combinations of different dosage forms. t is less than the amount of drug in at least one of the dosage forms, so the required amount A t Depending on A, some types of combinations may not be represented in the minimum combinations calculated in step 230. For example, t is less than the amount of drug contained in the dose of dosage form D1 or D2, the D1D2 combination may not be generated. In an embodiment, the amount of drug contained in each of the dosage forms (D1, D2) may be stored in memory 101 / 201 and retrieved by processor 102 / 202. Alternatively, the amount of drug contained in each of the dosage forms (D1, D2) may be provided by a user before processor 102 / 202 performs step 230.

[0054] In an embodiment, the drug should be administered to the subject in multiple phases that together form a course of treatment, and the dosage regimen may differ between the multiple phases. For example, the drug may be administered according to a first dosage regimen during a first phase, which may be called a "loading phase," and then according to a second dosage regimen, which may be called a "maintenance phase." The amount of drug (A) to be administered to the subject per base period (t) may be determined by the following formula: t) and / or one or more suitable intervals between administrations may vary between different stages of treatment. In an embodiment, each of steps 210, 220, and 230 may be performed for one or more of the stages that together form a course of treatment. In an embodiment, a selection of a stage of treatment in step 200 may be received as a parameter, and steps 210, 220, and 230 may be performed accordingly.

[0055] In steps 240, 250 (and 260, if applicable), a combination (A t In this particular embodiment, in step 240, a subset of the combinations (A[D1, D2, D1D2]) generated in step 230 is selected. t [D1, D2, D1D2], and A, if applicable n1t [D1, D2, D1D2], A n2tA first subset of combinations [D1, D2, D1D2]) is selected according to a first criterion. For example, the processor 102 / 202 may evaluate the combinations calculated in step 230 and stored in the memory 101 / 201 against the first criterion, select a first subset of combinations based on the evaluation, and store the first subset in the memory 101 / 201. Selecting the subset of combinations that meet the first criterion may include calculating the value of a parameter associated with the combinations and selecting combinations that maximize or minimize the parameter. Alternatively, combinations that have values ​​above or below a predefined threshold of the calculated parameter may be selected. Furthermore, combinations that have values ​​within a certain range of maximum / minimum values ​​across all combinations may be selected. As one skilled in the art will appreciate, depending on the combinations and criteria used, the subset may actually include all combinations, for example, if all combinations meet the criterion (e.g., because the value of the parameter is the same for all combinations or is within a certain range of the minimum / maximum value of the parameter across all evaluated combinations). Selecting a subset of combinations may be performed, for example, by ranking the combinations according to a criterion and selecting all combinations with the highest joint rank. In embodiments in which combinations are calculated for one or more values ​​of n (in addition to n=1), the selection may be performed separately for each of the base period (t) and the multiples (n) of the base period (t). Alternatively, the selection may be performed jointly for each of the base period (t) and the multiples (n) of the base period (t).

[0056] In step 250, the combination (A t [D1, D2, D1D2], and A, if applicable n1t [D1, D2, D1D2], A n2tA second subset of the subsets of [D1, D2, D1D2]) is selected according to a second criterion. The selection of the second subset from the first subset may be performed as described above in relation to step 240. For example, the processor 102 / 202 may evaluate the combinations calculated in step 230 and stored in the memory 101 / 201 (or only the subset selected in step 240) against a second criterion (e.g., by calculating values ​​of a second parameter associated with the combinations), and based on the evaluation, select a second subset of the combinations in the first subset and store the second subset in the memory 101 / 201.

[0057] In optional step 260, a third subset may be selected from the second subset according to a third criterion. The selection of the third subset from the second subset may be performed as described above in relation to step 240. For example, the processor 102 / 202 may evaluate the combinations calculated in step 230 and stored in the memory 101 / 201 (or only the subset selected in step 240, or only the subset selected in step 250) against a third criterion, select a third subset of the combinations in the second subset based on the evaluation, and store the third subset in the memory 101 / 201. As will be appreciated by those skilled in the art, any number of further criteria may be used to hierarchically select subsets of the previously selected subsets. For example, a fourth subset may be selected from the third subset using a fourth criterion, a fifth subset may be selected from the fourth subset using a fifth criterion, and so on.

[0058] In an embodiment, the further parameters received in step 200 include the selected criteria. In such an embodiment, the criteria may be used as a first criterion for selecting a dosing regimen in combination with one or more pre-set further criteria that may be stored in memory 101 / 201. For example, the second criterion and any further criteria (if used) may be automatically selected based on the criteria received in step 200. In other words, memory 101 / 201 may store a default criterion to be used in combination with the selected first criterion, and processor 102 or 202 may retrieve the value of this parameter from memory 101 / 201 based on the value received in step 200. Similarly, step 200 may include receiving at least two further parameters, including a first criterion and a second criterion. These may be used in combination with a third criterion that may be set as a default parameter stored in memory 101 / 201. Step 200 may also include receiving at least three further parameters, including a first criterion, a second criterion, and a third criterion. In an embodiment, a default selection may be stored in memory 201 / 101 for all criteria, including the first criterion.

[0059] Combination-related parameters that may be calculated to select a subset of combinations may include one or more of the waste amount associated with the combination of dosage forms, the total waste amount per period, the total number of physical administration steps required for administration of the combination, and the total number of physical preparation steps required for administration of the combination. The total waste amount per period may be calculated as the total waste amount per base period and / or the total waste amount over the period corresponding to the least common multiple of the multiples (n). The total waste amount per base period may be calculated by dividing the waste amount of each combination by its corresponding multiple n, where n=1 for the combination corresponding to the base period (t). The total waste amount over the period corresponding to the least common multiple of the multiples (n) may be calculated by multiplying the waste amount of each combination by the multiplier required to reach the least common multiple based on the multiple n associated with the combination. For example, when n=2 and n=4, the least common multiple is 4, and in this embodiment, the total waste amount can be calculated over four base periods. This calculation can be achieved by multiplying the waste amount of each combination of the basic period by 4 and the waste amount of each combination of the multiple n=2 of the basic period by 2. The total number of physical dosing steps required for the administration of the combination can be calculated as the minimum number of physical dosing steps that can be used to administer the combination and satisfy one or more rules. The rules and any other parameters of the dosage forms D1, D2 that may be required to apply the rules can be stored in the memory 101 / 201 and retrieved by the processor 102 / 202 to calculate the total number of physical dosing steps. The total number of physical preparation steps required for the administration of the combination can be calculated as the number of doses of each dosage form that constitutes the combination. If several preparation steps are applied to some dosage forms, this can be stored in the memory 101 / 201 as a parameter of the dosage forms D1, D2 and retrieved by the processor 102 / 202 to calculate the total number of physical preparation steps by multiplying the number of doses of each dosage form by the corresponding number of physical preparation steps.

[0060] In step 270, the (final) selected subset of combinations is output as an optimal dosing regimen for the subject according to the first and second criteria (and optionally a third or more criteria). In an embodiment, outputting the optimal dosing regimen may include the processor 202 causing the user interface 204 to display information identifying one or more optimal dosing regimens. For example, the processor 102 may communicate information identifying one or more optimal dosing regimens to the processor 202, which may cause the information to be displayed on the user interface 204. Alternatively, the processor 202 may be capable of performing at least some of the above calculations locally, thus selecting a combination and outputting information identifying the selected combination as an optimal dosing regimen. In an embodiment, a single optimal dosing regimen (i.e., combination of dosage forms) may be output. In an embodiment, multiple optimal dosing regimens (i.e., combination of dosage forms) may be output. In an embodiment, a single optimal dosing regimen may be output for each of the base period (t) and the multiple of the base period (n). In embodiments where multiple optimal dosing regimens are output, an indication of which of the outputted dosing regimens is optimal according to one of the criteria may also be output. For example, multiple optimal dosing regimens may be output with an indication of which of these multiple optimal dosing regimens optimizes a first criterion. For example, if optimal dosing regimens are output separately for each of the multiples n, they may not all be optimal across all combinations for all dosing intervals. In such cases, it may be useful to include an indication of which of these are optimal according to a criterion, such as a first criterion.

[0061] Outputting the combination includes providing information identifying the combination, including the identities and numbers of the dosage forms that make up the combination. If applicable, the information identifying the combination may further include the dosing interval (t, n*t). The information identifying the combination is provided to the user via a user interface or to a user device for providing to the user via a user interface. The user interface may be provided, for example, as a web page displayed on the user device. In such an embodiment, the user can input information, such as by entering or selecting an item, and have the user device retrieve the information from the server in the form of a new web page.

[0062] Additional parameters related to the output dosage regimen may also be calculated and optionally output in step 270. These parameters may include one or more of the waste amount associated with the combination, the total waste amount associated with the combination, the amount used from each dosage form, the amount of each dosage form used in each physical administration step, etc. If the drug is a liquid formulation for injection, these parameters may further include the volume of the injection device (e.g., syringe) used in each physical administration step. Advantageously, at least one of the above parameters may be calculated in at least two ways, and the results of the calculations may be compared to ensure that the parameters are consistent. Furthermore, at least two of the above parameters may be calculated by the processor 102 / 202 to ensure that at least two values ​​are consistent. For example, the processor 102 / 202 calculates the total amount of each dosage form used and the total waste amount, and compares the total waste amount with the total amount of each dosage form to ensure that the amount fits the multiple of the dosage form used.

[0063] As one skilled in the art will appreciate, the above general principles are applicable to situations where a drug is available in more than two dosage forms (e.g., four, five, or six dosage forms). For example, if a drug is available in four different dosage forms (D1, D2, D3, D4), a minimum of 15 combinations may be considered: D1, D2, D3, D4, D1D2, D1D3, D1D4, D2D3, D2D4, D3D4, D1D2D3, D1D2D4, D2D3D4, D1D3D4, and D1D2D3D4. As explained above, the amount of drug A required t Depending on the dosage form and the amount of drug in each, not all types of combinations may be represented. For example, t If the amount of drug in D4 is less than the amount of drug in D4, the minimum combination including D4 in combination with other dosage forms may not be calculated. In an embodiment, any two of the three or more dosage forms may differ by the total amount of drug in the dose of the dosage formulation. Similarly, any two of the three or more dosage forms may differ by the concentration of drug in the dose of the dosage formulation. Furthermore, any two of the two or more dosage forms may differ by both the concentration of drug in the dose of the dosage formulation and the total amount of drug in the dose of the dosage formulation.

[0064] Working Example An exemplary method for determining a drug administration regimen for a subject is now described. The examples described herein relate to administration of the drug emicizumab, commercially available as HEMLIBRA® (Roche Products Limited). Emicizumab is a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody produced using recombinant DNA technology in mammalian Chinese Hamster Ovary (CHO) cells. Emicizumab is described in EP2644698B1, which is incorporated herein by reference. Emicizumab is a bispecific antibody that specifically binds to blood clotting factors IX / IXa and blood clotting factor X, and replaces the cofactor function of blood clotting factor VIII by promoting the activation of factor X by factor IXa. This function is insufficient in patients with hemophilia A, leading to bleeding disorders. Emicizumab is commercially available in four different dosage forms, all of which are solutions for subcutaneous injection. - Hemlibra 30 mg: a 1 ml vial of solution containing 30 mg of emicizumab at a concentration of 30 mg / ml. Due to the packaging color of this dosage form, it is also referred to herein as the "sky blue vial." - Hemlibra 60 mg: a vial of 0.4 ml of solution containing 60 mg of emicizumab at a concentration of 150 mg / ml, also referred to herein as the "purple vial." - Hemlibra 105 mg: a vial of 0.7 ml of solution containing 105 mg of emicizumab at a concentration of 150 mg / ml, also referred to herein as the "turquoise vial." - Hemlibra 150 mg: a 1 ml vial of solution containing 150 mg of emicizumab at a concentration of 150 mg / ml, also referred to herein as the "brown vial."

[0065] Hemlibra is indicated for the routine prevention of bleeding episodes in patients with hemophilia A with factor VIII inhibitors (congenital factor VIII deficiency) and severe hemophilia A without factor VIII inhibitors (congenital factor VIII deficiency, factor VIII <1%).

[0066] Through clinical trials, it was determined that Hemlibra may be used in all age groups and should follow a two-step dosing regimen that includes: - Loading Phase: Recommended dose 3 mg / kg, administered once weekly for 4 weeks. - Maintenance Phase: Recommended dose of 1.5 mg / kg / week, administered a minimum of once every 4 weeks (maximum interval between doses is 4 weeks), i.e. 1.5 mg / kg administered once per week, 3 mg / kg administered once every 2 weeks, or 6 mg / kg administered once every 4 weeks.

[0067] In this example, further rules for administration were provided, including combining two different concentrations of Hemlibra in the same syringe, that when administered in a 1 ml or 2-3 ml syringe, each injection should not exceed 2 ml, and that a 1 ml syringe should be used to administer the specified amount with two decimal points (in ml). Data from clinical trials indicate that a maintenance regimen (weekly, every 2 weeks, or every 4 weeks) should be selected to support adherence, the amount of emicizumab should be calculated accordingly as "patient weight (kg) x dose (1.5, 3, or 6 mg / kg) = total amount of emicizumab to be administered (mg)", and the appropriate dose and volume should be selected from the available vial strengths, and once a vial is selected, the total amount of Hemlibra can be calculated as "total amount of emicizumab to be administered (mg) ÷ vial concentration (mg / mL) = total amount of Hemlibra to be injected (mL)".

[0068] This leaves many options open, and may lead to errors, since a regimen that supports adherence may not be selected completely independent of the choice of vial combination used. In fact, adherence may depend on factors such as the number of injections required, the amount of waste associated with the regimen, etc. Therefore, the inventors have identified that the selection of the dosage regimen should take into account multiple variables, including in this example the frequency of administration in the maintenance regimen, the patient's weight, the different dosage forms available, the restrictions on administration (volume and combination of dosage forms), and the patient-related criteria, including the amount of product to be wasted (per administration, over 4 weeks), the number of injections required (per administration), and the number of physical steps required to prepare the administration (which is proportional to the number of vial draws required). Therefore, the inventors have designed a tool that takes into account all of these variables to determine the patient's dosage regimen.

[0069] In the particular implementation described herein, the method takes as input the following: - Pre-set dose multipliers (x mg / kg) for the loading phase (QL=3mg / kg), weekly (Q1W=1.5mg / kg), biweekly (Q2W=3mg / kg), and every 4 weeks (Q4W=6mg / kg) maintenance phase regimens. - The concentration (C) of each of the four types of dosage forms (D1 = sky blue vial (SB), D2 = purple vial (P), D3 = turquoise vial (T), D4 = brown vial (B)) SB , C P , C T , C B ) and volume (V SB , V P , V T , V B ). - The weight range for which the dosing regimen should be determined, e.g., w=3-150 kg in whole-number increments. - Rules regarding administration procedures. For example, syringe V 1 , V 2Such as the two possible volumes of, conditions when a particular syringe volume cannot be used, and whether different vials / vials with different concentrations can be combined into the same syringe.

[0070] The method then performs three successive steps. 1. Calculate dose: total dose (mg) by body weight for each regimen (loading, maintenance-weekly, maintenance-every other week, maintenance-every 4 weeks). The loading dose is the same as the maintenance-every other week dose (but the dosing interval is different). 2. Calculate combinations: For each total dose, generate all minimal combinations of dosage forms that can be used to achieve the total dose and calculate the parameters of each minimal combination. 3. Generate recommendations: For each weight, identify combinations that minimize one or more criteria and generate these instructions.

[0071] These steps are described in more detail below. In the example described below, steps 1 through 3 are performed for a range of weights, and all combinations and recommendations for each of these weights are pre-calculated. Thus, when a particular weight is input from the user interface, recommendations can be easily extracted from the appropriate recommendation set. In other implementations not described in detail below, each of steps 1 through 3 is performed for a single particular weight. For example, steps 1 through 3 may be performed on-the-fly upon receiving a weight input from the user interface. In such cases, calculations similar to those described below are applied to a single weight rather than a list of weights.

[0072] In step 1, four total doses A L w t , A w t , A w n1t , A w n2t(t=1 week, n1=2, n2=4, L represents the dose in the loading phase) is calculated for each body weight w=3...150 as follows: A L w t =QL*w (Equation 1) A w t =Q1W*w (Formula 2) A w n1t =Q2W*w=Q1W*n1*w (Equation 3) A w n2t =Q4W*w=Q1W*n2*w (Equation 4)

[0073] Since QL=Q2W in this example, step 1 results in a list of 441 total doses (three different total doses for each of the 147 different body weights). This list is used as input to step 2, where all possible minimal combinations of the four dosage forms that can be used to achieve each of the amounts of drug represented by these 441 total doses are calculated. Specifically, the number of vials of SB, P, T, and B that make up the combination (n SB , n P , n T , n B To calculate the dose, (A L w t , A w t , A w n1t , A w n2t , or for efficiency, for each of the different total doses represented in this list), the following steps are performed: a. Sky blue as the main color i. Sky Blue only (A w [SB]):Dose(A w ) the minimum number of sky blue vials to achieve n SB =round.up(A w / (C SB *V SB )) (Formula 5]) where round.up() rounds the number between the parentheses to the nearest integer. ii. Sky blue and purple combination (A w [SBP]): The number of SB vials is increased until no additional vials are needed to make up the total (at this point, the number of SB vials is n vials calculated in step i). SB (just below), 1 SB vial + dose (A w ), the minimum number of P vials that achieves 2 SB vials + dose, etc. Number of SB vials n SB The minimum number of P vials per n P =round.up((A w -1*(C SB *V SB )) / (C P *V P )) (Formula 6) It is calculated as: iii. Sky blue and turquoise combination (A w [SBT]): 1 SB vial + dose (A) until the number of SB vials is reduced to a point where no additional vials are needed to make up the total amount. w ), the minimum number of T vials that achieves 2 SB vials + dose, etc. Number of SB vials n SB The minimum number of T vials per n T =round.up((A w -1*(C SB *V SB )) / (C T *V T )) (Formula 7) It is calculated as: iv. Sky blue and brown combination (A w [SBB]): The number of SB vials is calculated by dividing the total amount (i.e., n SB 1 SB vial + dose (A w), the minimum number of B vials that achieves 2 SB vials + dose, etc. Number of SB vials n SB The minimum number of B vials per n B =round.up((A w -1*(C SB *V SB )) / (C B *V B )) (Equation 8) It is calculated as: b. Repeat process a for the purple-dominant combinations. c. Repeat process a for the turquoise-dominant combination. d. Repeat process a for the Brown-dominated combination. e. Calculate the combination of three colors i. Sky blue + purple and turquoise (A w [SBPT]): x = number of SB vials, y = number of P vials, When x=1, 1 SB vial + 1 P vial + the minimum number of T vials to achieve a dose, 1 SB vial + 2 P vials + the minimum number of T vials to achieve a dose, etc., are calculated as follows: 1 SB vial + y P vials = A w Until it exceeds If x=2, then 2 SB vials + 1 P vial + the minimum number of T vials to achieve a dose, 2 SB vials + 2 P vials + the minimum number of T vials to achieve a dose, and so on until the total amount of 2 SB vials + y P vials is A. w Until it exceeds The total amount of SB x + P1 is A w Loop until it exceeds ii. Sky blue + purple and brown (A w Repeat step i for [SBPB] iii. Sky blue + turquoise and purple (A w Repeat step i for [SBTP] iv. Sky blue + turquoise and brown (A wRepeat step i for [SBTB] v. Sky blue + brown and purple (A w Repeat step i for [SBBP] vi. Sky blue + brown and turquoise (A w Repeat step i for [SBBT] vii. Purple + turquoise and sky blue (A w Repeat step i for [PTSB] viii. Purple main + turquoise and brown (A w Repeat step i for [PTB] ix. Purple + brown and sky blue (A w Repeat step i for [PBSB] x. Purple + brown and turquoise (A w Repeat step i for [PBT] xi. Turquoise + Purple and Sky Blue (A w Repeat step i for [TPSB] xii. Turquoise + purple and brown (A w Repeat step i for [TPB] xiii. Turquoise + brown and sky blue (A w Repeat step i for [TBSB] xiv. Turquoise + Brown and Purple (A w Repeat step i for [TBP] xv. Brown + purple and sky blue (A w Repeat step i for [BPSB] xvi. Brown + Purple and Turquoise (A w Repeat step i for [BPT] xvii. Brown + turquoise and sky blue (A w Repeat step i for [BTSB] xviii. Brown + Turquoise and Purple (A wRepeat step i for [BTP]

[0074] Step 2 also involves the calculation of several parameters for each minimal combination, including at least the total number of vial draws (total number of vials required), the amount of product (in mg and ml) to be drawn from each vial, the discard amount in mg of unused product per administration, and the number of injections required to administer the combination. The discard amount in mg of unused product can be calculated in several ways. For example, the total amount of drug in the combination can be calculated as: Total (n SB , n P , n T , n B )=(n SB *C SB *V SB )+(n P *C P *V P )+(n T *C T *V T )+(n B *C B *V B ) (Formula 9) It can be calculated as:

[0075] Also, a certain amount A w The waste amount W of the combination is W = total amount (n SB , n P , n T , n B )-A w (Formula 10) It can be calculated as:

[0076] Alternatively, the total amount (in ml or mg) drawn from each vial can be calculated and compared to the total amount (in ml or mg) available from each vial.

[0077] The total amount to be drawn from each vial can be calculated as the total amount present in all vials except the last one added, and the amount drawn is the amount required A wThe amount of injections required to reach the desired volume may be calculated as the volume required to reach the desired volume minus the amount already provided by other vials. As one of skill in the art will appreciate, the specific order of steps used to generate the combinations is arbitrary and any order may be used so long as all possible combinations are generated. Additionally, the parameters for each combination may be calculated as each combination is generated, or a list of combinations may be generated and looped through to calculate each parameter. The number of injections used to administer the combination may be calculated based on the volume of syringe V. 1 , V 2 Based on the above rules for volume and the rules for vial / concentration combinations. In this example, 1 ml or 2 ml syringes can be used, and the sky blue vial cannot be combined with the purple, turquoise, and brown vials. In this case, the number of injections can be calculated as follows: - If at least one sky blue vial is used (n SB ≧1) 〇 The V required to administer the total amount of product provided by combining sky blue vials 1 = 1ml or V 2 = Calculate the number of 2ml injections. o The amount (in ml) required to administer the total amount of product provided by combining all other vials, for example by calculating the number of injections required to administer the entire vial, with the further restriction that the amount (in ml) specified with an accuracy of two decimal points can only be administered with a 1 ml syringe. 1 = 1ml or V 2 Calculate the number of =2 ml injections and determine if a 1 ml syringe needs to be used for the remaining volume to be administered. Add up the four numbers above to get V 1 = Subcombination using only 1 ml, V 2 = Generate 3 subcombinations, one using only 2ml, and two using both volumes. - If you do not use the sky blue vial (n SB= 0): the amount (in ml) required to administer the total amount of product provided by combining all other vials together, with the further restriction that the amount (in ml) specified with an accuracy of two decimal points can only be administered with a 1 ml syringe 1 = 1ml or V 2 = Calculate the number of 2ml injections. - If necessary, filter the combinations to retain only those that have the smallest amount of injection, that use the smallest syringe possible, and / or that use only one type of syringe (i.e., one volume).

[0078] The result of step 2 is a data table containing information and parameters for each of the 85,008 combinations. Table 1 below shows a subset of this table containing several exemplary parameters for selecting possible combinations that achieve one of four different exemplary total doses. In the example shown, the various amounts A generated in step 1 are w For each of the weights w=3 to 150 kg, and for each of the four types of dosing regimens A L w t , A w t , A w n1t , A w n2t This table can be expanded to list all combinations of each of the four types of dosing regimens for each body weight, as well as their parameters. Alternatively, as explained above, the table generated in step 2 may also list all combinations for all four types of dosing regimens for each body weight.

[0079] When generating such an expanded table (or when generating the table in expanded form initially in step 2), the waste amount per equivalent period (e.g., 4 weeks) can also be calculated. In this example, the total waste amount per equivalent period is calculated by appropriately scaling the waste amount per dose, i.e., the total doses (A wn1t , A w n2t ) by 2 and 4, respectively, or n=1 (i.e., A w t ) and n1=2(A w n1t ) waste relative to the total dose, multiplied by 4 and 2. The latter may be preferred as it may lead to a more intuitive measure of waste.

[0080] The method then proceeds to step 3, where recommendations are generated. In this example, recommendations are generated using three different criteria: waste volume over a 4-week period, number of injections per dose, and number of vial draws. Specifically, the method generates a list of all evaluated dosing regimens for each patient weight w=3-150 kg. The method then ranks each list according to the above three criteria in a nested / hierarchical manner (by ranking combinations according to a first criterion, then within each rank, ranking combinations according to a second criterion, and within each of these ranks, ranking combinations according to a third criterion, and / or flagging the highest-ranked combination within each rank). Furthermore, in this example, the ranking is performed according to two different hierarchies.

[0081] In the first tier, minimization of waste per equivalent period (e.g., total waste over 4 weeks) is prioritized, and therefore the combinations in the table are ranked according to total waste. The highest ranked combinations (i.e., having the least amount of waste) are then ranked again according to the number of injections per administration. The highest ranked combinations (i.e., having the least number of injections) are then ranked according to the number of vial draws. The final highest ranked combinations (i.e., the top ranked combinations (based on vial draws) among the top ranked combinations (based on the number of injections) among the top ranked combinations (based on total waste)) are then stored in a "minimum waste recommendation" list. In this example, each ranking is performed separately for each of the four categories of dosing regimens (loading, maintenance-weekly, maintenance-biweekly, and maintenance-every 4 weeks), and the top ranked combinations are output to the "minimum waste recommendation" list for each of these. If two or more combinations have the same rank across all three criteria, then all of these combinations may be output in the "minimum waste recommended" list, or one may be arbitrarily selected. Furthermore, if a combination in the "minimum waste recommended" list has either or both (i) the same total waste as the overall minimum total waste combination (across all categories of dosing regimens) and (ii) the same number of injections as the overall minimum number of injections combination (across all categories of dosing regimens), then the list is flagged. Alternatively, nested ranking can be performed jointly for all maintenance regimens. In such a case, only the selection result with the optimum is output, which may not include solutions for each different category of maintenance regimens.

[0082] In the second tier, minimizing the number of injections is prioritized, and therefore the combinations in the table are ranked according to the number of injections per administration. The highest ranked combinations (i.e., the fewest number of injections) are then ranked again according to the number of vials drawn per administration. The highest ranked combinations (i.e., the fewest number of vials drawn) are then ranked according to the smallest total waste. The final highest ranked combinations are stored in the "minimum injections recommended" list. In this example, each ranking is performed separately for each of the four categories of dosing regimens (loading, maintenance-weekly, maintenance-biweekly, and maintenance-every 4 weeks), and the highest ranked combinations are output to the "minimum injections recommended" list for each of these. If two or more combinations have the same rank across all three criteria, all of these combinations may be output to the "minimum injections recommended" list, or one may be selected arbitrarily. A combination in the "Minimum Injections Recommended" list is flagged if it has either or both: (i) the same total discard amount as the combined overall minimum total discard amount (across all categories of dosing regimens); and (ii) the same number of injections as the combined overall minimum number of injections (across all categories of dosing regimens).

[0083] In this example, the method generates separate recommendation tables for loading and maintenance regimens by repeating the above process for the loading dose combination and the maintenance dose combination. As a result of step 3, four data tables are created that contain information and parameters for each combination that minimizes the above hierarchy criteria. A subset of these tables is shown below in Tables 2 through 5. Some of the values ​​in these tables may be derived in multiple ways from the values ​​in the other columns. For example, the total volume of each dosage form may be calculated by multiplying and summing the number and volume of vials (full vials [#V*Vol.], partial vials [#V*Vol.]) for each dosage form. Alternatively, the total volume of each dosage form may be derived from the total weight of product provided by each dosage form. In an embodiment, to ensure internal consistency of the generated data, each value that may be calculated in more than one way is calculated in at least two of the ways. Similarly, data regarding total volume of product and total amount of product should be mutually convertible based on data from the other columns. In an embodiment, to ensure consistency of the data, each volume / mg value is compared to its corresponding mg / volume value and / or its constituent volumes and / or mg values. JPEG0007676371000001.jpg255170JPEG0007676371000002.jpg255170JPEG0007676371000003.jpg255170JPEG0007676371000004.jpg255170JPEG0007676371000005.jpg255170JPEG0007676371000006.jpg255170JPEG0007676371000007.jpg255170JPEG0007676371000008.jpg255170JPEG0007676371000009.jpg255170JPEG0007676371000010.jpg255170JPEG0007676371000011.jpg255170JPEG0007676371000012.jpg255170JPEG0007676371000013.jpg255170JPEG0007676371000014.jpg255170JPEG0007676371000015.jpg255170JPEG0007676371000016.jpg255170JPEG0007676371000017.jpg255170JPEG0007676371000018.jpg255170JPEG0007676371000019.jpg255170JPEG0007676371000020.jpg255170JPEG0007676371000021.jpg255170JPEG0007676371000022.jpg255170JPEG0007676371000023.jpg255170JPEG0007676371000024.jpg255170JPEG0007676371000025.jpg255170JPEG0007676371000026.jpg255170JPEG0007676371000027.jpg255170JPEG0007676371000028.jpg255170JPEG0007676371000029.jpg255170JPEG0007676371000030.jpg255170JPEG0007676371000031.jpg255170JPEG0007676371000032.jpg255170JPEG0007676371000033.jpg255170JPEG0007676371000034.jpg255170JPEG0007676371000035.jpg255170JPEG0007676 371000036.jpg255170JPEG0007676371000037.jpg255170JPEG0007676371000038.jpg255170JP EG0007676371000039.jpg255170JPEG0007676371000040.jpg255170JPEG0007676371000041.jpg255170JPEG0007676371000042.jpg255170JPEG0007676371000043.jpg255170All calculations were performed using Visual Basic (Microsoft®) Excel macros. It will be appreciated that other programming languages ​​and software may additionally or alternatively be used for the analysis.

[0084] Next, an exemplary embodiment of a user interface to the method for determining a dosing regimen of a drug for a subject will be described. Once the above table is calculated by the processor, it can be stored, for example, in memory and used to provide a recommendation to a user via a user interface. Alternatively, the user interface can be used to send a request to the processor to perform the above calculations and generate a recommendation on the fly (i.e., live upon receipt of a request from the user). For example, the processor can perform steps 1 to 3 above for a single body weight using parameters stored in memory upon receiving a weight input via the user interface, and optionally a selection of criteria based on which recommendation to select. In this example, the parameters stored in memory can include any of the parameters of available dosage forms, the maximum syringe volume available, and the type of dose regimen (e.g., dose per kg per base period, acceptable multiples of base period, etc.).

[0085] FIG. 3 shows a home screen on an exemplary user interface from which the method of the present invention can be accessed. The home screen 300 includes a weight input box 310 and a start button 320. Entering the weight in the box 310 and selecting the start button 310 sends a request to a processor (local or on a server), which calculates a recommended dose regimen based on the weight information or searches for a suitable pre-calculated dose regimen stored in memory. The processor then provides the user device with the necessary information to display a result screen 400. An example of a result screen is shown in FIG. 4. If the entered weight is outside of a preset range, the processor may return an error message instead. The result screen 400 shown in FIG. 4 is divided into two parts: a loading dose portion 400A and a maintenance dose portion 400B. The loading dose portion 400A includes a single dose recommendation 420 in line with the clinical guidelines above. This may be obtained from the "TD" column in Tables 2 and 3 above. The maintenance dose portion 400B includes three dose recommendations 430A, 430B, 430C reflecting three different dosing intervals aligned with the clinical guidelines described above. These may be obtained from the "TD" columns of Tables 4 and 5 above. The results screen 400 further includes a criteria selection drop-down menu 410. In the example shown, the selected criteria is "residual optimization" (i.e., least waste) by default, but other configurations are possible. Through this drop-down menu 410, the user may be able to select different criteria to prioritize in selecting a recommended dose regimen, with the selection of the prioritized criteria being one of two different hierarchies of criteria, as explained above. Upon a new selection via the drop-down menu, the results screen 400 may be updated to display the corresponding recommended dose regimen. In the example shown, the displayed results page is generated by outputting information from Tables 2 and 4 above for the loading dose portion 400A and the maintenance dose portion 400B, respectively. When the "Minimum Injections" option is selected in drop down menu 410, the page updates to include data selected from Tables 3 and 5, respectively.Dose recommendations 430B, 430C that optimize the criteria across all types of dose regimens are flagged 440. This information can be extracted from the "Overall Maintenance Regimens / Minimum Discards" column in Table 4. Each portion further includes a "Details" button 450A, 450B that displays a details screen as shown in FIG.

[0086] FIG. 5 shows a loading dose details interface 500 that may be used to output a recommended loading dose regimen to the user. A similar interface (not shown) is created for the maintenance dose using the details button 450B. The maintenance dose details interface (not shown) includes three panels, one for each type of dose regimen (weekly, biweekly, 4 weeks) in this embodiment. In other embodiments, the maintenance dose details interface may include a single dose regimen that has been determined to be optimal across all types of dose regimens. The loading dose details interface 500 includes an optimization criteria dropdown menu 510 and details regarding the recommended loading dose based on the currently selected optimization criterion. The details include total dose 520 extracted from the "TD" column of Tables 2 to 5 (Table 2 is used in this case), total dose 530 extracted from the "TV" column of Tables 2 to 5 (Table 2 is used in this case), a warning 560 that two different strength vials are being used extracted from the "VCC" column of Tables 2 to 5 (Table 2 is used in this case), and vial information 540 (which vial should be used, how much should be used from the vial, and how many vials should be used extracted from the "#V" and "#Vol." columns of each dosage form in Tables 2 to 5). The interface 500 further includes an "Injection Details" button 550. The button 550 causes the processor to provide the information necessary to display an Injection Details screen 600, an example of which is shown in FIG. 6A. The "Injection Details" screen 600 includes an Injection Details panel 650 that provides details of each administration 650A, 650B extracted from the "Injection" column of Tables 2 to 5. Screen 600 further includes a remainder calculation 660 (derived from the "W4" column of Tables 2 to 5), a total dose detail calculation 670 (derived from the "Wt" and "TD" columns of Tables 2 to 5), and a total volume calculation 680 (derived from the "#V", "#Vol.", and "mg" columns of each dosage form in Tables 2 to 5).

[0087] The term "computer system" includes hardware, software, and data storage devices for embodying the system or for executing the method according to the above embodiments. For example, a computer system may include a central processing unit (CPU), input means, output means, and data storage, which may be embodied as one or more connected computing devices. Preferably, a computer system has a display or comprises a computing device having a display for providing a visual output display (e.g., in the design of a business process). The data storage may include RAM, disk drives, or other computer-readable media. A computer system may include multiple computing devices connected by a network and capable of communicating with each other via the network.

[0088] The methods of the above embodiments may be provided as a computer program or as a computer program product or computer readable medium carrying a computer program configured to perform the above methods when run on a computer.

[0089] The term "computer-readable medium" includes, but is not limited to, any non-transitory medium or media that can be directly read and accessed by a computer or computer system. Media include, but are not limited to, magnetic storage media, such as floppy disks, hard disk storage media, and magnetic tape, optical storage media, such as optical disks or CD-ROMs, electronic storage media, such as RAM, ROM, memory, including flash memory, hybrids and combinations of the above, and the like.

[0090] Unless the context dictates otherwise, the above feature descriptions and definitions are not limited to any particular aspect or embodiment of the invention, but apply equally to all aspects and embodiments described.

[0091] As used herein, "and / or" should be interpreted as a specific disclosure of each of the two specified features or components, with or without the other. For example, "A and / or B" should be interpreted as a specific disclosure of (i) A, (ii) B, and (iii) each of A and B, as if each were individually set forth herein.

[0092] It should be noted that the singular forms "a," "an," and "the" as used herein and in the appended claims include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by using the antecedent "about," it will be understood that the particular value forms another embodiment. The term "about" in connection with numerical values ​​is optional and may mean, for example, + / - 10%.

[0093] Throughout this specification, including the claims which follow, unless the context indicates otherwise, the words "comprise" and "include", as well as variations such as "comprises", "comprising" and "including", will be understood to include a stated integer or step or group of integers or steps but not to exclude any other integer or step or group of integers or steps.

[0094] Other aspects and embodiments of the present invention provide those aspects and embodiments described above, with the term "comprising" replaced with the term "consisting of" or "consisting essentially of", unless the context dictates otherwise.

[0095] The features disclosed in the foregoing description, or the following claims, or the accompanying drawings and expressed in their specific form or in terms of means for performing a disclosed function, or a method or process for obtaining a disclosed result, may be utilized, both individually and in any combination of such features, as appropriate, to realize the invention in diverse forms thereof.

[0096] Although the present invention has been described in conjunction with the above exemplary embodiments, many equivalent modifications and variations will be apparent to those skilled in the art given this disclosure. Accordingly, the above exemplary embodiments of the present invention are considered to be illustrative and not limiting. Various changes can be made to the described embodiments without departing from the spirit and scope of the present invention.

[0097] For the avoidance of doubt, the theoretical explanations provided herein are provided for the purpose of enhancing the understanding of the reader, and the inventors do not wish to be bound by any of these theoretical explanations.

[0098] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0099] All documents mentioned herein are incorporated by reference in their entirety.

Claims

1. A computer-implemented method for determining a drug administration regimen for a subject, comprising: receiving a value of at least one parameter associated with the subject; an amount (A) of drug to be administered to the subject per base period (t) based at least in part on the value of the at least one parameter associated with the subject; ｔ determining the amount of drug to be administered, wherein the drug is available in at least two different dosage forms (D1, D2) differing in total amount of drug and / or drug concentration in the dose of the dosage form; The amount of the drug to be administered to the subject (A ｔ All the minimum combinations (A) of the at least two different dosage forms that can be used to achieve ｔ [D1, D2, D1D2]), where the minimum combination is the amount of the drug (A [D1, D2, D1D2]) to be administered to the subject by using the minimum number of doses of each dosage form in the dosage form combination (D1, D2, D1D2). ｔ ) or the amount of the drug (A ｔ ) the smallest combination, The combination (A) that satisfies criteria including at least the first criterion and the second criterion ｔ [D1, D2, D1D2]), wherein the first criterion and the second criterion are: a criterion applied to the value of the total waste associated with said combination, wherein the waste associated with a combination of dosage forms (Wt[D1, D2, D1D2], Wnlt[D1, D2, D1D2], Wn2t[D1, D2, D1D2]) is calculated as the difference between the total amount of said drug in said combination of dosage forms and the amount of said drug to be administered to the subject (At, Anlt, An2t); a criterion applied to the value of the total number of physical administration steps associated with said combination; and The criteria applied to the total number of physical adjustment steps involved in said combination selecting a subset of said combinations (A t [D1, D2, D1D2]) that satisfy criteria including at least a first criterion and a second criterion, one of which applies to the total number of physical preparation steps associated with each selected combination; and outputting the selected subset of combinations as an optimal dosing regimen for the subject; 4. A computer-implemented method comprising:

2. The combination (A) that satisfies criteria including at least the first criterion and the second criterion ｔ [D1, D2, D1D2]) said combination (A) according to a first criterion selected from said set of criteria; ｔ [D1, D2, D1D2]); and selecting a second subset of combinations from the first subset according to a second criterion different from the first criterion selected from the set of criteria; selecting a third subset of combinations from the second subset according to a third criterion selected from the set of criteria; Including, 2. The computer-implemented method of claim 1, wherein outputting the selected subset of combinations as an optimal dosing regimen for the subject comprises outputting the final selected subset of combinations as an optimal dosing regimen for the subject.

3. Calculating, for each of a plurality of multiples (n) of the basic period (t), the amount (A n1t , A n2t ) of the drug to be administered to the subject during a period corresponding to each multiple (n*t) of the basic period; The amount of each of the drugs to be administered to the subject (A ｎ１ｔ , A ｎ２ｔ calculating all minimal combinations of said at least two different dosage forms that may be used to achieve each of said basic periods (t) for each multiple (n); selecting the subset of the combinations (A t [D1, D2, D1D2], A n1t [D1, D2, D1D2], A n2t [D1, D2, D1D2]) separately for each of the elementary period (t) and the multiples (n) of the elementary period (t); outputting said subset of said selected combinations for each of said elementary period and said multiples (n) of said elementary period (t); 3. The computer-implemented method of claim 1, comprising:

4. Calculating, for each of a plurality of multiples (n) of the basic period (t), the amount (A n1t , A n2t ) of the drug to be administered to the subject during a period corresponding to each multiple (n*t) of the basic period; calculating all minimal combinations of the at least two different dosage forms that can be used to achieve the respective amounts (A n1t , A n2t ) of each of the drugs to be administered to the subject for each multiple (n) of the base period (t); The combination (A ｔ [D1, D2, D1D2], A ｎ１ｔ [D1, D2, D1D2], A ｎ２ｔ selecting said subset of D1, D2, D1D2] for said base period (t) and all of said multiples (n) of said base period (t) such that said selected subset is optimal across all prescription regimens considered.

3. The computer-implemented method of claim 1, comprising:

5. A computer-implemented method as described in any one of claims 1 to 4, comprising receiving values ​​of one or more further parameters associated with the subject, the one or more further parameters comprising a selection result of a criterion to be used as the first criterion, a selection result of a criterion to be used as the second criterion, or both, optionally wherein the selection result is from a predetermined set of criteria.

6. The waste volume (W) associated with the combination of dosage forms ｔ [D1, D2, D1D2], W ｎ１ｔ [D1, D2, D1D2], W ｎ２ｔ [D1, D2, D1D2]) is calculated by dividing the total amount of the drug in the combination of dosage forms by the amount of the drug to be administered to the subject (A ｔ , A ｎ１ｔ , A ｎ２ｔ 6. The computer-implemented method of claim 1, further comprising: calculating the total waste as a waste amount per period, the difference between the waste amount per period and the waste amount per time period.

7. The computer-implemented method of claim 1, further comprising calculating the total number of physical administration steps required to administer the combination.

8. The computer-implemented method of claim 1, further comprising calculating the total number of physical preparation steps required for administration of the combination.

9. 9. The computer-implemented method of claim 1, wherein the method is performed by a computing device having a user interface, and receiving the value of at least one parameter associated with the subject includes the computing device receiving information entered by a user via the user interface, and outputting one or more optimal dosing regimens includes the computing device providing information identifying the one or more optimal dosing regimens to a user via the user interface.

10. 9. The computer-implemented method of claim 1, wherein the method is performed by a computing device configured to communicate with a second computing device, wherein receiving the value of at least one parameter associated with the subject includes the computing device receiving information from the second computing device, and outputting one or more optimal dosing regimens includes the computing device communicating information identifying the one or more optimal dosing regimens to the second computing device.

11. 5. The computer-implemented method of claim 3 or 4, wherein the multiple (n) is an integer multiple.

12. The computer-implemented method of claim 11, wherein the base period (t) is selected from one day, one week, and one month.

13. the drug is available in three dosage forms (D1, D2, D3), or the drug is available in four dosage forms (D1, D2, D3, D4), or the drug is available in five dosage forms (D1, D2, D3, D4, D5), or the drug is available in six dosage forms (D1, D2, D3, D4, D5, D6); 13. The computer-implemented method of claim 1, wherein at least two of the dosage forms differ from each other by the drug concentration in a dose of the dosage form.

14. A computing device having a processor and memory, configured to determine a drug administration regimen for a subject by performing a computer-implemented method according to any one of claims 1 to 13.

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