Determining the time window for ingestion of a substance by a subject

Abstract

According to one aspect, a method is provided that includes receiving (402) first data from a sensor indicative of a concentration of a first substance in sweat secreted from a sweat gland of a subject, determining (404) a relationship between (i) a time of occurrence of a characteristic event related to the concentration of the first substance in the sweat and (ii) a time of occurrence of a characteristic event related to the concentration of the first substance in blood, and determining (406) a time window for ingestion of a second substance by the subject based on the relationship and the received first data. Another aspect provides an apparatus for performing this method.

Description

[Technical field]

[0001] The present invention relates to determining a time window for the ingestion of a substance by a subject, and more particularly to determining such a time window based on data acquired regarding the subject's sweat. [Background technology]

[0002] During medical procedures, administering the correct dose of a drug to a subject (e.g., a human or animal) at the correct time can be extremely important, for example, in the case of drugs used to treat Parkinson's disease or diabetes, or for sedation and / or analgesia (i.e., pain relief).

[0003] It is known that a substance taken by or administered to a subject, such as a drug, can be detected to some extent not only in the subject's blood but also in the subject's sweat. However, the substance is present in the subject's blood at a different (e.g., higher or lower) concentration than the substance is present in the subject's sweat. This discrepancy is due to how the substance is transported from the blood through interstitial fluid to the sweat glands, its possible production in the sweat glands, its excretion by the sweat glands, and possible reabsorption in the sweat ducts. Furthermore, following ingestion of a substance, the rate at which the substance appears in the subject's blood (e.g., becomes detectable in the blood) is faster than the rate at which the substance appears in the subject's sweat (e.g., becomes detectable in the sweat). It is also known that the concentration of a xenobiotic substance in blood and sweat decreases over time after a single administration. Thus, it may be difficult to determine the exact and current concentration of a substance in a subject's blood by simply measuring the concentration of the substance in the subject's sweat.

[0004] For example, when a drug is taken by or administered to a subject (e.g., intravenously), the drug is transported through blood vessels and capillaries throughout the subject's body and into the tissues surrounding the capillaries. For the drug to have a desired effect, a certain amount of the drug's active substance must be present in the bloodstream. After a first bolus or dose of the drug is administered, the next bolus or dose must be administered at the correct time to avoid overdosing and to prevent the subject from losing the therapeutic effect of the drug. However, it can be difficult to know when the second bolus or dose needs to be taken or administered. Summary of the Invention [Problem to be solved by the invention]

[0005] There is therefore a need for a method for determining an appropriate time window for the ingestion of a substance by a subject based on measurements taken of the subject's sweat. The invention is defined by the independent claims. The dependent claims define advantageous embodiments. [Means for solving the problem]

[0006]

[0005] Embodiments of the present disclosure provide a mechanism by which a measurement of the concentration of a substance in a subject's sweat can be used to determine a time window for ingestion of another substance or further ingestion of the same substance. This is achieved by determining a relationship between the concentration of the substance in the subject's sweat and the concentration of the substance in the subject's blood. The inventors have recognized that by determining the time difference between the occurrence of a particular event (e.g., a maximum value) related to the concentration of the substance in the subject's sweat and the occurrence of a particular event (e.g., the same event) related to the concentration of the substance in the subject's blood, a time window for suitable (e.g., safe) or inappropriate (e.g., unsafe) dosing or ingestion of a further amount of the substance can be determined.

[0007] According to a first particular aspect, a method is provided comprising the steps of receiving first data from a sensor indicating a concentration of a first substance in sweat secreted from a sweat gland of a subject, determining a relationship between (i) a time of occurrence of a characteristic event related to the concentration of the first substance in the sweat and (ii) a time of occurrence of a characteristic event related to the concentration of the first substance in blood, and determining a time window for ingestion of a second substance by the subject based on the relationship and the received first data.

[0008] The method further includes determining a concentration of the first substance in the subject's blood based on the relationship and the received first data.

[0009] In some embodiments, the method further comprises, prior to the step of receiving the first data, receiving second data indicating a time of occurrence of a characteristic event related to the concentration of the first substance in the blood.

[0010] The method includes generating a signal to alert a user regarding the determined time window, hi some embodiments, the method includes generating a control signal to control dispensing of the second substance at a time based on the determined time window.

[0011] The method, in some embodiments, further comprises obtaining physiological data regarding the subject. Determining the time window is further based on the physiological data.

[0012] The method further comprises obtaining at least one of a first pharmacological model for the first substance and a second pharmacological model for the second substance, The determining of the time window is further based on at least one of the first pharmacological model and the second pharmacological model.

[0013] The step of determining the relationship is based on at least one of the following: a determination of the time it takes for the first substance to be detected in the blood of the subject after ingestion of the first substance by the subject, an estimate of the time it takes for the first substance to be detected in the blood of the subject after ingestion of the first substance by the subject, the estimate being based on a population of people, an indication of the time it takes for an effect of the first substance to be detected by a user after ingestion of the first substance by the subject, and an indication of the time it takes for an effect of the first substance to be detected by a sensor after ingestion of the first substance by the subject.

[0014] In some embodiments, the received first data includes data indicative of a concentration of a metabolite of a first substance in sweat secreted from a sweat gland of the subject over a period of time, and determining the relationship includes determining a relationship between a time of occurrence of a characteristic event related to a concentration of the metabolite of the first substance in sweat and a time of occurrence of a characteristic event related to a concentration of the metabolite of the first substance in blood.

[0015] The method further comprises determining a metabolic rate of the first substance in the subject using a pharmacological model for the first substance and physiological data for the subject. The determining of the time window is further based on the determined metabolic rate.

[0016] In some embodiments, the first substance and the second substance interact. In some embodiments, the metabolite of the first substance and the second substance interact.

[0017] According to a second particular aspect, there is provided a computer program product comprising a non-transitory computer readable medium having computer readable code embodied therein, the computer readable code being configured, when executed by a suitable computer or processor, to cause the computer or processor to perform any of the methods set forth in the preceding paragraph.

[0018] According to a third particular aspect, there is provided an apparatus comprising a processor configured to perform the steps of the methods disclosed herein.

[0019] According to a fourth particular aspect, a system is provided for measuring data indicative of sweat produced by sweat glands of a subject, the system comprising a sweat sensor and an apparatus as disclosed herein. First data is received from the sweat sensor.

[0020] The system further comprises a user interface configured to provide a notification to the subject at a time based on the determined time window.

[0021] These and other aspects will be apparent from and elucidated with reference to the embodiments described hereinafter.

[0022] Exemplary embodiments will now be described, by way of example only, with reference to the following drawings: [Brief description of the drawings]

[0023] [Figure 1] 1 is a graph showing an example of the concentration of a substance in the blood for two successive ingestions. [Diagram 2] 13 is a graph showing further examples of concentrations of substances in the blood for two successive ingestions. [Diagram 3] 13 is a graph showing further examples of concentrations of substances in the blood for two successive ingestions. [Figure 4] 1 is a flow diagram of an example method according to various embodiments of the present disclosure. [Diagram 5] 1 is a graph showing an example of change in concentration of a substance in blood and sweat as a function of time. [Figure 6] 6 is a graph showing further examples of changes in concentration of substances in blood and sweat as a function of time. [Figure 7] 7 is the graph of FIG. 6 with various time domains indicated. [Figure 8]11 is a flow diagram of a further example method according to various embodiments of the present disclosure. [Figure 9] 6 is a graph showing further examples of changes in concentration of substances in blood and sweat as a function of time. [Figure 10] 6 is a graph showing further examples of changes in concentration of substances in blood and sweat as a function of time. [Figure 11] 6 is a graph showing further examples of changes in concentration of substances in blood and sweat as a function of time. [Figure 12] 1 is a schematic diagram of an example of a processor in communication with a computer-readable medium. [Figure 13] 1 is a schematic diagram of an example of an apparatus according to various embodiments of the present disclosure. [Figure 14] FIG. 1 is a schematic diagram of an example of a system according to various embodiments of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The embodiments disclosed herein provide a mechanism by which a time window for safe ingestion or administration of a substance can be determined based on measurements of the concentration of a previously taken substance in the subject's sweat and knowledge of the relationship between the concentration of a previously taken substance in the subject's sweat and the concentration of a previously taken substance in the subject's blood. Substances referred to herein include pharmaceuticals (e.g., drugs), ingredients (e.g., of food or drink), or any other substance consumed, ingested, taken, or administered to a subject (e.g., a person), or the products of such substances after the substance is metabolized by the subject's body. The present invention will prove particularly advantageous in clinical therapeutic areas where a subject should or should be administered a drug. The subject, in such an example, needs to take an initial dose of a first drug, and then a second dose of the same drug, or a dose of a second drug. Once a drug is absorbed into a subject's tissues, the concentration of the drug will decrease over time, and it is desirable for the second dose to be taken before the concentration of the drug from the first dose has decreased below the threshold at which the drug is therapeutically effective (e.g., particularly if the drug is being taken for pain relief). Furthermore, it is important not to take the second dose too soon while the concentration of the drug from the first dose is still relatively high, as this could result in an overdose.

[0025] 1, 2, and 3 are graphs showing examples of concentrations (in arbitrary units) of a substance in the blood of a subject obtained when a first dose and a second dose of the substance are taken at different times. In the graphs shown in FIGS. 1, 2, and 3, line 102 represents the concentration of the substance of the first dose in the blood of the subject, line 104 represents the concentration of the substance of the second dose in the blood of the subject, and line 106 represents the combined (e.g., sum) total concentration of the substance in the blood of the subject caused by the first dose of the substance and the second dose of the substance. In the examples shown, it is assumed that the total concentration should not exceed 25 arbitrary units (au) and should not fall below 5 a.u. This is for examples where concentrations above 25 a.u. may be harmful (e.g., toxic) to the subject and concentrations below 5 a.u. are insufficient to obtain the desired therapeutic effect.

[0026] In FIG. 1, the second dose (line 104) is taken at the appropriate time after the first dose (line 102) is taken so that the total concentration of the substance (line 106) does not fall below a level at which the drug is ineffective, but does not rise above a level that may be dangerous to the subject. The graph shown in FIG. 2 represents a scenario in which the second dose (line 104) is taken too soon after the first dose (line 102), resulting in a particularly high total concentration (line 106) around the time the second dose is taken. This scenario may, in extreme cases, result in an overdose for the subject, which may cause medical complications. The graph shown in FIG. 3 represents a scenario in which the second dose (line 104) is taken too long after the first dose (line 102), resulting in a total concentration (line 106) falling to near zero (i.e., a potentially therapeutically ineffective level) just before the second dose is taken. Among other advantages, the embodiments disclosed herein help provide an indication of an appropriate time window for taking a second dose such that the total concentration of a substance in the subject's blood falls within an acceptable, safe, and effective range, such as the example shown in FIG.

[0027] In embodiments disclosed herein, a volume of a substance taken by or administered to a subject (e.g., a person) is referred to as a dose or bolus. The term "bolus," as used herein, is intended to refer to a discrete amount of a drug, medication, or other compound taken or administered within a specific time period to raise the concentration in the blood to an effective level. It can be difficult to determine when the concentration of a particular substance has dropped sufficiently that a further bolus of the substance can be safely taken. By taking periodic blood samples, it is possible to measure the amount (e.g., concentration) of a substance in the subject's blood. Because taking blood samples can be intrusive and painful, an alternative approach includes measuring the concentration of a substance present in the subject's sweat. However, as noted above, there is a time lag between a particular concentration of a substance in the subject's blood and the corresponding concentration of the substance in the subject's sweat. Similarly, there is a time lag between the occurrence of a particular feature (e.g., a maximum concentration) in the concentration profile of a substance in the subject's blood and the occurrence of the same feature in the concentration profile of the substance in the subject's sweat. In the disclosed embodiments, this time lag is taken into account. The time lag / lag varies depending on the nature of the substance (e.g., type of drug) and the subject, among others, and the time lag is influenced by factors such as the subject's physiological parameters, the subject's age, the subject's sex, and the subject's hormone levels, as well as interactions of the substance with other substances, such as food, drinks, and other medications. The subject's sweat rate and the subject's location also affect the time lag.

[0028] A first aspect of the invention relates to a method. Figure 4 is a flow diagram of an example of a method 400. The method 400 includes a method, for example, a method of determining a time window for ingestion of a substance by a subject. The method 400 includes, at step 402, receiving first data from a sensor indicative of a concentration of a first substance in sweat secreted from a sweat gland of the subject. The sensor in some embodiments forms part of (e.g., is incorporated into or associated with) a sweat sensing or sweat measuring device, which in some examples includes a patch or device configured to be placed on (e.g., attached to) the skin of the subject. In other embodiments, the sensor includes or forms part of (e.g., is incorporated into or associated with) a wearable device such as a smart watch.

[0029] In this disclosure, the term "subject" is intended to include any living organism capable of sweating, including a human or an animal. In some particular embodiments, the subject includes a human (i.e., a person), e.g., a person undergoing a medical procedure or health evaluation that involves detecting and / or measuring a concentration of a substance in the person's sweat. The first data indicative of the concentration of the first substance includes, e.g., a measurement of the concentration of the first substance in the subject's sweat. In some embodiments, sweat secreted from the subject's sweat glands is collected by a sweat collector (e.g., a sweat collecting portion at the location of a patch on the subject's skin) and transferred to a sensor for analysis. In other embodiments, the sensor directly receives and analyzes the secreted sweat.

[0030] The substance (e.g., first substance) measured or analyzed by the sensor includes a pharmaceutical (e.g., drug), a food or drink ingredient, or a biomarker present in sweat that indicates the presence of some other substance or condition, as described above. Thus, in some embodiments, the sensor includes a biosensor. The substance more generally includes a xenobiotic, and the sensor includes a biosensor for measuring a characteristic (e.g., concentration) of the xenobiotic in sweat. A xenobiotic substance is a substance that is not naturally found or naturally produced in a living organism (e.g., in the human body). While the sensor is configured or adapted to detect a specific substance for the analysis or measurement of the concentration of the substance, in other embodiments, the sensor is configured to identify several substances and analyze or measure the concentration of one or more of the substances in the sweat.

[0031] In some embodiments, the first data includes a single measurement of the concentration of the first substance in sweat (i.e., a measurement of the concentration of the first substance at a particular time). However, in other embodiments, the first data includes multiple measurements of the concentration of the first substance in sweat over a period of time. Measurements may be taken, for example, at intervals or periodically (e.g., every 30 seconds, every minute, every 2 minutes, every 5 minutes, every 10 minutes, every 30 minutes, every hour, etc.).

[0032] The method 400 includes determining a relationship between (i) the time of occurrence of a characteristic event related to the concentration of the first substance in sweat and (ii) the time of occurrence of a characteristic event related to the concentration of the first substance in blood, in step 404. This step 404 is performed once and then used multiple times. The results of step 404 are stored, for example, in a look-up table.

[0033] The method 400 includes, at step 406, determining a time window for ingestion of the second substance by the subject based on the relationship and the received first data. The time window includes one or both of a time window for appropriate / safe ingestion of the substance or a time window during which ingestion of the substance may be unsafe / inappropriate. In some embodiments, the first substance and the second substance include the same substance, while in other embodiments, the first substance and the second substance include different substances. The first substance and / or the second substance include a xenobiotic substance. Steps 404 and 406 are discussed in more detail below with reference to FIG. 5.

[0034] 5 is a graph 500 illustrating an example of the concentration of a substance (e.g., a first substance) in blood (line 502) and the concentration of the substance in sweat (504) as a function of time. admin In this example, the substance is detectable in the subject's blood (i.e., the concentration of the substance is measurable in the subject's blood) immediately after administration, and therefore the time at which the initial concentration of the substance in the blood changes, t bl,0 is equal to the time the substance was administered (i.e., t admin ≡t bl,0 ) is assumed. Therefore, the material bl,0 It begins to appear in the subject's blood at a maximum concentration of C bl,max 5, the concentration of the substance in the subject's blood then begins to decline approximately exponentially. For the purposes of this disclosure, it is assumed that the decline in concentration of the substance in the subject's body (e.g., in sweat and blood) is exponential. The concentration of the substance in the subject's blood declines by half after the end of the substance's half-life according to the exponential model. In FIG. 5, the first half-life is at time t bl,1 / 2 At this point, the concentration of the substance in the subject's blood is C bl,1 / 2 The second half-life is time t bl,1 / 4 At this point, the concentration of the substance in the subject's blood is C bl,1 / 4 As shown in the figure.

[0035] Now, referring to line 504, the time when the first concentration change of the substance appears in the sweat is t sw,0 and t sw,0 is the occurrence in the blood of the subject bl,0 Rather than time lag t diff Again, the concentration of the substance in the subject's sweat (due to the very fast uptake of the substance) reaches a maximum concentration C sw,max The concentration of the substance in the subject's sweat declines approximately exponentially, with an initial half-life of t sw,1 / 2 The concentration of the substance in the subject's sweat after sw,1 / 2 and the second half-life t sw,1 / 4 The concentration of the substance in the subject's sweat after sw,1 / 4 As shown in the figure.

[0036] The "signature event" associated with the concentration of the first substance referred to in step 404 includes any event that occurs in association with the concentration of the substance, as shown in the example of Figure 5. A signature event may be, for example, the time at which the concentration of the substance first begins to increase after administration of the substance (i.e., t bl,0 and t sw,0 Another characteristic event occurs when the concentration of the substance reaches a maximum (i.e., C bl,max and C sw,max Another characteristic event is the time when the concentration of the substance is halved (i.e., C bl,1 / 2 and C sw,1 / 2) (e.g., the half-life of the substance). Another characteristic event may occur at the moment an effect of the substance in the subject's body is first detected based on an indication from the subject. Another characteristic event is based on an estimate of the time it takes for the substance to be detected in the subject's blood, the estimate being based on estimates or measurements for a population of people (e.g., a population of people sharing similar physiological data or with similar attributes). Other characteristic events related to the concentration of the first substance may also be used, and further examples are discussed below. The step of determining the relationship (step 404) is generally based on at least one of the following: a determination of the time it takes for the first substance to be detected in the subject's blood after ingestion of the first substance by the subject; an estimate of the time it takes for the first substance to be detected in the subject's blood after ingestion of the first substance by the subject, the estimate being based on a population of people; an indication of the time it takes for the effects of the first substance to be detected by a user (e.g., by the subject, a caregiver, an observer) after ingestion of the first substance by the subject; and an indication of the time it takes for the effects of the first substance to be detected by a sensor after ingestion of the first substance by the subject. For example, as described below, a sensor (e.g., an accelerometer) is used to detect movement, such as vibration or trembling, which are known effects caused by some medical conditions. The sensor detecting a decrease in effect indicates that the medication (i.e., the first substance) has begun to take effect.

[0037] t diff (i.e., the time delay of a concentration change in sweat (e.g., a signature event) compared to an equivalent change in blood) is, in the following example, the time t admin and the initial concentration change of the substance in sweat, t sw,0 is approximated using the time difference or time delay between the measured time and t diff In other examples, t is represented by the time difference between the maximum concentration in blood and the maximum concentration in sweat, as described above, or the time difference between other characteristic events occurring on a concentration versus time curve. In this example, it is assumed that the amount of substance present in the subject's blood and sweat prior to the first administration of the substance is very small or zero.

[0038] The time difference in this example, t diff is expressed as follows: t diff =t sw,0 -t admin [1]

[0039] This situation occurs with a time t uptake is negligible or applies to very fast materials, so t uptake < <t diff Within the limits of t diff ≒t diff +t uptake This rapid uptake is due to the t admin ≡t bl,0 This means that the time between administration of the substance and its appearance in the blood is negligible. Normally, substances administered by inhalation or intravenous injection are taken up rapidly. The t admin The value of t is derived by the processor of the computing device executing method 400 from a record associated with the subject, such as an electronic medical record (EMR), by manual input by a user into a user interface associated with the processor, or, in instances where the substance is administered automatically, from an internal clock of the system or device administering the substance. diff Thus, according to a basic example, is determined by measuring the time between administering a substance (e.g., a drug) to a subject and the substance appearing in the subject's sweat (e.g., the concentration of the substance increases from zero).

[0040] t diff Once , is determined, the concentration of the substance in sweat can be directly mapped (e.g., by a processor) to the concentration in blood, where the peak concentration of the substance in blood, C bl,max But the time difference t diff After that, the peak concentration in sweat C sw,maxWe further assume that the change in concentration of the substance in sweat, after correcting for time delay, corresponds directly to the change in concentration of the substance in blood (i.e., the concentration trends between blood and sweat are 1:1 correlated). However, the concentrations of the substance in blood and sweat do not have the same scalar magnitude, since the concentration of the substance in sweat can be lower or higher than the concentration of the substance in blood. In the example shown in FIG. 5, the maximum concentration of the substance in sweat is lower than the maximum concentration of the substance in blood.

[0041] In practice, the relative concentration of a substance in blood at a given time t (i.e., C bl (t) / C bl,max ) is the relative concentration in sweat C sw (t) / C sw,max , and can be predicted, for example, by extrapolation using an exponential function applied to previously obtained measurements, as shown in FIG. 6 and discussed in more detail below. Alternatively, the relative concentration of a substance in blood at a given time t can be calculated based on the substance's half-life t 1 / 2 For example, hydroxychloroquine is an example of a substance that can be detected and the concentration measured in the blood and sweat of a subject. The half-life (i.e., absorption half-life) of hydroxychloroquine is 3.6 hours. The relative concentration of the substance in the blood of a subject at a given time t can be expressed as: C bl (t) / C bl,max =C sw (t+t diff ) / C sw,max [2] Here, C sw (t) is given by: C sw (t)=C sw,max ×exp(-λ(tt diff )) [3] Here, λ is a positive number called the decay constant of the attenuation (i.e., the material), which is determined by the half-life of the material (λ=ln(2) / t 1 / 2 etc.).

[0042] It should be noted that the time t [hours] is defined relative to an overall time scale, based on the initial administration of the active substance at time t=0.

[0043] 6 is a graph 600 illustrating a further example of the concentration of a substance (e.g., a first substance) in blood (line 602) and the concentration of a substance in sweat (solid line 604) as a function of time. In this example, measurements of the concentration of the substance in a subject's sweat (solid line 604) are only taken up to a certain time, and the dashed line 604' represents an estimate or prediction of the change in concentration of the substance in the sweat by extrapolating the concentration after a certain time.

[0044] To illustrate the use of such extrapolation to predict concentrations, assume that a substance with a half-life of 1 hour (i.e., λ = ln(2) / 1 ≈ 0.693) is administered at time t = 0 and it takes 15 minutes for this substance to first appear in sweat, therefore t diff = 0.25 hours. After 2 hours, the relative concentration of the substance in the subject's blood, C bl (2) / C bl,max It is desired to know. Substituting all the constants and values ​​into equations [2] and [3], we get: C sw (t) / C sw,max =exp(-ln(2)(2-0.25))=0.297 [4] This is the relative concentration of the substance in the sweat that is measured. C bl (t) / C bl,max =exp(-ln(2)(2))=0.250 [5] This is the actual relative concentration of a substance in the blood.

[0045] From this example, the measured sweat concentration C at a given time t sw (t), the maximum concentration in sweat, C sw,max , and the time difference t diff It is clear that it is possible to calculate the half-life from this and subsequently determine the relative concentration of the substance in the blood as a function of time.

[0046] Because it takes time for a substance to diffuse from the blood through the interstitium into the sweat gland, there is a time lag (i.e., t diff Note that due to the variability in sweat concentrations, the relative concentrations of a substance measured in sweat will be much greater than the relative concentrations of a substance measured in blood at a given time.

[0047] t diff The step of determining is considered a calibration step, preferably performed when the substance is first administered to the subject. Once correction for the time delay between the concentrations of the substance in sweat and blood has been made, the relative concentration of the substance in the blood may be determined at any time, as explained above. This allows a number of important parameters to be determined regarding the safe or appropriate administration of the substance within an appropriate time window, and / or the prevention of unsafe or inappropriate administration of the substance within a time window.

[0048] To determine an appropriate time window for administering an additional amount of the substance to the subject, a latest administration time and an earliest administration time are determined, the latest time being determined based on the intent of not allowing the concentration of the substance in the subject's body to fall below a lower limit, and the earliest time being determined based on the intent of not allowing the concentration of the substance in the subject's body to increase above an upper limit.

[0049] The therapeutic lower limit or threshold of the desired effect of a substance in blood is determined by the time t sw,ll occurs earlier than time t bl,ll (where the subscript "ll" represents the lower limit). Again, the time difference or time delay between events relating to the concentration of a substance in sweat and blood is expressed as t bl,ll is used to determine t bl,ll =t sw,ll -t diff [6]

[0050] The concentration of a substance in the blood is at the therapeutic lower limit C bl,llTo prevent the concentration of the substance from decreasing below t, further administration of the substance (e.g., a further bolus or dose of the drug) must be administered no later than time t latest =t bl,ll The drug must be given to the subject by 2 p.m., again assuming that uptake of the substance is immediate.

[0051] For a given substance, t latest is determined by rearranging and simplifying equation [3] and solving for t as follows: t sw,ll =-ln(C sw,ll / C sw,max ) / λ+t diff [7] therefore, t latest =t bl,ll =t sw,ll -t diff =-ln(C bl,ll / C bl,max ) / λ [8] where C sw,ll is the therapeutic lower limit of the substance in sweat. Substituting equation [6] into equation [2], C sw,ll / C sw,max ≡C bl,ll / C bl,max can be derived.

[0052] Equations [7] and [8] imply that due to a time lag, a lower limit for the concentration of a substance in blood occurs at a time when the relative concentration of the substance in sweat is greater than or equal to the relative concentration of the substance in blood.

[0053] For example, the therapeutic lower limit is C bl,max / 4 , a substance with a half-life of 1 hour (i.e., λ = ln(2) / 1 ≈ 0.693) is administered at time t = 0 and takes 15 minutes to first appear in sweat, i.e., t diff = 0.25 hours. By substituting the constants and values ​​into equation [8], it is possible to determine the latest time to administer an additional amount of substance (e.g., a bolus or dose of a drug). t latest =-ln(0.25) / 0.693=2 hours {tadmin {for} [9]

[0054] The step of determining the time window for administering a further amount of the substance may, as described above, be determined by determining the earliest time t within which a further amount of the substance needs to be administered to prevent the concentration of the substance from exceeding an upper threshold above which the subject may suffer an overdose. earliest An overdose can occur, for example, when a second amount of a substance (e.g., a second bolus of a drug) is administered too soon after a first amount of a substance (e.g., a first bolus of a drug). The earliest time is time t bl,ul (where the subscript "ul" stands for upper limit). Again, the time difference or time delay between events relating to the concentration of a substance in sweat and blood is calculated using the following formula: bl,ul is used to determine t bl,ul =t sw,ul -t diff

[10]

[0055] The concentration of a substance in the blood exceeds the therapeutic upper limit (i.e., the toxic threshold) C bl,ul To prevent the concentration of the substance from increasing to or exceeding the concentration of the substance, further administration of the substance (e.g., a further bolus or dose of the drug) is required no earlier than time t earliest =t bl,ul must be given to the subject after

[0056] For a given substance, t earliest rearrange equation [3] to solve for t, and find that the amount of excess material is C bl,ul -C bl,max By recognizing that the sigma θ is given by t sw,ul =-ln((C sw,ul -C sw,max ) / C sw,max ) / λ+t diff

[11] therefore, t earliest =t bl,ul =t sw,ul-t diff =-ln((C bl,ul -C bl,max ) / C bl,max ) / λ

[12] where C sw,ul is the upper therapeutic limit for substances in sweat.

[0057] For example, the therapeutic upper limit is 3 / 2 × C. bl,max , a substance with a half-life of 1 hour (i.e., λ = ln(2) / 1 ≈ 0.693) is administered at time t = 0 and takes 15 minutes to first appear in sweat, i.e., t diff = 0.25 hours. By substituting the constants and values ​​into equation

[12] , it is possible to determine the earliest time to administer an additional amount of substance (e.g., a bolus of drug). t earliest =t bl,ul =t sw,ul -t diff =-ln((1.5-1) / 1) / 0.693=1 hour {t admin {for}

[13] Thus, an appropriate time window t for administering a further amount of substance (e.g., a further bolus or dose of a drug) is determined. app t earliest and t latest Based on this, it is defined as follows: t earliest ≦t app ≦t latest

[14] Therefore, based on the above example, 1 hour ≤ t app ≦2 hours.

[0058] Determining such an appropriate time window may be particularly important and applicable to drugs with a narrow therapeutic window, such as lithium.

[0059] FIG. 7 shows the graph 600 of FIG. 6 with indications of various time windows. The first region 702 represents a period during which administration of a further amount of the substance would cause the concentration of the substance in the subject's blood to exceed the upper therapeutic limit. The first region 702 therefore represents a time window during which it is too early to administer a further amount of the substance, as this would cause an overdose. The second region 704 represents a period during which administration of a further amount of the substance would cause the concentration of the substance in the subject's blood to fall below the lower therapeutic limit. The second region 704 therefore represents a time window during which it is too late to administer a further amount of the substance. The third region 706 represents a period during which administration of a further amount of the substance is appropriate / safe. The third region 706 therefore represents a time window during which it is too late to administer a further amount of the substance. app Represents.

[0060] Therefore, C sw (t), C sw,max , and t diff By measuring or determining the value of earliest and the latest time t latest It is possible to derive the earliest and latest times, and hence t app By determining whether or not the substance is administered, further measures can be taken to ensure or facilitate administration of the substance at the appropriate time (e.g., within a determined time window) and to prevent administration of the substance within an undesirable (e.g., too early or too late) time window, as discussed in more detail below.

[0061] FIG. 8 is a flow diagram of a further example of a method 800, including methods such as a method for determining a time window for ingestion of a substance by a subject. Method 800 includes the steps of method 400 discussed above. Method 800 includes, at step 802, determining a concentration of a first substance in the blood of the subject based on the relationship and the received first data. Step 802 can be realized, for example, when a relationship between the concentration of the substance in blood and the concentration in sweat is known, e.g., for ammonium, the concentration in sweat is 20-50 times higher than the concentration in blood. Similarly, the concentration of the first substance in blood can be determined when a calibration has been performed, e.g., when blood measurements are available, and a delay time tdiff is determined, as well as the relationship between the measured concentrations in sweat and the measured concentrations in blood (eg, by looking at peak concentrations, taking into account time lags).

[0062] As described above, a measurement of the concentration of the first substance in the subject's blood is made when the substance is first administered to the subject. For example, if the patient is receiving a drug, an indication of the concentration of the drug in the subject's blood can be determined by taking a blood sample one or more times immediately after or shortly after the drug is first administered to the patient. From this measurement, it is possible to determine, among other things, the time when the drug first appears in the patient's blood (after administration), the time when the concentration of the drug in the patient's blood is at a maximum, and the actual maximum concentration of the drug in the patient's blood. The method 800 thus comprises, prior to the step of receiving the first data in step 804, receiving second data indicative of the time of occurrence of a characteristic event related to the concentration of the first substance in the blood.

[0063] The determined time window is used in several ways. In some embodiments, a time window during which the substance is safely administered to the subject is indicated to a user. Method 800 thus comprises generating a signal in step 806 to alert a user regarding the determined time window. The user may include the subject, a medical professional (e.g., a nurse administering a medication to a patient), or any other person (e.g., a caregiver) for whom an alert regarding the determined time window is useful. The signal generated in step 806 (e.g., by a processor executing method 800) includes a signal configured to cause a device to provide an alert to a user. The generated signal may, for example, cause the device to sound an alarm or alert the user that it is an appropriate time to administer an additional amount of the substance. In some embodiments, the alert is provided to the user via a user interface, visually, audibly, via tactile means, or in some other manner. The user interface may include a user interface of a patient device or a device accessible to the patient and / or medical professional, such as a smartphone, a workstation, a wearable device (e.g., a smart watch). The alert serves as a reminder to inform the user that a new bolus of medication needs to be administered to the patient, for example by presenting the user with the message "Take a new bolus of medication in 30 to 45 minutes from now". Similarly, a reminder alert is given at the time when a new bolus of medication actually needs to be administered: "Take medication now". Once the user complies with the alert and administers the substance / medication, the user can stop any further alerts. In some embodiments, the alert is automatically stopped when it is detected that the concentration of the substance in the sweat is starting to increase or has increased beyond a threshold amount. However, if the user does not administer the medication, a further signal is generated to alert the user, for example "Drug not administered during the appropriate time window. Administer medication as soon as possible", prompting the user to administer the substance / medication immediately.

[0064] In some embodiments, in addition to generating a signal to alert the user about the determined time window, the method 800 further generates a signal to alert the user about the nature of the substance to be taken (e.g., which medication needs to be taken) and / or the amount of the substance to be taken (e.g., the dose of medication to be taken), e.g., "Take [1 tablet / 5ml / 60mg] of medication."

[0065] The method 800 further comprises obtaining physiological data about the subject at step 808. Such physiological data may include details of the subject such as the subject's gender, age, medical background, weight or blood pressure, or other clinical data related to the subject. The step of determining the time window (step 406) is further based on the physiological data.

[0066] The physiological data includes, in one example, data indicating the time when the subject begins to get tired, the time when the subject usually goes to bed, and / or the time when the subject usually wakes up. Such data is taken into account when determining the time window, for example taking into account the sleep-wake pattern of the subject. For example, the subject may indicate that he or she usually wakes up at 7 am and may take the medication immediately after waking up. The user is alerted or informed of one or more possibilities for taking the medication, such as, in such an example, "If you take the medication at 10 pm, you should take 60 mg. If you instead take the medication at 11 pm, you should take 50 mg." The subject (e.g., patient) can then determine how much of a dose to take depending on the time they want to go to bed. The method further takes into account expected concentration levels and presents the subject with time ranges only for those substances / medications that have a half-life that is high enough to cover the night without an additional bolus that increases the concentration of the substance above a threshold (e.g., dangerous) limit before sleep, and thus have a high enough concentration of the substance when the subject wakes up. Otherwise, the subject would have to wake up during the night to administer the additional dose. The method, in such an example, includes generating a signal to notify the subject of the appropriate time window during the night during which the additional dose should be administered.

[0067] Method 800, in some examples, includes displaying to a user (e.g., a subject and / or a medical professional) a visual representation (e.g., a graph) of the measured concentration of the substance over time and / or an indication of the current status of the substance in the sweat and / or blood. Such information may be presented on a device (e.g., a smartphone) or device (e.g., a patch) that performs the subject's measurements. A visual indication of the determined time window (e.g., t earliest From latest ) will be displayed.

[0068] In some embodiments, a device (e.g., a processor) configured to execute the methods 400, 800 communicates with a device capable of administering a substance to the subject. The method 800 thus further comprises, in step 810, generating a control signal to control dispensing of the second substance at a time based on the determined time window. Such automatic drug administration is performed to avoid situations where a user forgets or is unable to administer the substance / medication themselves, or to reduce the burden on medical professionals. Automatic drug administration is achieved, for example, using an intravenous line or an infusion pump.

[0069] In some embodiments, one or more factors affect the concentration of a substance in the subject's sweat, such that the concentration does not decrease exponentially as expected. Thus, according to some embodiments, the first data indicative of the concentration of a first substance in sweat includes multiple measurements of the concentration of the first substance. The multiple measurements are used to determine a time difference (or time delay) t diff In some embodiments, a measurement or a series of measurements of the concentration of a substance in the subject's sweat is taken after each dose of the substance is administered (e.g., after each bolus of drug is administered). Each measurement is used to determine the time difference t diff is calculated and the average is calculated and used for further calculations. diff Use a comparison of values ​​of t to determine the variation at different times of day. diff Any differences between the values, and the reasons for any differences, are determined and action is taken based on the comparison. For example, it may be determined that the subject needs to reduce the dose of medication administered in the morning.

[0070] Additional measurements can be prompted or triggered by various events. For example, diffSince t may vary with sweat rate, if it is determined that the subject's sweat rate is changing significantly (e.g., if the subject begins to sweat more or less), additional measurements are taken. In some instances, additional measurements are taken if there is a significant change in the subject's weight. In other instances, additional measurements are taken if a significant change in hormone levels is detected (e.g., related to menstruation). diff In this case, t is determined from measurements at sweat rates equivalent to the current (or previous) sweat rate. In this situation, the substance is already present in the subject's bloodstream, so t diff is the time t for the peak concentration of a substance in the blood after a new bolus is administered. bl,max t , and the time when the concentration of the active substance in sweat is maximum sw,max This can be expressed as follows: t diff =t sw,max -t bl,max

[15]

[0071] If the uptake time of the substance can be neglected, as in the example shown in Figure 5, t bl,max is admin Let's make it equal to.

[0072] In the examples discussed above, it has been assumed that the uptake time of the substrate into the blood following administration of the substrate to a subject is very fast (i.e., negligible). However, in some cases, a substance may not be rapidly taken up into the bloodstream (i.e., t uptake ≧t diff , or t uptake <t diff However, t uptake < <t diff This is because the time t admin does not indicate the presence of the substance in the bloodstream, meaning that equation [1] does not hold. This occurs in the case of substances administered by ingestion or absorption through the skin. In these cases, t diff =t sw,0 -t uptake

[16] where tsw,0 is the time when the first concentration change of a substance in sweat occurs (i.e., the first detectable change in the concentration of a substance), and t uptake is given by the following formula: t uptake =t bl,0 -t admin

[17] Here, t bl,0 is the time when the substance is first taken up into the blood (e.g., first detected in the blood), and t admin is the time the substance was first administered.

[0073] t uptake is actually determined in one of several ways, for example by measuring the concentration of the substance in a blood sample taken from the patient at a given time point after the first administration of the substance (i.e., administration of the substance at a time when the substance is not currently in the subject's blood). This scenario occurs when using a blood gas analyzer, for example at the bedside or in a central laboratory in an intensive care unit (ICU), when a hospitalized subject (e.g., patient) first receives the substance and the blood gas analyzer is used to analyze the blood sample taken from the arterial or venous line. Alternatively, as mentioned above, a population-based estimate of the uptake time of a given substance is used. The population-based estimate is based on a specific population (e.g., a specific patient group) using parameters such as sex, age, and especially weight to improve accuracy. In another example, the subject manually provides an indication via a user interface of when he or she feels unwell and / or the effects of the active substance are beginning. As mentioned above, t bl,0 It is assumed that there are no concentrations of the substance already present in the subject's bloodstream that would confound the determination of

[0074] In some embodiments, another sensor can be used to determine when a substance (i.e., a drug) begins to take effect in the subject's body. This is associated with an increase in the concentration of the substance in the subject's blood. For example, a body part (e.g., a hand) of a subject suffering from Parkinson's disease will tremble if the subject does not take the drug. The tremor / vibration is measured using a motion sensor such as an accelerometer, which may be worn, for example, as a bracelet or ring, or measured every time the subject uses his or her phone. A decrease in trembling measured by the sensor indicates that the drug has begun to take effect in the subject's blood.

[0075] In an alternative embodiment, t diff is the time t when the concentration of a substance in the blood is measured. bl,meas and the time point at which the relative concentration of the substance in sweat, relative to the maximum concentration in sweat, matches the relative concentration of the substance in the measured blood sample (i.e., time t, where C sw / C sw,max =C bl,meas. / C bl,max ) is determined based on the time difference between the measured concentration of the substance in the sweat and the measured concentration of the substance in the sweat. In this embodiment, the measurement of the concentration of the substance in the sweat can be performed semi-continuously (e.g., at regular intervals) without causing any significant discomfort to the subject, so that the concentration can be measured sufficiently. According to this embodiment, the time difference can be expressed as follows: t diff =t (Csw / Csw,max=Cbl,meas. / Cbl,max) -t bl,meas

[18]

[0076] 9 is a graph 900 showing a further example of the concentration of a substance (e.g., a first substance) in blood (line 902) and the concentration of a substance in sweat (line 904) as a function of time for a substance that has slow uptake in the blood (and sweat) of a subject, as discussed above. The time lag / delay between blood and sweat can be determined by comparison of characteristic events in the graphs discussed above (e.g., when the concentration first begins to increase, when the concentration is at a maximum, or at the half-life of the concentration). However, the time lag / delay in this example is determined from the concentration of the sample (point 906 in FIG. 9 ) measured in a blood sample taken from the subject at any time t, and the measured concentration in sweat (point 908 in FIG. 9 ) at the time when the relative concentration in sweat matches the relative concentration of the substance in the blood sample at time t, as discussed above.

[0077] In this example, it is assumed that the measurement of the concentration of the substance in the blood is performed after the concentration in the blood has reached a maximum value, which can be determined, for example, by examining the trend of the concentration of the substance in the blood (e.g., by noticing when the concentration begins to decrease) over two successive blood measurements, or by using timing based on a known pharmacological model, such as a pharmacokinetic-pharmacodynamic (PK-PD) model, for the particular substance.

[0078] More generally, when determining the time window in step 406, a pharmacological model for any of the substances to be administered to the subject is taken into account. In some embodiments, the method 800 includes, in step 812, obtaining at least one of a first pharmacological model for the first substance and a second pharmacological model for the second substance. Thus, if the first substance and the second substance are the same substance, the same pharmacological model is used, whereas if the first substance and the second substance are different, separate pharmacological models are obtained and used. The step of determining the time window (step 406) is further based on at least one of the first pharmacological model and the second pharmacological model. As described herein, the one or more pharmacological models are supplemented with physiological data for the subject.

[0079] In some embodiments, the substance administered to the subject is not itself measurable in sweat. However, some substances are metabolized or biotransformed by the subject's body to produce metabolites that can be detected in sweat and whose concentrations can be measured in sweat. admin In such an example, t does not indicate the presence of the metabolite in the subject's blood, nor does it indicate the time it takes for the metabolite to appear in the subject's sweat. diff Equation [1] is no longer applicable to determine t diff When judging the capture time t uptake In addition, the time for metabolism or biotransformation must be taken into account. t diff =t sw,0 -(t uptake +t metabolism )

[19] Here, t uptake and t metabolism is given by the following formula: t uptake =t bl,0 -t admin

[20] t metabolism =t bl,metabolite -t bl,0 [twenty one] Here, tadmin is the time when the substance was first administered to the subject, t bl,0 is the time when the substance first appears in the blood, t bl,metabolite is the time at which a metabolite of a substance is first present in the blood.

[0080] Substituting equations

[20] and

[21] into equation

[19] , we get the following t diff We obtain a simplified formula for t diff =t sw,0 -(t bl,metabolite -t admin )=t sw,0 -t bl,metabolite [twenty two] [t admin → Because it is 0]

[0081] Equation

[22] expresses the time of uptake into the bloodstream, t uptake Note that this applies to substances with fast uptake times as well as substances with long uptake times. Furthermore, since the metabolism of a substance is not instantaneous, t bl,metabolite -t admin Note that will always be >0.

[0082] t bl,metabolite is actually determined in one of several ways. bl,metabolite is determined using, for example, the concentration of metabolites measured in a blood sample taken from the patient at a given time point after the first administration of the active agent. This scenario occurs when other methods are used, as discussed above, in instances where a hospitalized subject initially receives a substance but blood sampling is not possible.

[0083] In an alternative embodiment, t diff is the time t at which the concentration of the metabolite in blood was measured. bl,metabolite_meas and the time point at which the relative concentration of the substance in sweat, relative to the maximum concentration in sweat, matches the relative concentration of the metabolite in the measured blood sample (i.e., time t, where C sw,metabolite / C sw,metabolite,max =C bl,metabolite_meas. / C bl,metabolite,max) according to this embodiment, the time difference can be expressed as: t diff =t bl,metabolite_meas =t where (C bl,metabolite_meas. / C bl,metabolite,max )-t bl,metabolite_meas [twenty three]

[0084] 10 is a graph 1000 showing an example of the concentration of a metabolite of a substance (e.g., a metabolite of a first substance) in blood (line 1002) and the concentration of a metabolite of a substance in sweat (line 1004) as a function of time. As with the example shown in FIG. 9 above, the time difference / delay between blood and sweat can be determined not only from a comparison of the characteristic events in the graphs discussed above (e.g., when the concentration first begins to increase, when the concentration is at a maximum, and the half-life of the concentration), but also from the concentration of the metabolite in the sample (point 1006 in FIG. 10) measured in a blood sample taken from a subject at any time t, and the concentration of the metabolite measured in sweat (point 1008 in FIG. 10) at the time when the relative concentration of the metabolite in sweat matches the relative concentration of the metabolite in the blood sample at time t.

[0085] Therefore, from the above example, the measured concentration of the metabolite of the first substance in sweat is also calculated with a time lag t diff It is clear that the method can be used to determine the time window for appropriate / safe administration of a further amount of the first substance. Thus, according to some examples, the received first data includes data indicative of a concentration of a metabolite of the first substance in sweat secreted from the sweat glands of the subject over a period of time. The step of determining the relationship (step 404) comprises determining a relationship between the occurrence time of a characteristic event related to the concentration of the metabolite of the first substance in sweat and the occurrence time of a characteristic event related to the concentration of the metabolite of the first substance in blood.

[0086] It should be noted that in various examples discussed herein, a pharmacological model is used to assist in determining the relationship (step 404) and / or determining the time window (step 406). Because metabolic rates of substances vary from person to person, physiological data about the subject is also used to assist in such determination. Thus, referring again to FIG. 8, the method 800 includes, at step 814, determining a metabolic rate of the first substance for the subject using a pharmacological model for the first substance and physiological data about the subject. The step of determining the time window (step 406) is further based on the determined metabolic rate.

[0087] In some embodiments, a substance (e.g., a first substance) is measurable in sweat, but the substance is metabolized in the subject's body and metabolites of the substance are not measurable in sweat. The metabolites, in this example, are considered "active" metabolites because they have an effect in the subject's body, whereas the (non-metabolized) substance is considered "inactive" because it has no effect in the subject's body. diffis determined in this example using equation [1],

[16] , or

[19] depending on whether the substance has negligible or slow uptake into the blood or is metabolized or biotransformed in the human body. However, as noted, the metabolites of the substance are active, but the substance itself is not. Thus, in this embodiment, the concentration of the inactive substance in sweat is used to determine the concentration of the inactive substance in the blood. Thus, the concentration of the active metabolite in the blood can be inferred. Note that the concentration of the metabolite is affected not only by the rate at which the inactive substance is metabolized or biotransformed in the body, but also by the rate at which the active metabolite is consumed in the body. These two rates are usually not equal, resulting in a non-trivial transfer function between the concentration of the inactive substance and the concentration of the active metabolite. This can be overcome by obtaining and using a pharmacological model (e.g., a pharmacokinetic-pharmacodynamic, or PK-PD, model). Data showing the rate of absorption of drugs after oral ingestion and subsequent metabolism is generally available from pharmaceutical companies for each substance or drug and is usually based on the age, weight, and sex of the subject. With this patient-specific data input, the concentration of the drug's metabolites is estimated from metabolic data available from pharmaceutical databases or pharmacological models. Once the concentration of the metabolites is determined, it can be correlated with the concentration of inactive substances in sweat. An example of this embodiment is shown below in FIG. 11.

[0088] 11 is a graph 1100 showing an example of the concentration of a substance (e.g., a first substance) in blood (line 1102) and the concentration of the substance in sweat (line 1104) as a function of time. In this example, dashed line 1106 shows the time lag t using measurements of the concentration of metabolites of the substance and the concentration of inactive substances in sweat that are inferred or predicted based on a pharmacological model using patient-specific data. diff and the concentration of the inactive substance in the blood, determined by taking into account

[0089] Up to now, embodiments of the present invention have been discussed in which the second amount of a substance to be administered is the same substance as that administered in the first administration. In other words, in method 400, the first substance and the second substance are the same substance. However, different substances (e.g., active substances) may interact with each other. For example, a drug or nutrient (e.g., a nutrient such as a vitamin, mineral, or food or drink ingredient) may interact with another type of drug or nutrient. In some cases, interactions between different substances have adverse effects on the subject's body and need to be avoided or minimized. To achieve this, embodiments of the present disclosure enable the determination of a suitable time window in which the second substance can be safely administered after the administration of the first different substance.

[0090] The steps of method 400 are performed for each type of substance (e.g., each drug and ingredient to be administered to / consumed by the subject). diff , and / or the time difference t taking into account any acquisition time diff +t uptake is performed as a calibration step for each substance. This is done, for example, for drugs, nutrients, and / or components of the first substance and at least one of the drugs, nutrients, and components with which it reacts. Once the time difference is determined, a time window is determined and information or advice is given to the user (e.g., the subject and / or a medical professional) as to when and when not to administer the drug or consume the substance. For example, If the subject has taken a medication that should not be combined with alcohol, a "green light" (e.g., a tolerance notification) will be displayed to the user when it is again safe for the subject to consume alcohol, and / or a "red light" (e.g., a warning notification) will be displayed to the user when alcohol should not be consumed. If the subject is planning to take a medication that can be taken after drinking alcohol, the subject will be informed when it is safe to take it. For example, by extrapolation, the time at which the concentration of alcohol in sweat falls below a lower limit can be determined, and from that time, t diff,alcohol +t uptake,medicationSubtracting this gives the earliest time the medication can be taken. The subject is informed of the safe or appropriate time window for taking an iron supplement after vitamin C has been taken (as vitamin C enhances the uptake of iron by the body) or the safe or appropriate time window for taking vitamin C when an iron supplement has been taken; or Subjects are informed of the time window after an iron supplement has been taken during which calcium should not be taken (because calcium reduces iron uptake) or the time window after calcium has been taken during which iron supplements should not be taken.

[0091] In a further refinement of this embodiment, it is possible to determine whether potentiation or depotentiation is occurring (e.g., when the effect of one substance is increased in the presence of another substance, or when one drug acts to reduce the effect of another drug). This can occur, for example, when a patient eats a food, such as grapefruit, that is known to interact with some drugs. The method includes, in such an example, generating a signal to notify or alert the subject that a food-drug interaction is occurring. This is particularly important in the case of potentiation, as the effect of the drug on the patient is stronger despite the administration of an appropriate bolus of the drug.

[0092] Thus, some embodiments of the present disclosure are used in scenarios in which a first substance interacts with a second substance, or in scenarios in which a metabolic product (e.g., a metabolite) of a first substance interacts with a second substance.

[0093] In the above-discussed examples, interactions between various substances are detected from the concentrations of substances measured in sweat. For example, if the concentration of a particular substance (e.g., a biomarker) is significantly higher or lower than expected, it is determined that a particular drug is not working as expected. Thus, it is determined that some interaction is occurring. Similarly, if the decrease in concentration deviates from the expected exponential decrease, it is determined that another substance is interacting with the substance, decreasing (or enhancing) the effect of the substance.

[0094] In some cases, a subject may be taking multiple different substances / drugs simultaneously, which allows each substance to be taken up separately into the blood and undergo drug metabolism / biotransformation. In such cases, the methods described herein may be used to determine the time t diff +t uptake , and / or t diff , t latest , and t erliest can be determined and recorded for each substance (e.g., drug A, drug B, drug C, etc., or metabolite A, metabolite B, metabolite C, etc.). It should be noted that these various substances are administered at various times (i.e., not simultaneously). Thus, in some embodiments, the method includes generating a signal to provide an alert / reminder / alert / advice, etc. to guide the patient and / or user as to when the various medications should and / or should not be administered. The subject may be informed, for example, to "take Drug A at 12:00, Drug B at 12:30, and Drug C at 13:00."

[0095] Additionally, in some embodiments, the amount or dosage of each medication is communicated to the subject. For example, the subject may be provided with a notification that reads, "Take 1 tablet of medication A at 12:00, 10 mg of medication B at 12:30, and 60 ml of medication C at 13:00."

[0096] In a further embodiment, the method detects whether a patient has taken the wrong medication or amount of medication, or whether a medication has been taken at the wrong time, based on the concentration of the medication in the subject's sweat. An alert / warning / alarm can be provided to the subject and / or a medical professional. This is particularly advantageous as many elderly polypharma patients have difficulty taking the right medication at the right time due to the large number of different medications that need to be administered.

[0097] The substance is dispensed or administered to the subject as a bolus in some examples described herein. However, in some drug delivery systems, such as those used in infusion therapy, the medical drug or nutrient is dissolved and administered in an infusion liquid, and is not administered as a bolus, but is given by regulating the flow rate of the infusion liquid to the body. Thus, some of the embodiments described above cannot be used with infusion therapy systems. In such systems, a quasi-bolus administration method is implemented. When infusion therapy is started, the flow rate is set to a high value for a short period of time and then reduced to a normal flow rate. A bolus of the substance is then administered (e.g., injected), which allows the concentration of the substance in the blood to be determined from the measured concentration in the sweat. As described in the above embodiments, a parameter is determined that allows the concentration of the substance in the subject's blood to be determined from the measured concentration of the substance in the subject's sweat, even during periods when a bolus is not administered. In this way, the concentration of the substance in the subject's blood can be determined based on the measured concentration of the substance in the subject's sweat during infusion therapy. The determined information can therefore be used to increase or decrease the flow rate of the infusion liquid. This applies to drugs that occur naturally in the human body, such as insulin.

[0098] It will be apparent from the above discussion that the steps of the methods 400, 800 are performed using one or more processors of one or more computer processing devices. A further aspect of the present invention therefore provides a computer program product. Figure 12 is a schematic diagram of an example of a processor 1202 in communication with a computer readable medium 1204. According to some embodiments, the computer program product comprises a non-transitory computer readable medium 1204, the computer readable medium having computer readable code embodied therein, which, when executed by a suitable computer or processor 1202, is configured to cause the computer or processor to perform the steps of the methods 400, 800 disclosed herein.

[0099] The processor 1202 may in turn form part of an apparatus, such as a computing device (e.g., a desktop computer, a laptop computer, a tablet computer, a smartphone, or a wearable device) or a server. A further aspect of the invention therefore provides an apparatus. FIG. 13 is a schematic diagram of an example of an apparatus 1300. The apparatus 1300 comprises a processor 1202 configured to perform steps of the methods 400, 800 disclosed herein. In some embodiments, the apparatus 1300 further comprises a computer readable medium 1204.

[0100] In some embodiments, the device 1300 further comprises a sensor for, among other things, measuring a concentration of a substance in the subject's sweat. However, in other embodiments, the sensor and the device 1300 are separate components that can communicate with each other as part of a system. FIG. 14 is a schematic diagram of an example of such a system 1400. The system 1400 comprises a sweat sensor 1402 for measuring data indicative of sweat produced by the subject's sweat glands. The sweat sensor 1402 includes, for example, a sensor capable of measuring a concentration of a substance (e.g., a first substance, a biomarker, etc.) in the subject's sweat. The system 1400 further comprises a device (e.g., the device 1300) disclosed herein. The first data received by the processor 1202 of the device 1300 is received from the sweat sensor 1402.

[0101] In some embodiments, the system 1400 further comprises a user interface 1404 configured to provide a notification to the subject at a time based on the determined time window. The user interface 1404 comprises, for example, a display or a speaker (e.g., of a portable device such as a smartphone, or of the apparatus 1300 itself) for presenting information regarding the determined time window to a user (e.g., the subject or a medical professional). Such a notification may, for example, inform the user that taking or administering the second substance is safe, or that taking or administering the second substance is currently unsafe, as described above. Other alerts, notifications, and warnings may be presented via the user interface 1404, as discussed herein.

[0102] The embodiments described herein provide a mechanism by which valuable information can be determined from measurements obtained from a subject's sweat. Analysis of a subject's sweat is much less intrusive than drawing blood from the subject for analysis. Based on the data obtained on the sweat, a relationship between the concentration of a substance in the sweat and the concentration of the substance in the subject's blood can be determined, and then a time window for administering further substances to the subject can be determined. Thus, the subject can know whether it is safe to take further amounts of a substance or to take another substance, such as another drug, based solely on the measurements obtained on the subject's sweat.

[0103] Processor 1202 may include one or more processors, processing units, multi-core processors, or modules configured or programmed to control device 1300 in the manner described herein. In certain implementations, processor 1202 may include multiple software and / or hardware modules, each configured to or for performing individual or multiple steps of the methods described herein.

[0104] The term "module" as used herein is intended to include a hardware component, such as a processor or a component of a processor configured to perform a particular function, or a software component, such as a set of instruction data that has a particular function when executed by a processor.

[0105] It will be understood that the embodiments of the present invention also apply to computer programs adapted to implement the present invention, in particular computer programs on or in a carrier. The programs may be in the form of object code, such as source code, object code, code intermediate source and partially compiled form, or in any other form suitable for use in implementing the method according to the embodiments of the present invention. It will also be understood that such programs have many different architectural designs. For example, the program code implementing the functions of the method or system according to the present invention is subdivided into one or more subroutines. Many different ways of distributing functionality among these subroutines will be apparent to those skilled in the art. The subroutines are recorded together in an executable file to form a self-contained program. Such an executable file comprises computer executable instructions, such as processor instructions and / or interpreter instructions (e.g. Java interpreter instructions). Alternatively, one or more or all of the subroutines are stored in at least one external library file and linked statically or dynamically, for example at run-time, with the main program. The main program includes at least one call to at least one of the subroutines. The subroutines also have function calls between each other. An embodiment of a computer program product has computer-executable instructions corresponding to each processing step of at least one of the methods described herein, the instructions being subdivided into subroutines and / or stored in one or more statically or dynamically linked files. Another embodiment of a computer program product has computer-executable instructions corresponding to each means of at least one of the systems and / or products described herein, the instructions being subdivided into subroutines and / or stored in one or more statically or dynamically linked files.

[0106] The carrier of a computer program is any entity or device capable of carrying the program. The carrier includes, for example, a data storage device, such as a ROM, for example a CD ROM or a semiconductor ROM, or a magnetic recording medium, for example a hard disk. Furthermore, the carrier is a transmissible carrier, such as an electric or optical signal, conveyed via an electric or optical cable or by radio or other means. When the program is embodied in such a signal, the carrier is constituted by such a cable or other device or means. Alternatively, the carrier is an integrated circuit in which the program is embedded, the integrated circuit being adapted for or used in carrying out the method in question.

[0107] Variations to the disclosed embodiments can be understood and produced by those skilled in the art from a study of the drawings, the disclosure, and the appended claims, when practicing the principles and techniques described herein. In the claims, the word "comprises" does not exclude other elements or steps, nor does the singular form of an element exclude a plurality. A single processor or other unit performs the functions of several items recited in the claims. Means recited in mutually different dependent claims may be used in an advantageous combination. The computer program may be stored or distributed in a suitable medium, such as an optical storage medium or a solid-state medium, provided integrally with or as part of other hardware, or distributed in other forms, such as via the Internet or other wired or wireless telecommunication systems. Any reference signs in the claims should not be interpreted as limiting the scope.

Claims

1. Using the processor, receiving first data from a sensor indicative of a concentration of a first substance in sweat secreted from a sweat gland of the subject; acquiring physiological data regarding the subject; determining a time window for the ingestion of a second substance by the subject based on the received first data, the physiological data and a relationship between, on the one hand, the occurrence time of a characteristic event related to the concentration of the first substance in sweat and, on the other hand, the occurrence time of a characteristic event related to the concentration of the first substance in blood; The method comprising:

2. determining a concentration of the first substance in the subject's blood based on the relationship and the received first data. The method of claim 1 further comprising:

3. receiving, prior to the step of receiving the first data, second data indicative of the time of occurrence of the characteristic event related to the concentration of the first substance in blood; The method of claim 1 or 2, further comprising:

4. generating a signal to alert a user regarding the determined time window. The method of claim 1 , further comprising:

5. generating a control signal to control dispensing of the second substance temporally based on the determined time window. The method of claim 1 , further comprising:

6. obtaining at least one of a first pharmacological model for the first substance and a second pharmacological model for the second substance; 6. The method of claim 1 , further comprising: determining the time window further based on at least one of the first pharmacological model and the second pharmacological model.

7. 7. The method of claim 1, wherein the step of determining the relationship is based on at least one of: a determination of the time it takes for the first substance to be detected in the blood of the subject after ingestion of the first substance by the subject; an estimate of the time it takes for the first substance to be detected in the blood of the subject after ingestion of the first substance by the subject, the estimate being based on a population of people; an indication of the time it takes for an effect of the first substance to be detected by a user after ingestion of the first substance by the subject; and an indication of the time it takes for an effect of the first substance to be detected by a sensor after ingestion of the first substance by the subject.

8. the first data received includes data indicative of a concentration of a metabolite of the first substance in the sweat secreted from the sweat glands of the subject over a period of time; and 8. The method of claim 1, wherein the step of determining the relationship comprises a step of determining a relationship between a time of occurrence of a characteristic event related to a concentration of the metabolite of the first substance in sweat and a time of occurrence of the characteristic event related to a concentration of the metabolite of the first substance in blood.

9. determining a metabolic rate of the first substance in the subject using a pharmacological model for the first substance and the physiological data for the subject; 9. The method of claim 1, further comprising: determining the time window further based on the determined metabolic rate.

10. The method according to any one of claims 1 to 9, wherein the first substance interacts with the second substance, or a metabolic product of the first substance interacts with the second substance.

11. A computer program comprising computer readable code which, when executed by a suitable computer or processor, causes said computer or processor to carry out a method according to any one of claims 1 to 10.

12. An apparatus comprising a processor for performing the steps of the method according to any one of claims 1 to 10.

13. a sweat sensor for measuring data indicative of sweat produced by sweat glands of the subject; An apparatus according to claim 12. wherein the first data is received from the sweat sensor.

14. The system of claim 13 , further comprising a user interface that provides a notification to the subject at a time based on the determined time window.

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