Drug dosage determination devices and methods

Abstract

To provide devices and methods for determining an administration regimen of a drug for a subject.SOLUTION: A method of determining a drug administration regimen for a subject is provided, comprising computing an amount of drug to be administered to the subject per unit period of time, and determining combinations of at least two dosage forms that can be used to administer the amount of drug, and comparing the combinations against at least two different criteria.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to a computer-implemented method for determining a drug dosage regimen for a subject, and to a computing device for carrying out the method. The method and device of the present invention are applicable to determining a drug dosage regimen for a drug available in multiple dosage forms with different drug amounts and / or drug concentrations, particularly for drugs 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 medications for treatment and / or prevention. Clinical trials typically determine the safe and effective drug loading, along with the drug dose and administration interval that can be used to achieve that load. These may further depend on one or more patient-related parameters, such as the patient's weight, age, and gender. There may be various combinations of drug dose and administration interval that can meet the requirements set by the clinical trial. Furthermore, to increase administration flexibility, drugs can be made available in multiple different dosage forms.

[0003] Typically, it is up to medical professionals to select a dosage regimen that meets the requirements set by clinical trials and is appropriate for a particular patient. This selection can be a complicated task, and therefore, selecting a particular regimen may result in avoidable inconvenience and / or expense for the patient. These may be particularly problematic for expensive products administered over long periods of time and / or when administration is relatively complicated (e.g., by injection). Thus, there is an unmet need for a means for determining a patient's dosage regimen when choosing between multiple possibilities is not easy. Simple tools exist for calculating 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 error in calculating the amount of drug to be administered. Nevertheless, given the significant practical impact of selecting a dosage regimen for a patient, there remains a need in the art for more efficient and accurate means for determining a patient's dosage regimen. Summary of the Invention

[0004] The present 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 present method and device stem from the discovery that suboptimal dosage regimens may be regularly selected by medical professionals in such situations, and that the complexity of the problem of selecting an appropriate dosage regimen may far exceed the intelligence of the medical professional tasked with this selection. The inventors have determined that this discovery can be explained, at least in part, 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 counterintuitive to a set of criteria of patient relevance.

[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 t [D1, D2, D1D2]), and the minimum combination is calculated 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 (A t [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 can 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 minimal combinations 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 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 minimum combinations may include (c) starting with each dosage form, calculating the amount of drug (A) to be administered to the subject in sequential combination 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 above stated dose.

[0008] Also provided herein is a computer-implemented method for determining a drug administration regimen for a subject, the method comprising receiving a value of at least one parameter associated with the subject; and determining an amount (A) of drug to administer 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 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 and second criteria (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 apply 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 administered to a subject for treatment or prevention 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 differ depending on the concentration of the drug in the dosage form. Regardless of whether an excipient is included in the dosage form, the dosage form may differ depending on 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 prescribed according to the dosage form.

[0011] The disclosed devices and methods 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 be used only 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 subsequent administrations. For example, a single-use dosage form may be a vial of sterile solution or any other dosage form that is sterilized before consumption, and consuming 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 consuming a portion of the dosage form compromises the properties of the remaining dose. The properties may be related to safety (e.g., contamination, creation of derivative forms of the drug, etc.) or efficacy (e.g., drug degradation). For example, the dosage form may contain components that oxidize or decompose when exposed 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, as different combinations can be associated with different discard volumes (residual portion of the dose remaining after partial consumption).

[0012] The drug may be a biopharmaceutical. In embodiments, the drug is a polypeptide or protein. For example, the drug may consist of or include an antibody. In embodiments, the drug is an antibody such as described in EP2644698B1, which is incorporated herein by reference. In embodiments, the drug is emicizumab (marketed as HEMLIBRA®). The devices and methods of the present disclosure may be particularly advantageous in the context of biopharmaceuticals, as biopharmaceuticals can 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 disclosed device and method are particularly advantageous when a drug is available in at least two different dosage forms (D1, D2) that differ in the drug concentration in the dosage form. Indeed, in such cases, selecting an appropriate combination of dosage forms without using the present invention may be particularly difficult. Furthermore, the disclosed device and method may be particularly advantageous when the drug is administered at regular intervals over an extended period of time. Indeed, when a drug is administered over an extended period of time, it is particularly important to reduce, as much as possible, the inconveniences and disadvantages associated with administering the drug. A long period of time may refer to the period over which multiple administrations of the drug are required to achieve a therapeutic or prophylactic effect associated with the drug. For example, treatment of a prophylactic effect associated with a drug may require a minimum concentration of the drug to be maintained in the patient (e.g., in plasma) for a predetermined period of time, necessitating multiple separate administrations of the drug over that period. In some cases, the period of time may be the subject's lifetime. In embodiments, the drug is administered for the routine prevention of a disease or disorder. In embodiments, the disorder 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 methods and devices are 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, a 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 [D1, D2, D1D2]) is selected according to the first criterion. t The method may include selecting a first subset of combinations (D1, D2, D1D2) according to a second criterion different from the first criterion, 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 finally selected subset of combinations as the optimal dosing regimen for the subject. Furthermore, selecting a subset of combinations according to a criterion may include ranking the combinations according to the criterion and selecting all combinations with the highest ranks. Implementations based on sequential selection of subsets (i.e., hierarchical or nested application of criteria) are particularly simple and efficient. Furthermore, in embodiments using ranking to select a subset of combinations, it may be possible to track unselected combinations, since the ranked list of combinations created in the first selection can be used as a starting point for the second selection, e.g., by ranking the combinations according to a second criterion within the ranks 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 a subset of [D1, D2, D1D2] may include selecting a subset of combinations that satisfy first, second, and third criteria, 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 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 embodiments, 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 methods 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 relationships 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 (A) to be administered to the subject per basic period (t). tDetermining the amount of drug (A) to be administered to a subject per base period (t) based at least in part on a received value for the subject's weight. Relationships between the amount of drug to be administered per base period (e.g., per day, week, or month) and the subject's 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 weight) per base 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 base period (t) based at least in part on the subject's 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, disease severity / stage, etc.). In embodiments, 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 indicator of disease severity, identity, stage, co-occurrence of another disease or disorder, etc. The treatment-related parameter may be an indicator of another treatment the subject is receiving or has received. Thus, the computing device may be configured to select a relationship between the subject's weight and the amount of drug to be administered per basic period (t) (e.g., from a set of relationships stored in memory) 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) to be administered to the subject per basic period (t) based on at least the subject's weight and a further parameter related to the subject. tDetermining the amount of medication per selected basic period (t) may include the processor retrieving from memory a preset amount of medication per selected basic period (t) in response to the value of at least one further parameter associated with the subject, and multiplying the subject's body weight by the preset amount of medication per selected basic period (t).

[0019] The inventors have further recognized that in some situations, an appropriate dosing regimen may be based on one of multiple 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 likelihood of identifying a particularly advantageous dosing regimen. To accommodate and exploit this possibility, the computing device may calculate 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) to be administered to the subject is calculated for each multiple (n) of the base period (t). n1t , A n2t The method may be further configured to calculate all minimal combinations of at least two different dosage forms that can be used to achieve the desired dose.

[0020] In embodiments, one or more suitable intervals between administrations (e.g., a maximum suitable interval between administrations, etc.) are provided as input to the methods 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 associated with the subject. The one or more suitable intervals may be used to define another multiple (n) of the base period (t) suitable for use in the methods disclosed herein. For example, one or more amounts of drug to be administered per kg per week may be provided in combination with a maximum suitable interval of 4 weeks. In embodiments, the computing device is further configured to determine a multiple (n) of the base period (t) that is a submultiple of a particular multiple (n) of the base period (t), the particular 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 fall within preset limits (e.g., limits that may have been previously established by clinical trials, etc.).

[0021] In embodiments, 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 memory. Similarly, the methods 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 using one or more predetermined 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 dosing 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 must be determined for each subject, which may further complicate the work of the medical professional 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 referred to as a "loading phase." Following the loading phase, the drug may be administered according to a second dosage regimen, which may be referred to as a "maintenance phase." A predetermined amount (A) of the drug to be administered to the subject per base period (t) may be determined. 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 use based on a preset value for the first phase (e.g., loading phase) and based on a preset 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 result of the selection of the phase of treatment may be the amount of drug (A) to be administered to the subject per base period (t). t ) and / or a value for an appropriate interval between doses may be selected as input.

[0023] Some steps of the disclosed methods (and corresponding steps that the disclosed devices are configured to perform) may be performed before receiving a value for at least one parameter related to the subject. For example, the amount of drug (A) to be administered to the subject may be determined. 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 (A, B, C, D, E ... t ) and the amount of drug to be administered (A t , A nt ) the closest total amount of drug (A t , A nt ) and the amount of the closest identified drug (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 amount of drug (A) to be administered to the subject per base period (t) based at least in part on a predetermined set of values for 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 nt) The computing device may be configured to calculate all minimal combinations of at least two different dosage forms that can be used to achieve each of the following: Upon receiving a value for at least one parameter associated with the subject, the computing device may identify a closest value among a predetermined set of values for the at least one parameter, and calculate an amount of medication (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 ) to find the closest dose of drug to be administered (A t , A nt ) and the amount of the closest identified drug (A t , A nt The system may be further configured to select a subset of combinations from pre-computed combinations that may be used to achieve the desired result. Pre-computing the combinations may enable extensive automated and / or manual validation of the combinations before using them to generate recommendations to the user. Additionally, pre-computing the combinations may improve the speed at which output is provided to the 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 disclosed methods and devices. The user may be the subject themselves, or may be a person who uses the disclosed methods and devices 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 as 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 embodiments where 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 base period (t) and each multiple (n) of the base period (t), or may be performed jointly for all base periods (t) and multiples (n) of the base period (t). If the selection is performed individually, outputting the (final) selected subset of combinations may include outputting the (final) selected subset of combinations for each base period (t) and each multiple (n) of the base period (t). In other words, a separate optimal dosing regimen may be provided for each different dosing interval (t, and each multiple n of t) that has been considered. This advantageously allows the user to be presented with an optimal solution for each possible dosing interval that the user may wish to use, and the user can then select the most convenient dosing interval, knowing that they are 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 their preferences, combined with knowledge of whether some dosing intervals may allow for the selection of a more advantageous dosing regimen. For example, if multiple dosing intervals are possible, it may not be immediately apparent that some of these dosing intervals cannot be selected without compromising performance on one of the criteria that the user may be interested in. The disclosed methods and devices 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 all 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 the value of one or more additional parameters associated with the subject. For example, a criterion to be used as the 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 default values (e.g., default criteria stored in memory) may be used. Furthermore, the default values 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 predetermined criteria. For example, the method may include providing a set of predetermined criteria to a user and receiving the selection result of one or more criteria from the predetermined set as the value of the additional parameter associated with the subject.

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

[0029] In embodiments, the method further comprises determining 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 based on 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 multiples (n) and the waste amount (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 procure, and / or difficult to dispose of residuals. Furthermore, tracking the waste amount with respect to the amount of drug may be particularly advantageous if some of the dosage forms vary by their strength. Indeed, in such cases, even if the amount of dosage form used according to each dosage regimen could be determined, it may not be immediately apparent which dosage regimen is associated with the lowest waste amount. Furthermore, calculating the total waste (whether for the base period or a common multiple of the different n multiples considered) can be particularly advantageous, as it allows for determining optimal dosing regimens 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 embodiments, one of the criteria used to select the subset is applied to the value of 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 discard amount, the total number of physical administration steps required to administer the combination can be calculated, which can be used as one of the criteria used to select a subset of combinations. Calculating the total number of physical administration steps required to administer the combination can include calculating the minimum number of physical administration steps that can be used to administer the combination and that satisfy one or more rules selected from a preset maximum amount of drug for each physical administration step, a preset maximum amount of dosage form for each physical administration step, and restrictions on combinations of dosage forms with different concentrations in a single physical administration step. Furthermore, the rules regarding the preset amount of drug / dosage form for each physical administration step can be applied differently depending on the precision required to administer a specific amount. For example, an amount specified with a specific precision can be associated with a different preset maximum amount of drug / dosage form than an amount specified with another, lower specific precision. Each of these rules can be predetermined (e.g., stored in memory) or received as an additional parameter associated with the subject. Furthermore, the selection of one or more such predetermined rules can 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 may be available for each physical administration step, and selecting 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 administering the drug is difficult, painful, or inconvenient. Moreover, 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, automated calculation of the total number of steps required for administration and comparison of combinations based thereon may advantageously enable the selection of a combination that may not be intuitively preferable due to the complexity of factors that must be considered when administering a 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 dosage form. In some embodiments, each single injection has a preset maximum volume selected from a group including two preset maximum volumes (V1, V2). In some embodiments, each single injection has a preset maximum volume selected from a group including three preset maximum volumes (V1, V2, V3). In some embodiments, the computing device is further configured to prioritize administration regimens that do not combine single injections with different maximum volumes. For example, when calculating the number of physical administration steps associated with a combination, the computing device may associate the smallest possible number that does not use different maximum volumes with the combination. This may be useful for reducing the number of different syringes used. In embodiments, a single physical administration step can be a single ingestion of a volume of a dosage form that is a liquid formulation. In embodiments, a single physical administration step can be the unit of time required to administer a volume of a dosage form as a liquid formulation by intravenous means, for example, using an IV drip. In embodiments, the dosage form is a solid (e.g., tablet, powder, etc.) or encapsulated formulation. In some such embodiments, a 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 administration steps required for administration of the combination, the total number of physical preparation steps required for 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 administration of the combination can include calculating the number of doses of each dosage form that make up 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 packaging and, optionally, placed in a form suitable for administration (e.g., drawn into a syringe for injection, poured into a container for consumption, etc.). The total number of physical administration steps required for administration of the combination can be particularly useful when considering cases where administration requires preparation steps that are complex, error-prone, and / or prone to waste. For example, if the dosage forms must be placed in a form suitable for administration by heating, injection, dilution, dissolution, etc., each such step may be associated with the risk of error, waste, contamination, etc. Furthermore, since multiple doses of a dosage form may be suitable for administration in a combined form, the number of preparation steps may not be the same as the number of administrations. Similar to 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 embodiments, 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, further information about each combination can advantageously be calculated and optionally output to the user. This information can include one or more of the following: waste associated with the combination (as the amount of drug and / or the amount of dosage form combined across the dosage forms of the combination and / or separately for each dosage form of the combination), total waste associated with the combination (as the amount of drug and / or the amount of dosage form combined across the dosage forms of the combination and / or separately for each dosage form of the combination), the number of doses in each dosage form, the total number of doses across the dosage forms, the amount used from each dosage form (as the amount of drug and / or the amount of dosage form) and / or from each dose of each dosage form, the amount of each dosage form and / or each dose of each dosage form used in each physical administration step, the 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 of each dosage form used and the total amount of waste, and compare the total amount of waste 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 be generated.

[0035] In embodiments, a user interface may be provided that allows a user to input information including the 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 communicate 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 the user interface of the second computing device), and outputting one or more optimal dosing regimens by the computing device includes communicating information identifying the one or more optimal dosing regimens to the second computing device (which information the second computing device may be able to provide to the user via the user interface of the second computing device). Embodiments in which the same computing device performs the methods described herein and receives input / provides output via the 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 that performs 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 that implement 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 easily provided as cross-platform implementations, as they can be provided as, for example, web applications rather than platform-specific applications.

[0036] Also provided is a device for automatically determining a drug administration regimen for 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 the 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 drug to administer 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 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 ), and calculating the smallest combination (A t The device may have any of the above functionality.

[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 stored thereon instructions that, when executed by a processor, cause the processor to perform the 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 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 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 ), and calculating the smallest combination (A t [D1, D2, D1D2]) and outputting the selected subset of combinations as an optimal dosing regimen for the subject.

[0039] Also provided herein are methods 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 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 and second criteria (A t Also provided is a method of treating a subject with a drug, comprising automatically determining (e.g., by a processor) a drug dosage regimen for a subject by selecting a subset of combinations [D1, D2, D1D2], outputting the selected subset as an optimal dosage regimen for the subject, and treating the subject with the optimal dosage regimen (or one of the optimal dosage regimens) for the subject. Embodiments of this aspect may include any of the features described in connection with any other aspect.

[0040] Additionally, the present invention 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 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 and second criteria (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 D1, D2, D1D2] and output the selected subset of combinations as an optimal dosing regimen for a subject. [Brief explanation of the drawings]

[0041] [Figure 1] FIG. 1 illustrates an exemplary computing system in which embodiments of the present invention may be used. [Figure 2] 1 is a flow chart illustrating a method for determining a drug administration regimen for a subject. [Figure 3] FIG. 1 illustrates a home screen of an exemplary embodiment of a user interface for a method of determining a drug administration regimen for a subject. [Figure 4] 10A-10C illustrate result screens of an exemplary embodiment of a user interface for a method of determining a drug administration regimen for a subject. [Figure 5] FIG. 1 illustrates a dose details interface of an exemplary embodiment of a user interface for a method of determining a drug administration regimen for a subject. [Figure 6] 10A-10C illustrate an injection details interface of an exemplary embodiment of a user interface for a method for determining a drug administration regimen for a subject. DETAILED DESCRIPTION OF THE INVENTION

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

[0043] Specific embodiments of the present 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] FIG. 1 illustrates a first computing device 1. 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 multiple 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, or the like. The computing device 2 has at least one processor 202 and at least one memory 201, which together provide at least one execution environment. Typically, a mobile device has firmware and applications running in at least one regular execution environment (REE) with an operating system, such as iOS, Android, or Windows. 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. This 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 that typically includes a display. The display 204 may be a touchscreen. Other types of user interfaces may be provided, such as a speaker, a keyboard, one or more buttons (not shown), etc. 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, e.g., via the public Internet 3. The first computing device 1 may further be configured to output information to the user computing device 2, e.g., via the public Internet 3. The information may then be displayed by the user computing device 2, e.g., 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, web application, or progressive web application. In an embodiment, the method is implemented as a progressive web application running on the first computing device 1 and delivered 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 the 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 via its user interface 204 upon input from a user. The second computing device 2 may further be configured to output information to the 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 perform the steps of a method for determining a drug dosing regimen for a subject as described herein, which method 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 in 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 drug concentration in the dosage forms.

[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 administration, 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 indicator of disease severity, identity, stage, coexistence of another disease or disorder, etc. The treatment-related parameter may be an indicator of another treatment the subject is receiving or has received. The values of the one or more parameters may be entered by a user at user interface 204 and communicated to 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 at least in part based 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 embodiments, appropriate (e.g., safe and effective) amounts of drug to be administered per basic period (t) as a function of one or more parameters associated with the subject are provided as inputs to the methods 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 weight) per basic period may be provided as an input to the methods described herein. Furthermore, multiple such amounts of drug per kg per basic period may be provided, and the selection of such an 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 memory 101 / 201 a relationship linking one or more parameters related to the subject to a (e.g., safe and effective) amount of drug to be administered per basic period (t). Furthermore, if multiple such relationships are stored in memory 101 / 201, the selection of the relationship to be retrieved 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 the amount of drug (A) 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 processor 102 / 202 multiplying the subject's body weight by a preset amount of medication per base period (t). The base period t used may depend on the particular medication used, such as the minimum interval between doses evaluated in clinical trials. In embodiments, the base time t is selected from 1 day, 1 week, and 1 month. In embodiments, 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 one or more multiples (n) are calculated. One or more multiples (n) may be received in step 200 as further parameters associated with the subject (i.e., as user preferences). In embodiments, one or more multiple (n) values may be stored in memory 101 / 201. One or more multiple (n) values may be retrieved by processor 102 / 202 and used in step 220 (as default values), or one or more multiple (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, multiple n is typically 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) can be calculated by multiplying the amount of drug per dose by each value n. n1t , A n2t) can 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 can be stored in memory in combination with a maximum suitable interval of 4 weeks. These can 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 one skilled in the art will appreciate, the mathematical relationship between the amount of drug and the value of at least one parameter associated with the subject can also be provided by a user prior to 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 minimum combinations of at least two dosage forms of the drug that can be used to achieve the desired dose (A) are calculated. For example, the processor 102 / 202 may calculate all possible minimum combinations and store them in the memory 101 / 201. A minimum combination is one that can achieve the desired dose (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., two doses in dosage form D1), 4*D2 (i.e., four doses in dosage form D2), and 1*D1+2*D2 (i.e., one dose in dosage form D1 and two 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 will achieve 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 A t The minimum dose combination that achieves some amount A t and for several dosage forms D1, D2 (e.g., using 1*D1+2*D2 or 2*D1+1*D2, several amounts A t In an embodiment, the amount A t is less than the amount of drug contained in at least one of the dosage forms, so the required amount A t Depending on the type of combination, some types of combinations may not be represented by the minimum combination calculated in step 230. For example, A 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 embodiments, 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 embodiments, the drug should be administered to the subject in multiple phases that together form a course of treatment, and the dosage regimen may vary between the 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 dosage regimen. t) and / or one or more suitable intervals between administrations may vary between different stages of treatment. In embodiments, 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 embodiments, the 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 values of a parameter associated with the combinations and selecting combinations that maximize or minimize the parameter. Alternatively, combinations having values above or below a predetermined threshold of the calculated parameter may be selected. Furthermore, combinations having 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 parameter's minimum / maximum value 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 base period (t) and each multiple (n) of the base period (t). Alternatively, the selection may be performed jointly for each base period (t) and each multiple (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 connection with step 240. For example, processor 102 / 202 may evaluate the combinations calculated in step 230 and stored in 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), select a second subset of combinations in the first subset based on the evaluation, and store the second subset in 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 connection with step 240. For example, processor 102 / 202 may evaluate the combinations calculated in step 230 and stored in memory 101 / 201 (or only the subset selected in step 240, or only the subset selected in step 250) against the third criterion, select a third subset of combinations within the second subset based on the evaluation, and store the third subset in memory 101 / 201. As one skilled in the art will appreciate, any number of additional criteria may be used to hierarchically select subsets of 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 embodiments, the additional parameters received in step 200 include a selected criterion. In such embodiments, the criterion may be used as a first criterion for selecting a dosing regimen in combination with one or more preset additional criteria, which may be stored in memory 101 / 201. For example, the second criterion and any additional criteria (if used) may be automatically selected based on the criterion 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 additional parameters, including a first criterion and a second criterion, which may be used in combination with a third criterion, which may be set as a default parameter stored in memory 101 / 201. Step 200 may also include receiving at least three additional 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 criteria.

[0059] Combination-related parameters that can 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 to administer the combination, and the total number of physical preparation steps required to administer 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 a 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 combinations corresponding to the base period (t). The total waste amount over a 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 accomplished by multiplying the discard amount for each combination in the basic period by 4 and the discard amount for each combination in the multiple n=2 of the basic period by 2. The total number of physical preparation steps required to administer the combination can be calculated as the minimum number of physical preparation 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 memory 101 / 201 and retrieved by processor 102 / 202 to calculate the total number of physical preparation steps. The total number of physical preparation steps required to administer the combination can be calculated as the number of doses of each dosage form that makes up the combination. If multiple preparation steps are applied to some dosage forms, this can be stored in memory 101 / 201 as parameters of the dosage forms D1, D2 and retrieved by 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 the optimal dosage regimen for the subject according to the first and second criteria (and optionally a third or more criteria). In embodiments, outputting the optimal dosage regimen may include processor 202 causing user interface 204 to display information identifying one or more optimal dosage regimens. For example, processor 102 may communicate information identifying one or more optimal dosage regimens to processor 202, which may cause the information to be displayed on user interface 204. Alternatively, processor 202 may be capable of performing at least some of the above calculations locally, thus selecting combinations and outputting information identifying the selected combinations as optimal dosage regimens. In embodiments, a single optimal dosage regimen (i.e., combination of dosage forms) may be output. In embodiments, multiple optimal dosage regimens (i.e., combinations of dosage forms) may be output. In embodiments, a single optimal dosage regimen may be output for each of the base period (t) and multiples of the base period (n). In embodiments where multiple optimal dosing regimens are output, an indication of which of the output dosing regimens is optimal according to one of the criteria may also be output. For example, multiple optimal dosing regimens may be output along with an indication of which of the multiple optimal dosing regimens optimizes a first criterion. For example, if optimal dosing regimens are output separately for each n multiple, 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 them is optimal according to a criterion, such as the first criterion.

[0061] Outputting the combination includes providing information identifying the combination, including the identities and numbers of dosage forms comprising the combination. If applicable, the information identifying the combination may further include the administration interval (t, n*t). The information identifying the combination is provided to the user via a user interface or provided to a user device for provision to the user via the user interface. The user interface may be provided, for example, as a web page displayed on the user device. In such embodiments, the user can input information, such as by entering or selecting items, 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 following: waste volume associated with the combination; total waste volume associated with the combination; the amount used from each dosage form; the amount of each dosage form used in each physical administration step; and the like. 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 the at least two values are consistent. For example, the processor 102 / 202 may calculate the total amount of each dosage form used and the total waste volume, and compare the total waste volume with the total amount of each dosage form to ensure that the amount is consistent with the multiple of the dosage forms used.

[0063] As one skilled in the art will appreciate, the above general principles are applicable to situations where a drug is available in three or more 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, and 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 contained in each, not all types of combinations may be represented. For example, A t If the amount of the drug in D4 is less than the amount of the drug in D4, the minimum combination containing D4 in combination with other dosage forms may not be calculated. In embodiments, any two of the three or more dosage forms may differ by the total amount of the drug in the dosage formulation. Similarly, any two of the three or more dosage forms may differ by the concentration of the drug in the dosage formulation. Furthermore, any two of the two or more dosage forms may differ by both the concentration of the drug in the dosage formulation and the total amount of the drug in the dosage formulation.

[0064] Example An exemplary method for determining a drug administration regimen for a subject is described below. The described example relates to the 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, incorporated herein by reference. Emicizumab is a bispecific antibody that specifically binds to blood clotting factors IX / IXa and X and promotes the activation of factor X by factor IXa, thereby substituting for the cofactor function of factor VIII. This function is insufficient in patients with hemophilia A, resulting in 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 0.4 ml vial 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 0.7 ml vial 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 (congenital factor VIII deficiency) with factor VIII inhibitors and severe hemophilia A (congenital factor VIII deficiency, factor VIII <1%) without factor VIII inhibitors.

[0066] Clinical trials have determined that Hemlibra can be used in all age groups and should follow a two-step dosing regimen that includes: - Loading phase: The recommended dose is 3 mg / kg, administered once a week for 4 weeks. - Maintenance phase: The recommended dose is 1.5 mg / kg / week, administered at a minimum frequency of once every 4 weeks (maximum interval between doses is 4 weeks), i.e., 1.5 mg / kg administered once a week, 3 mg / kg administered once every 2 weeks, or 6 mg / kg administered once every 4 weeks.

[0067] In this example, additional dosing rules were provided, including combining two different concentrations of Hemlibra in the same syringe, ensuring that each injection does not exceed 2 ml when administered using a 1 ml or 2-3 ml syringe, and using a 1 ml syringe to administer the specified amount with two decimal points of accuracy. 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) × 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 available vial strengths. 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, potentially introducing errors because the regimen selected may not support adherence completely independently of the vial combination used. Indeed, adherence may depend on factors such as the number of injections required and the amount of waste associated with the regimen. Therefore, the inventors determined that the selection of a dosing regimen should take into account multiple variables, including, in this example, the frequency of administration in the maintenance regimen, patient weight, the different dosage forms available, restrictions on administration (volume and combination of dosage forms), and patient-related criteria, including the amount of product waste (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 designed a tool that takes all of these variables into account to determine a patient's dosing regimen.

[0069] In the particular implementation described here, the method takes as input: - Pre-set dose multipliers (x mg / kg) for the loading phase (QL=3 mg / kg), weekly (Q1W=1.5 mg / kg), biweekly (Q2W=3 mg / kg), and every 4 weeks (Q4W=6 mg / 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 to 150 kg in whole-number increments. - Rules regarding the administration procedure, such as the two possible volumes of syringes V1 and V2, the conditions under which a particular syringe volume cannot be used, and whether different vials / vials with different concentrations can be combined in the same syringe.

[0070] The method then performs three successive steps. 1. Calculate the dose: total dose (mg) by body weight for each regimen (loading, maintenance-weekly, maintenance-every other week, maintenance-every 4 week). 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 the combination that minimizes 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 specific weight is input through a user interface, recommendations can be easily extracted from the appropriate recommendation set. In other embodiments not described in detail below, steps 1 through 3 are each performed for a single specific weight. For example, steps 1 through 3 may be performed on-the-fly upon receiving a weight input through a 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 as follows for each body weight w=3...150: A L w t =QL*w (Equation 1) Aw 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] In this example, QL=Q2W, so Step 1 results in a list of 441 total doses (3 different total doses for each of the 147 different body weights). This list is used as input to Step 2, which calculates 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. 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 total 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 combination i. Sky Blue only (A w [SB]):Dose(A w ) to achieve the minimum number of sky blue vials, n SB =round.up(A w / (C SB *V SB )) (Formula 5]) In the formula, 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 increases until no additional vials are needed to make up the total volume (at this point, the number of SB vials is equal to the n vials calculated in step i). SB (Just below), 1 SB vial + dose (A w ) and the minimum number of P vials to achieve 2 SB vials + dose, etc. Number of SB vials n SB The minimum number of 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 reaches a point where no additional vials are needed to make up the total amount. w ) and the minimum number of T vials to achieve 2 SB vials + dose, etc. Number of SB vials n SB The minimum number of vials per n T =round.up((A w -1*(C SB *V SB )) / (C T *V T )) (Equation 7) It is calculated as: iv. Sky blue and brown combination (A w [SBB]): The number of SB vials is calculated based on the total amount (i.e., n calculated in step i). SB 1 SB vial + dose (A) until no additional vials are needed to make up w ) and 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 step a for the purple-dominated combinations. c. Repeat step a for the turquoise-dominated combination. d. Repeat step a for the Brown-dominated combination. e. Calculate the combination of three colors i. Sky blue + purple and turquoise (A w [SBPT]): where x = number of SB vials and y = number of P vials; When x=1, 1 SB vial + 1 P vial + the minimum number of T vials required to achieve a dose, 1 SB vial + 2 P vials + the minimum number of T vials required to achieve a dose, etc., the total amount of 1 SB vial + y P vials is A w Until it exceeds If x=2, then 2 SB vials + 1 P vial + the minimum number of T vials required to achieve the dose, 2 SB vials + 2 P vials + the minimum number of T vials required to achieve the dose, etc., 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 w Repeat step i for [SBTB] v. Sky blue + brown and purple (A w Repeat step i for [SBBP] vi. Sky blue + brown and turquoise (A wRepeat step i for [SBBT] vii. Purple + Turquoise and Sky Blue (A w Repeat step i for [PTSB] viii. Purple + 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 w Repeat step i for [BTP]

[0074] Step 2 also involves calculating several parameters for each minimum 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 amount (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 volume (ml or mg) drawn from each vial can be calculated and compared to the total volume (ml or mg) available from each vial.

[0077] The total volume aspirated from each vial can be calculated as the total volume present in all vials except the last one added, and the volume aspirated is the required volume A wThe total volume of the combination can be calculated as the volume required to reach the target volume minus the amount already provided by the other vials. As one skilled in the art will appreciate, the specific order of steps used to generate the combinations is arbitrary, and any order can be used as long as all possible combinations are generated. Furthermore, the parameters for each combination can be calculated as each combination is generated, or a list of combinations can be generated and looped through to calculate each parameter. The number of injections used to administer the combination is calculated based on the above rules regarding the volumes of syringes V1 and V2 and the rules regarding 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) Calculate the number of V1 = 1 ml or V2 = 2 ml injections required to administer the total amount of product provided in the combined sky blue vials. Calculate the number of V1 = 1 ml or V2 = 2 ml injections required to administer the total amount of product provided in all other vials combined, 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, and determine whether 1 ml syringes will be required for the remaining volume to be administered. Add up the four numbers above to generate three subcombinations: one that uses only V1 = 1 ml, one that uses only V2 = 2 ml, and two that use both volumes. - If you do not use the sky blue vial (n SB=0): Calculate the number of injections of V1 = 1 ml or V2 = 2 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. - If necessary, filter the combinations to retain only those that have the smallest volume 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 produced in step 1 are w For each of the weights w = 3 to 150 kg, a table listing all combinations and their parameters is obtained. 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 per equivalent period (e.g., 4 weeks) can also be calculated. In this example, the total waste per equivalent period is calculated by appropriately scaling the waste per dose, i.e., for n1=2 and n2=4 total doses (A w n1t , A wn2t ) by 2 and 4, respectively, or n=1 (i.e., A w t ) and n1=2(A w n1t ) is calculated by multiplying the waste relative to the total dose 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 the first criterion, then within each rank, ranking combinations according to the second criterion, and within each of these ranks, ranking combinations according to the third criterion, and / or flagging the highest-ranking combination within each rank). Furthermore, in this example, the ranking is performed according to two different hierarchies.

[0081] In the first tier, minimizing waste per equivalent period (e.g., total waste over four 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 fewest number of injections) are then ranked according to the number of vial draws. The final highest-ranked combinations (i.e., the highest-ranked combinations (based on vial draws) among the highest-ranked combinations (based on number of injections) among the highest-ranked combinations (based on total waste)) are then stored in a "Minimum Waste Recommendations" 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-four weeks), and the highest-ranked combinations are output to the "Minimum Waste Recommendations" 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 in a "Minimum Waste Suggested" list, or one may be arbitrarily selected. Furthermore, if a combination in the "Minimum Waste Suggested" 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), 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 optimal value 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 a "Minimum Injection Recommendations" 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-four weeks), and the highest-ranked combinations are output to the "Minimum Injections Recommendations" 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 Recommendations" list, or one may be arbitrarily selected. A combination in the "Minimum Injection Recommendations" list is flagged if it has either or both (i) the same total waste amount as the combined overall minimum total waste 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. The result of Step 3 is the creation of four data tables containing information and parameters for each combination that minimizes the above tier criteria. A subset of these tables is shown in Tables 2 through 5 below. Some of the values in these tables can be derived in multiple ways from values in other columns. For example, the total volume of each dosage form can be calculated by multiplying the number of vials and volume (Vials Whole [#V*Vol.], Vials Partial [#V*Vol.]) for each dosage form and summing them. Alternatively, the total volume of each dosage form can be derived from the total weight of product provided by each dosage form. In embodiments, to ensure internal consistency of the generated data, each value that can be calculated in more than one way is calculated in at least two of the ways. Similarly, data regarding total product volume and total product quantity should be convertible to each other based on data from other columns. In embodiments, to ensure consistency of the data, each volume / mg value is compared to its corresponding mg / volume value and / or its component volume and / or mg values. JPEG2025118728000002.jpg255170JPEG2025118728000003.jpg255170JPEG2025118728000004.jpg255170JPEG2025118728000005.jpg255170JPEG2025118728000006.jpg255170JPEG2025118728000007.jpg255170JPEG2025118728000008.jpg255170JPEG2025118728000009.jpg255170JPEG2025118728000010.jpg255170JPEG2025118728000011.jpg255170JPEG2025118728000012.jpg255170JPEG2025118728000013.jpg255170JPEG2025118728000014.jpg255170JPEG2025118728000015.jpg255170JPEG2025118728000016.jpg255170JPEG2025118728000017.jpg255170JPEG2025118728000018.jpg255170JPEG2025118728000019.jpg255170JPEG2025118728000020.jpg255170JPEG2025118728000021.jpg255170JPEG2025118728000022.jpg255170JPEG2025118728000023.jpg255170JPEG2025118728000024.jpg255170JPEG2025118728000025.jpg255170JPEG2025118728000026.jpg255170JPEG2025118728000027.jpg255170JPEG2025118728000028.jpg255170JPEG2025118728000029.jpg255170JPEG2025118728000030.jpg255170JPEG2025118728000031.jpg255170JPEG2025118728000032.jpg255170JPEG2025118728000033.jpg255170JPEG2025118728000034.jpg255170JPEG2025118728000035.jpg255170JPEG2025118728000036.jpg255170JPEG2025118 728000037.jpg255170JPEG2025118728000038.jpg255170JPEG2025118728000039.jpg255170JP EG2025118728000040.jpg255170JPEG2025118728000041.jpg255170JPEG2025118728000042.jpg255170JPEG2025118728000043.jpg255170JPEG2025118728000044.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 for the method for determining a drug administration regimen for a subject will be described. Once calculated by the processor, the table above can be stored, for example, in memory and used to provide recommendations to a user via a user interface. Alternatively, the user interface can be used to send a request to the processor to perform the calculations above and generate recommendations on the fly (i.e., live upon receiving a request from the user). For example, upon receiving a weight input via the user interface and, optionally, a selection of criteria based on which recommendation to select, the processor can perform steps 1 through 3 above for a single weight using parameters stored in memory. In this example, the parameters stored in memory can include parameters for available dosage forms, maximum available syringe volumes, and types of dosage regimens (e.g., doses per kg per base period, allowable multiples of base period, etc.).

[0085] FIG. 3 shows a home screen on an exemplary user interface from which the methods of the present invention can be accessed. Home screen 300 includes a weight input box 310 and a start button 320. Entering weight in box 310 and selecting 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 an appropriate pre-calculated dose regimen stored in memory. The processor then provides the user device with the information necessary to display results screen 400. FIG. 4 shows an example of a results screen. If the entered weight is outside of a preset range, the processor may instead return an error message. Results screen 400 shown in FIG. 4 is divided into two sections: a loading dose section 400A and a maintenance dose section 400B. Loading dose section 400A includes a single dose recommendation 420 aligned with the clinical guidelines described above. This can be obtained from the “TD” column in Tables 2 and 3 above. The maintenance dose portion 400B includes three dose recommendations 430A, 430B, and 430C, reflecting three different dosing intervals aligned with the clinical guidelines described above. These may be obtained from the “TD” columns in 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 defaults to “residue optimization” (i.e., minimum waste), although other configurations are possible. Through this drop-down menu 410, the user may be able to select different criteria to prioritize when selecting a recommended dose regimen; selecting a preferred criterion results in selecting one of two different hierarchies of criteria, as described above. Upon making a new selection via the drop-down menu, the results screen 400 may update 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. If the "Minimum Injection" 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 also includes a "Details" button 450A, 450B that displays a details screen as shown in FIG.

[0086] 5 shows a loading dose details interface 500 that can 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, four-weekly) 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 drop-down menu 510 and details about the recommended loading dose based on the currently selected optimization criterion. The details include a total dose 520 extracted from the "TD" column of Tables 2 through 5 (Table 2 is used in this example), a total dose 530 extracted from the "TV" column of Tables 2 through 5 (Table 2 is used in this example), a warning 560 that two different strength vials are being used extracted from the "VCC" column of Tables 2 through 5 (Table 2 is used in this example), 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 through 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 through 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 implementing the system or for performing 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 with a display for providing a visual output display (e.g., in designing a business process). Data storage may include RAM, a disk drive, or other computer-readable medium. 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 read and accessed directly by a computer or computer system, including, but 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, as used in this specification and the appended claims, the singular forms "a," "an," and "the" 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 use of 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 means, for example, + / - 10%.

[0093] Throughout this specification, including the claims which follow, unless the context requires otherwise, the words "comprise" and "include", and variations such as "comprises", "comprising", and "including", will be understood to include the specified 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" substituted 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] While 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 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 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 should not be construed as limiting the subject matter described.

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

Claims

1. A computing device comprising a processor and a memory, 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 2. Determining the amount of drug to be administered, 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; The amount of the drug to be administered to the subject (A ｔ All the minimum combinations of said at least two different dosage forms that can be used to achieve ｔ [D1, D2, D1D2]), wherein 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 Calculating the smallest combination that is greater than The combination (A) satisfies at least the first and second criteria. ｔ [D1, D2, D1D2]), and outputting the selected subset of combinations as an optimal dosing regimen for the subject; determining a dosing regimen for the drug to the subject by

2. The combination (A) satisfies at least the first and second criteria. ｔ [D1, D2, D1D2]) According to the first criterion, the combination (A ｔ [D1, D2, D1D2]), and selecting a second subset of the combinations from the first subset according to a second criterion different from the first criterion, and optionally selecting a third subset of the combinations from the second subset according to a third criterion. Including, 10. The computing device 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. the computing device: The amount of the drug to be administered to the subject (A ｎ１ｔ , A ｎ２ｔ ) for one or more multiples (n) of said base period (t); The amount of the drug to be administered to the subject (A ｎ１ｔ , A ｎ２ｔ and calculating, for each of said multiples (n) of said base period (t), all minimal combinations of said at least two different dosage forms that can be used to achieve said The computing device of claim 1 or 2, further configured to:

4. the computing device: The combination (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 multiple (n) of the elementary period (t); outputting a selected subset of the combinations for each of the base period and the multiples (n) of the base period (t); The computing device of claim 3 configured to:

5. the computing device: The combination (A ｔ [D1, D2, D1D2], A ｎ１ｔ [D1, D2, D1D2], A ｎ２ｔ 4. The computing device of claim 3, wherein the computing device is configured to jointly select the subset of [D1, D2, D1D2]) for the basic period (t) and all of the multiples (n) of the basic period (t).

6. 6. The computing device of claim 1, wherein the computing device is configured to receive values of one or more further parameters related to the subject, the one or more further parameters including a selection result of a criterion used as the first criterion, a selection result of a criterion used as the second criterion, or both, and optionally the selection result is from a set of predetermined criteria.

7. The computing device calculates 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 7. The computing device of claim 1, further configured to calculate a total waste amount as a waste amount per period, where the total waste amount is calculated as a difference between the selected combinations and the total waste amount per period, and optionally one of the criteria is applied to the total waste amount value associated with each selected combination.

8. 8. The computing device of claim 1, wherein the computing device is further configured to calculate a total number of physical administration steps required for administration of the combination, and optionally, one of the criteria is applied to the total number of physical administration steps associated with each selected combination.

9. 9. The computing device of claim 1, wherein the computing device is further configured to calculate a total number of physical preparation steps required for administration of the combination, and optionally, one of the criteria is applied to the total number of physical preparation steps associated with each selected combination.

10. 10. The computing device of claim 1, wherein the computing device comprises a user interface, wherein receiving the value of at least one parameter associated with the subject comprises the computing device receiving information input by a user via the user interface, and wherein outputting one or more optimal dosage regimens comprises the computing device providing information identifying the one or more optimal dosage regimens to a user via the user interface.

11. 10. The computing device of claim 1, wherein the computing device is configured to communicate with a second computing device, wherein receiving the value of at least one parameter associated with the subject by the computing device comprises receiving information from the second computing device, and outputting one or more optimal dosage regimens by the computing device comprises communicating information identifying the one or more optimal dosage regimens to the second computing device.

12. 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) that differ in the total amount of the drug and / or in the drug concentration in the dose; The amount of the drug (A ｔ All the minimum combinations of said at least two different dosage forms that can be used to achieve ｔ [D1, D2, D1D2]), wherein 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 Calculating the smallest combination that is greater than The combination (A) satisfies at least the first and second criteria. ｔ [D1, D2, D1D2]); outputting the selected subset of combinations as an optimal dosing regimen for the subject; 20. A computer-implemented method comprising:

13. The method comprises: The amount of the drug to be administered to the subject (A ｎ１ｔ , A ｎ２ｔ ) for one or more multiples (n) of said base period (t); The amount of the drug to be administered to the subject (A ｎ１ｔ , A ｎ２ｔ calculating, for each of said multiples (n) of said base period (t), all minimal combinations of said at least two different dosage forms that can be used to achieve said and the combination (A ｔ [D1, D2, D1D2], A ｎ１ｔ [D1, D2, D1D2], A ｎ２ｔ 13. The computer-implemented method of claim 12, wherein selecting the subset of [D1, D2, D1D2]) is performed individually for the basic period (t) and each of the multiples (n) of the basic period (t), or jointly for the basic period (t) and all of the multiples (n) of the basic period (t).

14. 14. A computing device as claimed in claim 3, or any one of claims 4 to 11 dependent on claim 3, or a computer-implemented method as claimed in claim 13, wherein the multiple (n) is an integer multiple and, optionally, the basic period (t) is selected from one day, one week, and one month.

15. 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); at least two of the dosage forms differ from one another by the drug concentration in the dose of the dosage form; A computing device according to any one of claims 1 to 11 or 14, or a computer-implemented method according to any one of claims 12 to 14.

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