Methods and systems for performing dose escalation

Abstract

The present invention provides a computer-implemented method for controlling dose escalation of a drug administered to a subject to treat obstructive sleep apnea, the method comprising obtaining a dose level of a previous dose of the drug administered to the subject and obtaining a measure of drug efficacy based on the subject's response to the previous dose, and determining dose escalation for future doses of the drug based on the measure of drug efficacy and the dose level of the previous dose.

Description

[Technical Field]

[0001] The present invention relates to the field of dose titration, and more particularly to the field of automatic dose titration. [Background technology]

[0002] Obstructive sleep apnea (OSA) is typically treated with continuous positive airway pressure (CPAP) therapy. While CPAP therapy is typically well tolerated by subjects, it requires sleeping with a CPAP machine and mask, which can cause discomfort.

[0003] Recent research in the field of pharmacotherapy has demonstrated the feasibility of treating OSA using pharmacotherapy. Summary of the Invention [Problem to be solved by the invention]

[0004] Although drug therapy for OSA has several drawbacks, the effectiveness of the drug, the side effects caused by the drug, and the subject's long-term tolerance of the drug are important factors that require close monitoring. Furthermore, because patients change over time, for example, in terms of weight, sleeping position, and age, the drug dosage level determined at a previous time point may no longer be proven to be optimal.

[0005] Therefore, there is a need for a means to determine the optimal dosage level of a drug for a subject over time. [Means for solving the problem]

[0006] The invention is defined by the claims.

[0007] According to an example according to one aspect of the present invention, there is provided a computer-implemented method for controlling dose escalation of a drug administered to a subject to treat obstructive sleep apnea, the method comprising: obtaining a dose level of the last dose of a drug administered to the subject; obtaining a measure of drug efficacy based on the subject's response to the previous dose; and determining a dose escalation for future doses of the drug based on the measure of efficacy of the drug and the dose level of the previous dose; It has.

[0008] The method provides a means for automatically controlling the dosage level of a drug administered to a subject, thus achieving an optimal dosage level of the drug for an individual subject based on the subject's response to previous doses of the drug.

[0009] In one embodiment, the method comprises obtaining dose levels of a plurality of previous doses and obtaining a measure of drug efficacy for each of the plurality of previous doses, wherein determining dose escalation is based on the plurality of measures of drug efficacy and the dose levels of the plurality of previous doses.

[0010] In this way, the subject's response to dose levels of the drug over time is taken into account, thereby improving the dose escalation decisions made for subsequent doses.

[0011] In a further embodiment, the method further comprises determining the proportion of the plurality of previous doses that was successfully taken by the subject.

[0012] In this way, subject compliance with administered doses of the drug can be taken into consideration when determining dose escalation for subsequent doses.

[0013] In one embodiment, the drug has multiple component drugs and the dose level has multiple component levels, where each component level indicates a proportion of a component drug in a dose of the drug, and determining dose escalation comprises determining dose escalation for one or more of the component drugs.

[0014] In this way, multiple different drug components are controlled in conjunction with one another. Furthermore, dose escalation may additionally take into account the interaction between two or more drug components and the effects of said drug components in a given subject.

[0015] In a further embodiment, the drug comprises oxybutynin and atomoxetine.

[0016] In one embodiment, the measure of drug efficacy is: input provided by the subject of the method or another user; movement signals, pressure signal, Acoustic signal visual signals, SpO2 signal, the subject's heart rate, an ECG obtained from the subject; PPG obtained from the subject, and Apnea-hypopnea index It is derived from one or more of the following:

[0017] Thus, the effectiveness of a drug's dose level can be achieved in a number of ways.

[0018] In one embodiment, the method further comprises obtaining a measure of side effects based on the subject's response to a previous dose, wherein determining dose escalation is further based on the measure of side effects.

[0019] In this way, both the efficacy of the drug and the side effects associated with the drug are taken into account when determining dose escalation for subsequent doses, and the method can therefore balance the efficacy and side effects of the drug for an individual subject to arrive at an optimal dose level.

[0020] In a further embodiment, the measure of side effects is obtained from input provided by the subject or another user of the method.

[0021] Thus, the side effects of a drug dose level are obtained based on the subjective experience of the subject in response to a given dose of the drug.

[0022] According to an example according to one aspect of the present invention, there is provided a processing system for controlling dose escalation of a drug administered to a subject to treat obstructive sleep apnea, the processing system comprising: Obtaining the dose level of the last dose of drug administered to the subject; obtaining a measure of drug efficacy based on the subject's response to the previous dose; and determining dose escalation for future doses of the drug based on the measure of efficacy of the drug and the dose level of the previous dose; Adapt to this.

[0023] In one embodiment, the processing system is further adapted to determine a supplemental treatment for the subject based on the measure of drug efficacy.

[0024] In this way, any remaining obstructive sleep apnea that cannot be treated via medication, for example, due to side effects caused by the required doses of medication, can be treated in an alternative manner.

[0025] According to an example according to one aspect of the present invention, there is provided a system for controlling dose escalation of a drug administered to a subject to treat obstructive sleep apnea, the system comprising: a processing system as described above, and Subject monitoring system adapted to obtain drug efficacy measures from a subject - Patent Application 20070122999 It has.

[0026] In one embodiment, the subject monitoring system is further adapted to obtain a measure of side effects based on the subject's response to a previous dose.

[0027] In one embodiment, the system has an automated drug dispensing system that is adapted to dispense future doses of the drug.

[0028] In this manner, the medication dispensing system is continuously updated to automatically dispense the determined dose of medication.

[0029] In one embodiment, the subject monitoring system comprises: a user interface adapted to receive input from the subject of the method or another user; motion sensors, pressure sensors, microphone, camera, pulse oximeter, Heart rate monitor, and ECG Sensor It has one or more of the following.

[0030] In one embodiment, the subject monitoring system comprises a smart device, wherein the smart device comprises: Smartphone, Smartwatches, and Smart Home Devices It has one or more of the following.

[0031] These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter. [Brief explanation of the drawings]

[0032] For a better understanding of the present invention, and to show more clearly how the same may be carried into effect, reference will now be made, by way of example only, to the accompanying drawings in which: [Figure 1] FIG. 1 illustrates a method according to one embodiment of the present invention. [Figure 2] FIG. 2 shows a system for controlling drug dose titration. [Figure 3A] FIG. 3A shows a graph depicting the trend of drug efficacy versus dose level. [Figure 3B] FIG. 3B shows a graph depicting the trend of side effect severity against dose level. [Figure 4] FIG. 4 shows a graph depicting the relationship between drug efficacy and side effect severity for a given drug. DETAILED DESCRIPTION OF THE INVENTION

[0033] The present invention will now be described with reference to the drawings.

[0034] It should be understood that the detailed description and specific examples, while indicating exemplary embodiments of the devices, systems, and methods, are intended for purposes of illustration only and are not intended to limit the scope of the invention. These and other features, aspects, and advantages of the devices, systems, and methods of the present invention will become better understood from the following description, appended claims, and accompanying drawings. It should be understood that the drawings are merely schematic and are not drawn to scale. It should also be understood that the same reference numerals are used throughout the drawings to indicate the same or similar parts.

[0035] The present invention provides a computer-implemented method for controlling dose escalation of a drug administered to a subject to treat obstructive sleep apnea, the method comprising obtaining a dose level of a previous dose of the drug administered to the subject and obtaining a measure of drug efficacy based on the subject's response to the previous dose, and determining dose escalation for future doses of the drug based on the measure of drug efficacy and the dose level of the previous dose.

[0036] FIG. 1 illustrates a computer-implemented method 100 for controlling dose escalation of a drug administered to a subject to treat obstructive sleep apnea.

[0037] Dose escalation is the process of adjusting the dosage level of any suitable therapeutic drug to provide maximum therapeutic benefit without causing adverse side effects in a subject. Each drug has a therapeutic index, where a narrow therapeutic index indicates a narrow range of dosage levels within which the drug provides therapeutic benefit. Furthermore, drugs with a narrow therapeutic index have a low dosage level at which side effects occur. Thus, dose escalation is particularly beneficial when drugs with narrow therapeutic indices are administered to a subject.

[0038] The method begins in step 110 by obtaining the dose level of the previous dose of medication administered to the subject.

[0039] A measure of drug effectiveness is obtained based on the subject's response to the previous dose in step 120. The measure of drug effectiveness may be any suitable measure of the effectiveness of the previous dose of drug in treating obstructive sleep apnea.

[0040] For example, a measure of a drug's effectiveness is user input, e.g., user input provided by a clinician monitoring the subject; input provided by the subject, e.g., input provided by the subject providing input indicating their perceived effectiveness of the drug; movement signals, e.g., accelerometers adapted to measure the subject's movements during sleep; a pressure signal, for example a pressure signal measuring the change in pressure measured from under the mattress on which the subject is sleeping; an acoustic signal, e.g., an acoustic signal acquired by a microphone in the room where the subject is sleeping; visual signals, e.g., visual signals acquired by a camera located in the room where the subject is sleeping; an SpO2 signal, e.g., an SpO2 signal obtained by a pulse oximeter in communication with the subject; the subject's heart rate, e.g., the subject's heart rate obtained by a heart rate monitor in communication with the subject; An ECG obtained from the subject; and Apnea-hypopnea index (AHI) indicates the number of apnea and hypopnea events that occur per hour of sleep It is derived from one or more of the following:

[0041] In other words, a measure of drug efficacy can include any data provided by or collected from a subject that represents the change in OSA that occurs in the subject in response to a previous dose of drug.

[0042] The method can utilize data from two or more previous doses of the drug, each having a dose level associated with it, and a measure of drug efficacy associated with each previous dose. In other words, multiple previous dose levels and drug efficacy measures are obtained to track a subject's response to doses of the drug over time.

[0043] In addition to measuring the effectiveness of the drug, the proportion of the previous doses that the subject successfully took may also be taken into account. Even if a dose is administered to a subject, the subject may not always take the dose as intended. In this case, the subject can still be monitored to assess the impact of the missed dose on the subject's treatment.

[0044] In step 130, a dose escalation for future doses of the drug is determined based on the measure of efficacy of the drug and the dose level of the previous dose.

[0045] This dose escalation is increasing dose levels; reduction in dose level; No change in dose level; discrete increases in dose levels, for example depending on whether a measure of drug efficacy exceeds or does not exceed a given threshold; Individualized reductions in dose levels, for example, depending on whether a measure of the drug's effectiveness exceeds or does not exceed a given threshold; Sequential increases in dose levels based on measures of drug efficacy; and Sequential reduction of dose levels based on measures of drug effectiveness Dose escalation includes upper and lower limits on dose levels, which are controlled by the subject, the clinician, or the drug manufacturer.

[0046] Following the determination of dose escalation, future doses of the drug are administered or administered to the subject at the appropriate time according to the subject's dosing regimen.The effectiveness of subsequent doses is then measured, and the drug dose escalation is carried out in a continuous, iterative manner based on each subsequent dose taken by the subject.Dose escalation ultimately leads to the optimal dose of the drug that provides optimal efficacy for the subject based on the subject's individual response to a given drug.The effectiveness of the drug can be continuously monitored to adjust the dose level according to changes in the subject, such as changes in the subject's physiology or environment.

[0047] The drug comprises multiple component drugs, each of which is intended to provide a given therapeutic effect. Accordingly, the drug dosage level has multiple component levels, each component level representing a proportion of the component drug in the total dose of the drug. Accordingly, adjusting the drug dosage level, as described above, further comprises adjusting one or more of the multiple component levels based on a measure of drug efficacy associated with each of the component drugs.

[0048] For example, a drug may have two component drugs, such as oxybutynin and atomoxetine, in which case the dosage level of the drug has an oxybutynin component level and an atomoxetine component level.

[0049] In OSA, the muscles that maintain an open upper airway often collapse. The hypoglossal nerve controls many of these muscles, including the crucial tongue muscle, the genioglossus. Oxybutynin blocks acetylcholine receptors on hypoglossal motor neurons, increasing genioglossus reactivity during rapid eye movement (REM) sleep. Atomoxetine prevents norepinephrine from being reabsorbed by norepinephrine-releasing neurons, increasing their signaling. In combination with oxybutynin, atomoxetine increases genioglossus reactivity during non-rapid eye movement (NREM) sleep.

[0050] The combination of oxybutynin and atomoxetine increases genioglossus activation during REM and NREM sleep, thereby increasing airway patency and significantly reducing AHI in subjects.

[0051] By monitoring the effectiveness of each drug component, dose titration of the individual components and the combination of these components can be more accurately performed. In other words, automated dose titration of a drug to treat OSA can titrate each of the drug components separately and independently. In a specific example where a drug has an oxybutynin drug component and an atomoxetine drug component, if there is a REM-predominant residual AHI as indicated by a measure of drug efficacy, the dose level of the oxybutynin component is increased, whereas if there is a NREM-predominant residual AHI as indicated by a measure of drug efficacy, the dose level of the atomoxetine component is increased.

[0052] In addition to monitoring the effectiveness of the dose of drug administered to the subject, measures of side effects are also obtained from the subject based on the subject's response to previous doses of drug, and therefore dose escalation is additionally determined based on said measures of side effects.

[0053] Any drug may cause one or more side effects in a subject, which are different from the intended therapeutic effect of the drug or drug component. Side effects range from mild side effects that a subject can tolerate to severe side effects that a subject cannot tolerate. Side effects and their severity vary from subject to subject and depend on the dosage level of the drug administered.

[0054] The scale of side effects is user input, e.g., user input provided by a clinician monitoring the subject; input provided by the subject, for example, input provided by the subject providing input indicating side effects of the drug that he or she perceived; movement signals, e.g., accelerometers adapted to measure the subject's movements during sleep; pressure signals, for example, measuring the change in pressure of a subject on a mattress while sleeping; an acoustic signal, e.g., an acoustic signal acquired by a microphone in the room where the subject is sleeping; visual signals, e.g., visual signals acquired by a camera located in the room where the subject is sleeping; an SpO2 signal, e.g., an SpO2 signal obtained by a pulse oximeter in communication with the subject; the subject's heart rate, e.g., the subject's heart rate obtained by a heart rate monitor in communication with the subject; and ECG obtained from the subject It is derived from one or more of the following:

[0055] The subject efficacy measure and the side effect measure may be obtained from one or more of the same signals obtained from the subject, or from different signals.

[0056] For example, if a movement signal, also called an actigraphy, is obtained from a subject, e.g., by an actimetric sensor, a reduction in the subject's movement during sleep indicates undisturbed sleep, which in turn indicates a high level of drug effectiveness. In other words, the actigraphy signal is processed to generate information about the subject, e.g., in the form of a sleep / wake hypnogram or arousal index, which is then used to draw a conclusion about the subject's sleep quality. This sleep quality conclusion is then used to determine a measure of drug effectiveness.

[0057] Furthermore, a movement signal showing a reduced amount of movement also indicates a low level of side effects that typically disrupt the subject's sleep, such as frequent urination, whereas a movement signal showing a high level of movement during sleep indicates a sleep disorder, which may indicate a low drug efficacy that may result in sleep disturbance, or a high side effect that may result in sleep disturbance that may result in sleep disturbance regardless of the drug's efficacy.

[0058] Similarly, a pressure signal showing small changes in the subject's pressure on the mattress indicates undisturbed sleep, which corresponds to a measure of high drug effectiveness and / or low drug side effects, while a large change in the subject's pressure on the mattress indicates sleep disturbance, which corresponds to a measure of low drug effectiveness and / or high drug side effects.

[0059] Furthermore, since the pressure sensor under the mattress is sensitive to the subject's breathing and heart rate and can provide respective signals, the acquired pressure signals can be processed to determine the subject's sleep stage, e.g., wakefulness, light sleep, deep sleep and REM sleep, as well as indices of sleep disorders, such as AHI, Respiratory Disorder Index (RDI) and Arousal Reactivity Index.

[0060] When the signal obtained from the subject is an acoustic signal or a visual signal, the amount of activity detected from the subject indicates the frequency of sleep disturbances. For example, frequent audible changes in breathing patterns or footsteps, and the subject being noticeably out of their bed, indicate sleep disturbances, which correspond to a measure of low drug efficacy and / or a measure of high drug side effects.

[0061] Additionally, if the signals obtained from the subject are acoustic signals, the acoustic signals may be used to determine one or more of the subject's movements, the subject's snoring, apnea events, and respiration, which may be used to determine an arousal response index, as well as other measures of sleep quality and drug effectiveness, such as an AHI or a snoring index.

[0062] Furthermore, frequent changes in a subject's heart rate or SpO2 measurements indicate sleep disturbances, which correspond to a measure of poor drug efficacy and / or a measure of high drug side effects. Stable heart rate or SpO2 measurements over an extended period of time correspond to a measure of high drug efficacy and / or a measure of low drug side effects.

[0063] SpO2 is one of the key metrics used to monitor OSA, which is most often associated with a high arousal response index and a high oxygen desaturation index (ODI), as obtained from SpO2 measurements. Specifically, a high ODI indicates poor medication effectiveness.

[0064] Additionally, instantaneous heart rate measurements are used to determine heart rate variability (HRV), which is used to determine sleep stages, arousal reactivity index, and the like.

[0065] If the signal obtained from the subject is an ECG signal or a PPG signal, the subject's sleep stages are determined over a sleep session, which indicates the quality of the subject's sleep during the sleep session. A large number of sleep stage transitions from a deep sleep stage, such as stage 3 non-REM sleep, to a lighter sleep stage, such as stage 1 or 2 non-REM sleep, indicates sleep disturbance, which corresponds to a measure of low drug effectiveness and / or a measure of high drug side effects. A smaller number of sleep stage transitions indicates undisturbed sleep, which corresponds to a measure of high drug effectiveness and / or a measure of low drug side effects.

[0066] Alternatively or additionally to the above examples, the side effect scale can be obtained based on subjective input provided by the subject indicating their perceived side effect experience and the intensity of that side effect in response to a dose of drug.

[0067] When the medication comprises oxybutynin, measures of side effects are derived from additional objective data, such as daytime sleepiness measured by daytime wakefulness monitoring and reduced sweating measured by a GRS sensor.

[0068] If the drug is atomoxetine, the side effect scale may include additional objective data, For example, by monitoring the subject's weight, and more specifically, by the subject's weight loss.

[0069] Thus, separate and independent titration of each component of the drug may be performed based on side effects noted by the user. In an example where the drug comprises oxybutynin and atomoxetine, if the subject self-reports difficulty urinating or if the amount of REM sleep is significantly reduced, the oxybutynin component dose level is decreased, whereas if the subject self-reports nausea, the atomoxetine component dose level is decreased.

[0070] As mentioned above, the subject's adherence to the dosing regimen, i.e., the percentage of previous doses that the subject successfully takes, is monitored in combination with side effects. If the subject is determined to be non-compliant with the regimen due to excessive side effects, lower targets are set for measures of drug efficacy and the drug dosage level is reduced.

[0071] In practice, the above-described method is implemented by a system for controlling the titration of a drug administered to a subject to treat obstructive sleep apnea. Figure 2 shows a schematic diagram of such a system 200.

[0072] In the example shown in FIG. 2, the system comprises a processing system 210 adapted to perform the methods described above, and a subject monitoring system 220 adapted to obtain a measure of drug effectiveness from a subject 230.

[0073] The processing system may be any suitable processing system, including a remote processing system in communication with the subject monitoring system.

[0074] The subject monitoring system includes: a user interface adapted to receive input from a user and / or subject; motion sensors, pressure sensors, microphone, camera, pulse oximeter, Heart rate monitor, and ECG Sensor It has one or more of the following.

[0075] The subject monitoring system and / or the processing system can be partially or fully implemented within a subject's smart device, such as a smartphone, a smartwatch, or a smart home device. For example, a smartwatch can include a motion sensor and a heart rate sensor, and a smartphone can include a motion sensor, a microphone, a camera, and a processing system capable of performing the methods described above.

[0076] Additionally, the subject monitoring system may be further adapted to obtain a measure of side effects based on the subject's response to a previous dose, which may be obtained using any of the sensor configurations described above.

[0077] System 200 may further include an automatic drug dispensing system 240 adapted to dispense subsequent doses of the drug, which may be any suitable system capable of receiving the adjusted dose level and dispensing subsequent doses of the drug to the subject.

[0078] The system can continue to monitor any indicators of residual AHI based on a measure of drug effectiveness and determine supplemental treatment for the subject. As is known with active mentalis muscle stimulation, not all patients respond to treatments that simply increase the passive critical closing pressure (Pcrit) in the subject's airway. For example, the subject monitoring system can determine whether the subject has a decreased awakening threshold or increased loop gain. If the subject has a high loop gain, supplemental oxygen therapy or acetazolamide is suggested as a supplemental treatment. If the patient has a low awakening threshold, a hypnotic drug is suggested as a supplemental treatment.

[0079] In practice, doses of the drug at various different dose levels are provided to the subject over time based on the dose escalation method described above. For example, if the drug comprises oxybutynin and atomoxetine, the multiple previous doses may include a series of doses such as 5 mg oxybutynin + 80 mg atomoxetine, 2 mg oxybutynin + 40 mg atomoxetine, 2 mg oxybutynin + 80 mg atomoxetine, and 1 mg oxybutynin + 20 mg atomoxetine, etc.

[0080] The effectiveness of the treatment is monitored each time a dose is administered to the subject in the form of a measure of drug effectiveness. The measure of drug effectiveness can be obtained by various means, such as under-mattress sensors, smartphone applications, wearable sensors worn on the wrist, SpO2 sensors, and in-room sensors such as microphones or cameras. While accurate AHI measurements are a useful measure of drug effectiveness, approximations and / or trend data over time can also be used to assess the relative effectiveness of the treatment. Treatment effectiveness can be trended across different dose levels.

[0081] In addition to monitoring the effectiveness of treatment, drug side effects are also monitored and / or reported by the subject. Measures of side effects may be self-reported by the subject, for example, provided by a smartphone application. Alternatively or additionally, measures of side effects may be monitored objectively and may include non-respiratory sleep disorders, reduced REM sleep, and abnormalities in sleep architecture. The severity of side effects may be trended across different dose levels.

[0082] The effectiveness of the treatment and the severity of side effects are monitored by the system in order to optimize the therapeutic regimen and drug dose levels by dose escalation as described above.

[0083] 3A and 3B show a graph 300 representing the trend of a drug's effectiveness across dose levels and a graph 310 representing the trend of a drug's side effect severity across different dose levels of the drug. According to FIGS. 3A and 3B, different points (A, B, and C) are determined on the dose curve of a patient profile. Point A is an example of a dose level where the treatment is not effective and needs to be increased. Point C is an example of a dose level where the treatment is effective but the side effects are severe. Point B is an example of a dose level where the treatment is effective but the side effects are not severe.

[0084] FIG. 4 shows a graph 320 illustrating the relationship between drug effectiveness and side effect severity for a given drug.

[0085] It should be noted that each subject's dose curve will appear different and may change over time in response to changes in the subject's physiology and / or environment. Therefore, continuous dose escalation is performed to allow for continuous trend analysis of treatment efficacy and side effect severity, and to indicate whether efficacy is maintained at lower doses, especially when lower dose levels are possible.

[0086] Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, nor does it exclude a plurality of them if a plurality is not stated.

[0087] A single processor or other unit may fulfill the functions of several items recited in the claims.

[0088] The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0089] The computer program may be stored / distributed on a suitable medium, for example an optical storage medium or a solid-state medium provided together with or as part of other hardware, but may also be distributed in other forms, such as via the Internet or other wired or wireless telecommunications systems.

[0090] When the term "adapted to" is used in the claims or the specification, it is intended to be equivalent to the term "configured to."

[0091] Any reference signs in the claims should not be construed as limiting the scope.

Claims

1. 1. A computer-implemented method for controlling dose escalation of a drug administered to a subject to treat obstructive sleep apnea, the drug having a plurality of component drugs, the component drugs including an oxybutynin drug component and an atomoxetine drug component, the method comprising: obtaining a dose level of a previous dose of a drug administered to a subject, the dose level having a plurality of component levels, each component level indicating a proportion of a component drug in the dose of the drug; obtaining a measure of drug efficacy based on the subject's response to the previous dose; and determining a dose escalation for one or more of the component drugs for future doses of the drug based on the drug efficacy measure and the dose level of the previous dose, wherein if there is REM-predominant residual AHI as indicated by the drug efficacy measure, the dose level of the oxybutynin component is increased, whereas if there is NREM-predominant residual AHI as indicated by the drug efficacy measure, the dose level of the atomoxetine component is increased.

10. A computer-implemented method comprising:

2. The method comprises: obtaining a dose level of a plurality of previous doses; and obtaining a measure of drug efficacy for each of said plurality of previous doses. and determining the dose escalation is based on a plurality of measures of efficacy of the drug and the dose levels of the plurality of previous doses. The computer-implemented method of claim 1 .

3. 3. The computer-implemented method of claim 2, further comprising determining a percentage of the plurality of previous doses that was successfully taken by the subject.

4. The measure of the drug's effectiveness is input provided by the subject or another user of the method; Movement signals, pressure signal, Acoustic signals, visual signals, SpO ２ signal, the subject's heart rate; an ECG obtained from the subject; PPG obtained from the subject; and Apnea-hypopnea index 4. The computer-implemented method of claim 1, wherein the method is obtained from one or more of the following:

5. 5. The computer-implemented method of claim 1, further comprising obtaining a side effect measure based on the subject's response to the previous dose, and wherein determining the dose escalation is further based on the side effect measure.

6. 6. The computer-implemented method of claim 5, wherein the measure of side effect is obtained from input provided by the subject or another user of the method.

7. 1. A processing system for controlling dose escalation of a drug administered to a subject to treat obstructive sleep apnea, the drug having a multi-component drug having an oxybutynin drug component and an atomoxetine drug component, the processing system comprising: obtaining a dose level of a previous dose of a drug administered to a subject, the dose level having a plurality of component levels, each component level indicating a proportion of a component drug in the dose of the drug; obtaining a measure of drug efficacy based on the subject's response to the previous dose; and determining a dose escalation for one or more of the component drugs for future doses of the drug based on the measure of efficacy of the drug and the dose level of the previous dose; wherein the dose level of the oxybutynin component is increased when there is REM-predominant residual AHI as indicated by the medication efficacy measure, whereas the dose level of the atomoxetine component is increased when there is NREM-predominant residual AHI as indicated by the medication efficacy measure.

8. The processing system of claim 7 , wherein the processing system is further adapted to determine a supplemental treatment for the subject based on the measure of drug effectiveness.

9. 1. A system for controlling dose escalation of a drug administered to a subject to treat obstructive sleep apnea, the system comprising: A processing system according to claim 7 or 8, and Subject monitoring system adapted to obtain drug efficacy measures from a subject - Patent Application 20070122999 A system having:

10. 10. The system of claim 9, wherein the subject monitoring system is further adapted to obtain a measure of side effects based on the subject's response to the previous dose.

11. 11. The system of claim 9 or 10, wherein the system comprises an automated drug dispensing system adapted to dispense future doses of the drug.

12. The subject monitoring system includes: a user interface adapted to receive input from the subject or another user of the system; motion sensors, pressure sensors, microphone, camera, pulse oximeter, Heart rate monitor, and ECG sensor 12. The system of claim 9, comprising one or more of:

13. The subject monitoring system is implemented in a smart device, and the smart device comprises: Smartphone, Smartwatches, and Smart Home Devices 13. The system of any one of claims 9 to 12, comprising one or more of:

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