WO2020023954A1 - Devices and methods for medication monitoring - Google Patents

Abstract

A method for measuring analyte concentrations in a biofluid sample to determine patient compliance with a drug regimen. These analytes include a tracer having a half-life that is longer than the drug dosage interval, the drug, or a second tracer with a half-life similar to that of the drug. Further, a method for measuring biofluid concentrations of an analyte and correlating those measurements to plasma concentrations of a drug. The biofluid concentrations are then used to compare drug plasma concentrations to toxic or minimum effective drug levels. Furthermore, a method for selecting tracer compounds for medication monitoring by biofluid sensing devices. Such tracer selection includes the following factors: percentage and molarity of dosed tracer that emerges in biofluid; timing and mechanism of the tracer emerging in biofluid; suitability of the tracer or its characteristics for drug monitoring requirements; and amenability of the tracer to interact with a randomized aptamer sequence.

Description

DEVICES AND METHODS FOR MEDICATION MONITORING

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62/703,983, filed July 27, 2018, and U.S. Provisional Application No. 62/796,877, filed January 25, 2019, and has specification that builds upon PCT/US 15/32866, filed May 28, 2015, and U.S. Application No. 15/314,414, filed November 26, 2016, the disclosures of which are hereby incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] Sweat contains many of the same biomarkers, chemicals, or solutes that are carried in blood, which can provide significant information enabling the diagnosis of health conditions, wellness, toxins, performance, and other physiological attributes, even in advance of any physical sign. Furthermore, sweat itself, and the action of sweating, or other parameters, attributes, solutes, or features on or near the skin or beneath the skin, can be measured to further reveal physiological information. Accordingly, wearable sensing devices that measure one or more attributes in sweat hold tremendous promise for use in workplace safety, athletic, military, and clinical diagnostic settings. In particular, wearable devices can allow substantially continuous or prolonged monitoring of medication effectiveness, by monitoring a patient’s sweat or other biofluid for analytes that indicate whether or how the patient is taking a prescribed medication. Monitoring an individual’s sweat for analyte signatures of a particular medication or condition can also provide an indication of non-medicinal abuse of prescription drugs such as opioids. The analytes measured by the wearable device can include the drug itself, a tracer, a metabolite of the drug, a biomarker for a relevant physical condition, or other analyte. Such analytes will include many different types of substances that recommend the use of biorecognition sensors, such as electrochemical aptamer-based (“EAB”) sensors. Because of their versatility with respect to potential target analytes and their wide concentration range, EAB sensors enable the development of a wearable device platform capable of detecting these disparate analytes. [0003] However, selection of the randomized aptamer sequences compatible with sensing a particular analyte is a time-consuming and expensive prospect. Further, medication-related analytes emerging in sweat can be at very low molarities, e.g., fM, pM, or nM range, which may be below the dynamic range of an EAB sensor. Tracer molecules represent a solution to this difficulty, since tracers can be selected or developed for compatibility with a particular drug, as well as for potential interaction with a randomized biorecognition element. Further, tracers potentially can be dosed at levels that are detectible by EAB sensors when the tracer, or a metabolite of the tracer, emerges in sweat.

[0004] Accordingly, it is desirable to have techniques for identifying tracer compounds that can be co administered with an active medication for measuring medicinal adherence with a biofluid sensing device. In particular, it is desirable to have methods for identifying tracer compounds that take into consideration the compatibility of the tracer with the active drug, the medical use of the active drug, and the selection of suitable aptamers for detecting the tracer, or a metabolite thereof, using electrochemical aptamer-based sensors. Also disclosed are methods for using a tracer or other substance for monitoring patient adherence to a drug regimen. Further, monitoring drugs themselves, drug metabolites, and/or other biomarkers allows assessments of the effectiveness or safety of a medication dose for a patient.

SUMMARY OF THE INVENTION

[0005] A method is disclosed for measuring analyte concentrations in a biofluid sample to determine patient compliance with a drug regimen. These analytes include a tracer having a half-life that is longer than the interval between doses of the drug, the drug itself, or a second tracer with a half-life that is similar to that of the drug. Also disclosed is a method for measuring biofluid concentrations of an analyte and correlating those measurements to concentrations of a drug in plasma. The biofluid concentrations are then used to compare drug plasma concentrations to toxic or minimum effective drug levels. Also disclosed is a method for selecting tracer compounds to facilitate medication monitoring by biofluid sensing devices. Such tracer selection includes the following factors: the percentage and molarity of dosed tracer that emerges in biofluid; the timing and mechanism of the tracer emerging in biofluid; the suitability of the tracer or its characteristics for drug monitoring requirements; and the amenability of the tracer to interact with a randomized aptamer sequence.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] The objects and advantages of the present invention will be further appreciated in light of the following detailed description and drawings in which:

[0007] Fig. 1 is a diagrammatic view of an exemplary wearable biofluid sensing device;

[0008] Fig. 2 depicts an exemplary embodiment for administering a tracer with an active drug;

[0009] Fig. 3 depicts another exemplary embodiment for administering a tracer with an active drug;

[0010] Fig. 4A depicts an embodiment for combining multiple tracers with an active drug;

[0011] Fig. 4B is a diagram depicting representative release rates of the multiple tracers in Fig. 4A;

[0012] Fig. 5 is a representative response profile of a single dose of a drug and two tracers.

[0013] Fig. 6 is a representative response profile of steady state concentrations a drug and tracers.

[0014] Fig. 7 is a representative response profile of steady state concentrations of a drug and tracers with a single missed dose.

[0015] Fig. 8 is a is a representative response profile of steady state concentrations of a drug and tracers with multiple missed doses.

[0016] Fig. 9 is a table summarizing interpretations of concentrations of a longer half-life tracer (T₂) and a shorter half-life tracer (Ti).

[0017] Fig. 10 is a representative drug response profile showing concentration levels in plasma of a drug sequentially dosed over a period time.

DEFINITIONS

[0018] Before continuing with a description of the present invention, a variety of definitions should be made. The following definitions will gain further appreciation and scope in the detailed description of exemplary embodiments of the present invention.

[0019] As used herein,“biofluid” may mean any human biofluid, including, without limitation, sweat, interstitial fluid, blood, plasma, serum, tears, and saliva. A biofluid may be diluted with water or other solvents inside a device because the term biofluid refers to the state of the fluid as it emerges from the body.

[0020] As used herein,“fluid” may mean any human biofluid, or other fluid, such as water, including without limitation, groundwater, sea water, freshwater, etc., or other fluids.

[0021] As used herein,“continuous monitoring” means the capability of a device to provide one or more measurements of fluid collected continuously or on multiple occasions, or to provide a plurality of fluid measurements over time.

[0022] “Biofluid sensor” means any type of sensor that measures a state, presence, flow rate, solute concentration, or solute presence, in absolute, relative, trending, or other ways in biofluid. Biofluid sensors can include, for example, potentiometric, amperometric, impedance, optical, mechanical, antibody, peptide, aptamer, or other means known by those skilled in the art of sensing or biosensing.

[0023] “Analyte” means a substance, molecule, ion, or other material that is measured by a biofluid sensing device.

[0024] “Measured” can imply an exact or precise quantitative measurement and can include broader meanings such as, for example, measuring a relative amount of change of something. Measured can also imply a qualitative measurement, such as‘y^es’ ^or‘^no’ type measurements.

[0025] “Chronological assurance” means the sampling rate or sampling interval that assures measurement(s) of analytes in biofluid in terms of the rate at which measurements can be made of new biofluid analytes emerging from the body. Chronological assurance may also include a determination of the effect of sensor function, potential contamination with previously generated analytes, other fluids, or other measurement contamination sources for the measurement(s). Chronological assurance may have an offset for time delays in the body (e.g., a well-known 5 to 30-minute lag time between analytes in blood emerging in interstitial fluid), but the resulting sampling interval (defined below) is independent of lag time, and furthermore, this lag time is inside the body, and therefore, for chronological assurance as defined above and interpreted herein, this lag time does not apply. [0026] “Analyte-specific sensor” means a sensor specific to an analyte and performs specific chemical recognition of the analyte’s presence or concentration (e.g., ion-selective electrodes (“ISE”), enzymatic sensors, electro-chemical aptamer based sensors, etc.). Sensors could also be optical, mechanical, or use other physical/chemical methods which are specific to a single analyte. Further, multiple sensors can each be specific to one of multiple analytes.

[0027] “Biofluid sensor data” means all of the information collected by device sensor(s) and communicated to a user or a data aggregation location.

[0028] “Correlated aggregated biofluid sensor data” means biofluid sensor data that has been collected in a data aggregation location and correlated with outside information such as time, temperature, weather, location, user profile, other biofluid sensor data, or any other relevant data.

[0029] “Volumetric sweat rate measurement” means a measurement of sweat rate based on the time required for sweat to fill a known volume in a biofluid sensing device. Devices for volumetric sweat rate measurement are disclosed in U.S. Application No. 15/653,494, which is hereby incorporated herein in its entirety.

[0030] “EAB sensor” means an electrochemical aptamer-based biosensor that is configured with multiple aptamer sensing elements that, in the presence of a target analyte in a fluid sample, produce a signal indicating analyte capture, and which signal can be added to the signals of other such sensing elements, so that a signal threshold may be reached that indicates the presence or concentration of the target analyte. Such sensors can be in the forms disclosed in U.S. Patent Nos. 7,803,542 and 8,003,374 (the “Multi-capture Aptamer Sensor” (MCAS)), or in U.S. Provisional Application No. 62/523,835 (the “Docked Aptamer Sensor” (DAS)).

[0031] “Analyte capture complex” means an aptamer, or other suitable molecules or complexes, such as proteins, polymers, molecularly imprinted polymers, polypeptides, and glycans, that experience a conformational change in the presence of a target analyte, and are capable of being used in an EAB sensor. Such molecules or complexes can be modified by the addition of one or more linker sections comprised of nucleotide bases. [0032] “Aptamer sensing element” means an analyte capture complex that is functionalized to operate in conjunction with an electrode to detect the presence of a target analyte. Such functionalization may include tagging the aptamer with a redox moiety, or attaching thiol binding molecules, docking structures, or other components to the aptamer. Multiple aptamer sensing elements functionalized on an electrode comprise an EAB sensor.

[0033] “Sensitivity” means the change in output of the sensor per unit change in the parameter being measured. The change may be constant over the range of the sensor (linear), or it may vary (nonlinear).

[0034] “Signal threshold” means the combined strength of signal-on indications produced by a plurality of aptamer sensing elements that indicates the presence of a target analyte.

[0035] “Delivered solute” means any substance that is at least partially soluble in plasma (blood), tissue or biofluid and that may be delivered into the human body. For example, any drug, fluid, vitamin, inert substance, salt, sugar, molecule, grain, or other suitable substance or compound may be a delivered solute.

[0036] “Tracer compound” or “tracer” means a compound used to inform the presence or concentration of a primary drug in blood, plasma, or an organ. The tracer may be more readily detectible in biofluid than the drug itself, in a different concentration, non-toxic, and less or differently bioactive than the primary drug.

[0037] “Tracer profile” means the collection of biofluid sensor data on analytes that indicate the concentration and ratios of a primary drug, one or more tracer compounds, and/or relevant metabolites over a relevant period after delivery of the drug and tracer(s).

[0038] “Indirect detection” means determining the presence or concentration of a primary drug in the blood or an organ by detecting in biofluid one or more tracer compounds, one or more tracer metabolites, or one or more other analytes, or through some combination of these analytes.

[0039] “Drug response profile” means the collection of biofluid sensor data on sweat rate, temperature, pH, and/or analytes that indicate the chronological concentration and ratios of those analytes in the blood stream of a target individual that is correlated to the presence of a primary drug. [0040] “Drug compliance profile” means a known set of directly detected analytes, a tracer profile and/or a response profile that is unique to compliance with a particular drug regimen.

[0041] “Drug detection threshold” means a calculated detection level in biofluid of a primary drug, tracer(s), metabolite(s), other analyte(s), or a combination of these analytes that shows the primary drug is present in the blood or an organ with reasonable certainty.

DETAILED DESCRIPTION OF THE INVENTION

[0042] Several specific, but non-limiting embodiments of the present invention will now be described. The described embodiments will be primarily, but not entirely, limited to devices, methods and sub-methods using wearable biofluid sensing devices. The described embodiments portray inventive steps, but do not necessarily cover all possible embodiments commonly known to those skilled in the art, or all obvious features needed for operation. This disclosure incorporates by reference in their entirety the article published in the journal IEEE Transactions on Biomedical Enginee ring, titled“Adhesive RFID Sensor Patch for Monitoring of Sweat Electrolytes”; and the article published in the journal AIP Biomicrofluidics, 9 031301 (2015), titled“The Microfluidics of the Eccrine Sweat Gland, Including Biomarker Partitioning, Transport, and Biosensing Implications”.

[0043] Referring now to the drawing figures, Fig. 1 depicts a wearable biofluid sensing device 10 placed on or near skin 12. In alternate embodiments, the biofluid sensing device 10 may be fluidically connected to skin or regions near skin by contact with microfluidic components or other suitable techniques. The device 10 is in wired communication 152 or wireless communication 154 with a reader device 150. In some embodiments, the reader device 150 may be a smart phone or portable electronic device. In alternate embodiments, the device 10 and reader device 150 can be combined. In further alternative embodiments, communications 152 and/or 154 may not be constant, but rather one-time or periodic data transmissions from the device following sweat sensing.

[0044] The biofluid sensing device may include a plurality of sensors to detect and improve the detection of biofluid analytes, including ISEs, analyte-specific sensors, a reference sensor, a pH sensor, a temperature sensor, a skin impedance sensor, a capacitive skin proximity sensor, an accelerometer, a heart rate sensor, and a blood pressure sensor. In many embodiments, the sensors may require two or more electrodes, reference electrodes, or additional supporting technology or features which are not captured in the description herein. Sensors are preferably electrical in nature, but may also include optical, chemical, mechanical, or other known biosensing mechanisms. Sensors can be in duplicate, triplicate, or more, to provide improved data and readings. Sensors may be referred to by what the sensor is sensing, for example: a biofluid sensor, an impedance sensor, a sweat volume sensor, a sweat generation rate sensor, and a solute generation rate sensor. Many of the auxiliary features of the invention may require other aspects of a biofluid sensing device, including one or more counter electrodes, reference electrodes, or additional supporting technology or features, which are not captured in the description herein, such as an onboard realtime clock, onboard flash memory (i.e., 1 MB minimum), Bluetooth™ or other communications hardware, and a multiplexer to process a plurality of sensor outputs.

[0045] The biofluid sensing device also includes computing and data storage capability sufficient to operate the device, which incorporates the ability to conduct communication among system components, to perform data aggregation, and to execute algorithms capable of generating notification messages. The device may have varying degrees of onboard computing capability (i.e., processing and data storage capacity). For example, all computing resources could be located onboard the device, or some computing resources could be located on a disposable portion of the device and additional processing capability located on a reusable portion of the device. Alternatively, the device may rely on portable, fixed, or cloud-based computing resources.

[0046] The biofluid sensing device’s data aggregation capability can include collecting all of the biofluid sensor data generated by the device and/or communicated to the device. The aggregated biofluid sensor data can be de-identified from individual wearers or can remain associated with an individual wearer. Such data can also be correlated with outside information, such as the time, date, air temperature, humidity, activity performed by the individual, motion level, fitness level, mental and physical performance during the data collection, body orientation, temporal proximity to significant health events or stressors, age, sex, medications, drug sensitivity, medical condition, health history, heart rate, blood pressure, or other relevant information. The reader device or companion transceiver can also be configured to correlate speed, location, environmental temperature, or other relevant data with the biofluid sensor data. The biofluid sensor data that can be monitored by a user includes real-time data and trend data; and may also include aggregated biofluid sensor data drawn from the system database and correlated to a particular wearer, a wearer profile (such as age, sex, or fitness level), weather condition, activity, combined analyte profile, or another relevant metric. Trend data, such as a target individual’s hydration level over time, could be used to predict future performance, or the likelihood of an impending physiological event. Such predictive capability can be enhanced by using correlated aggregated biofluid sensor data, which would allow the user to compare an individual wearer’s historical analyte and external data profiles to a real-time situation as it progresses, or even to compare thousands of similar analyte and external data profiles from other individuals to the real-time situation.

[0047] Sweat can be stimulated or activated in conjunction with use of a sensing device by known methods. For example, sweat stimulation can be achieved by iontophoretic transdermal administration of sweat stimulating drugs, such as pilocarpine, carbachol, or methacholine, sudo-motor axon reflex stimulation, simple thermal stimulation, orally administering a drug, or intradermal injection of sweat stimulating drugs such as methacholine or pilocarpine. Sweat can also be controlled or created by asking the subject using the device to enact or increase activities or conditions that cause them to sweat. These techniques may be referred to as active control of sweat generation rate. Additionally, embodiments of the sensing devices may take differing forms, including patches, bands, straps, portions of clothing, wearables, or any suitable mechanism that reliably brings sweat stimulation, biofluid collection, and/or biofluid sensing technology into intimate proximity with a biofluid as the biofluid is generated.

[0048] The ability to detect the concentration of a drug in a biofluid over time requires the use of a chronologically assured biofluid sampling rate. In order to understand the proper numerical values or representations of biofluid sampling rates, the concepts of biofluid generation rate and biofluid volumes will now be described. Based on the assumption of a sweat gland density of lOO/crn², a sensor that is 0.55 cm in radius (1.1 cm in diameter) will cover about a 1 cm² area, or approximately 100 sweat glands. Assuming a sweat volume under a skin-facing sensor (space between the sensor and the skin) of 50 pm average height, or 5xl0³ cm, that same 1 cm² area will provide a sweat volume of 5xl0³ cm³, or about 5xl0³ mL or 5 pL of volume. With the maximum sweat generation rate of 5 nL/min/gland and 100 glands, it would require 10 minutes to fully refresh the sweat volume (using lst principles/simplest calculation only). With the minimum sweat generation rate of 0.1 nL/min/gland and 100 glands, it would require 500 minutes (8 hours) to fully refresh the sweat volume. If the sweat volume could be reduced by 10 times to a volume height of 5 pm roughly, the max and min times would be 1 minute and 1 hour, respectively, but the min time would also be subject to diffusion and other contamination issues, and a 5 pm dead volume height would be technically challenging. Times and rates are inversely proportional (rates having at least partial units of l/seconds), therefore a short time required to refill the sweat volume can also be said to have a fast or high sweat sampling rate.

[0049] The disclosed invention relates to the use of biofluid sensing devices to detect or measure the concentration of tracer molecules to monitor adherence with a drug regimen, and in some embodiments, to assess and monitor the effectiveness of a medication. The selection and dosing of tracer molecules is a key component of these applications and is informed by the needs of the biofluid sensing modality, namely electrochemical aptamer-based sensors. Tracer molecule selection, therefore, includes consideration of the metabolic, absorption, and delivery characteristics of the active drug, as well as the dynamic range and other capabilities of the EAB sensors configured to detect the tracer, metabolites of the tracer, or other analytes whose presence in biofluid is correlated to the presence of the active drug. In short, tracer molecule selection and aptamer selection inform each other when developing a biofluid sensing device for medication monitoring.

[0050] Therefore, the co-selection of tracers with their corresponding aptamers must account for at least four related considerations: 1) the percentage and molarity of dosed tracer that emerges in sweat or other biofluid; 2) the timing and mechanism of the tracer emerging in sweat or other biofluid; 3) the suitability of the tracer or its characteristics for drug monitoring requirements; and 4) the amenability of the tracer to interaction with an aptamer at sweat molarities. These requirements will now be addressed in turn.

[0051] Tracer selection must first account for the percentage and molarity of tracer that will emerge in biofluid after being administered to a patient, which directly affects patient safety and the practicality for use with the active medication. For oral medications, this factor reduces to the amount of tracer that must be consumed to produce a detectable concentration of the tracer in sweat or other biofluid. For sweat in particular, there are a number of factors that affect the ability of molecules to partition from the body into sweat. The most significant of these factors are molecular size, lipophilicity, and polarity.

[0052] The size of the tracer molecule is the most important factor determining how much of the molecule emerges in sweat. The sweat production process, and the way in which substances are drawn into sweat from fluid sources within the body, causes smaller molecules to enter sweat more readily, while larger molecules, such as proteins, are less abundant in sweat. For example, ions such as Na⁺ (22.9 Da), Cl (35.4 Da), and K⁺ (30 Da), are found abundantly in sweat at least in part due to their small size. Similarly, hormones such as cortisol (360 Da), estradiol (272 Da), and vasopressin (1084 Da) emerge in sweat in relative abundance compared to larger proteins (~30 kDa). Lipophilicity is also a key consideration, since lipophilic substances, e.g., unbound cortisol, typically pass readily through membranes, and hence into sweat. While certain non-lipophilic substances, such as oxybenzone (228 Da), readily partition into sweat, this is the exception, not the rule. Amphiphilic substances, such as surfactants and alcohols, readily partition into sweat; making surfactants, including biosurfactants, potential tracer candidates. Sophorolipids and rhamnolipids are two classes of biosurfactants that may be safe for use as tracers. Many substances that passively diffuse into sweat will do so more readily if they are non-polar, i.e., have a neutral electric charge. Polar (charged) particles tend to be more hydrophilic, and hence less readily partition into sweat.

[0053] The concentration of tracer molecules emerging in sweat will preferably be in the mM range, but nM and high pM ranges may prove acceptable for some sensing applications. In order to achieve these tracer concentrations in sweat, a certain amount of the tracer will have to be consumed by the patient or otherwise administered to the body. With regard to safety, many candidates for tracer substances are U.S. Food and Drug Administration (FDA) approved at certain maximum levels. If the tracer must be administered at higher levels than that approved by the FDA in order to emerge in sweat, then additional safety studies may be required to confirm tracer safety at the higher exposure levels The amount of tracer that must be administered is ideally as little as possible. At the upper limit, the tracer amount should not be so much as to render the medication delivery impractical. For example, if a medication is delivered as a pill, the tracer should not render the pill too large for a patient to take comfortably. Similarly, if medication delivery is transdermal, the tracer amount must be sufficiently small to allow timely absorption through the skin.

[0054] As a second factor, tracer selection must also account for the timing and mechanisms by which the tracer enters the body, emerges and persists in sweat. For example, medication monitoring applications, such as adherence to a drug regimen, may require a tracer that emerges in sweat in a timely manner to allow for monitoring of closely spaced doses, e.g., a medication that must be taken every 4 hours may require a tracer that emerges in sweat less than 4 hours after administration. Alternately, a medication monitoring application may simply require the tracer to emerge in sweat at detectible levels within 24 hours of active drug administration.

[0055] The amount of time a drug remains in the body will greatly affect the suitability of a tracer for particular applications. A drug’s ability to persist in the body is frequently indicated in terms of the substance’s half-life, which is the length of time required for the amount of substance to decrease by 50% in the bloodstream after administration. Ibuprofen (206 Da), for example, has a half-life of 2-4 hours and, therefore, will have a concentration 50% of its maximum plasma concentrations (C_max) two to four hours after administration. Tracer persistence qualities, e.g., half-life, may be chosen to facilitate different adherence applications, such as long-term or short-term compliance monitoring.

[0056] The mechanism for emergence of the tracer in sweat also may be relevant for physiological translation and, consequently, another factor in tracer selection is how the active medication is metabolized by or eliminated from the body. For example, certain applications may require that the tracer be metabolized by or eliminated from the body similarly to the active drug. A drug for improving kidney function may be paired with a tracer that is dependent on elimination by the kidneys. Similarly, certain classes of drugs are hepatically metabolized, and a tracer substance that is similarly metabolized, e.g., ibuprofen, may be selected to improve correlation of the tracer molarities in sweat to bloodstream or tissue levels of the active drug. Such tracers may also be used to inform kidney or liver function, or the efficacy kidney or liver processing of the active medication.

[0057] A third consideration in tracer selection is the suitability of the tracer characteristics for drug monitoring requirements. In particular, the tracer needs to be compatible with the active drug. Compatibility may include a number of factors, including shelf stability when the substances are stored together, or whether there is reactivity between the tracer, an excipient, the active drug, or delivery means (such as a capsule material) during storage. Much of the work done in selecting excipients to accompany active medications involves characterizing such compatibility factors. If other tracer selection criteria require selection of a tracer that exhibits poor compatibility with the active drug, compensating formulations, such as protecting the tracer with a non-reactive coating, may be required. Another suitability factor is whether dietary or other non-medical secondary sources of the tracer compound are low enough that the secondary sources do not significantly contribute to the sweat concentrations of the tracer. For example, vitamin E (g~ tocopherol) might prove to be a suitable tracer molecule for some applications, however, dietary sources of vitamin E can be significant. Accordingly, a less common form of vitamin E, such as d-tocopheroL may be used

[0058] As a final suitability factor, the tracer should be chosen to match the method of admin istering the active drug, e.g., oral, injection, IV drip, or transdermal application. For example, excipients for orally administered drugs typically need to be solid at room temperature and amenable to absorption by the digestive tract. Orally administered medications may take one of several forms for co-administration with a tracer compound. For example, with reference to Fig. 2, a medication can be administered in a capsule or tablet form 200, with an amount of tracer 220 mixed or otherwise combined with the active drug 210. Alternatively, with reference to Fig. 3, the medication can be in a partitioned capsule or tablet form 300, with a first portion of the pill comprising the tracer 320 and a second portion comprising the active drug 310. The first and second portions 310, 320 can be separated by an optional divider. The tracer 320 may be 3D printed onto the rest of the pill, or otherwise adhered, pressed together, or combined with the active drug portion. Excipients approved by the FDA for parenterally administered drugs typically function as stabilizers, preservatives, or solubilizing agents. Certain of these capabilities may prove useful for biofluid sensing applications, in addition to the tracer function. FDA approved excipients for topically administered drugs are typically agents for increasing skin permeability, e.g., propylene glycol. Penetration enhancers may function in a dual role as penetration enhancers and tracer molecules for the active topical drug or may be used solely as a tracer.

[0059] Finally, tracer selection must consider aptamer selection and functionality requirements. EAB sensors can be configured, theoretically, to detect or measure concentrations of a wide variety of analytes. Such broad capabilities are dependent on selection of aptamers as biorecognition elements for the particular analyte to be detected. Aptamers are strands of 20 to 40 random nucleotide bases that assume various folded structures in three dimensions. Aptamers that interact with particular molecules are selected through various processes, most commonly by variations of systematic evolution of ligands by exponential enrichment (SELEX). SELEX begins with billions of random aptamer sequences, and down selects those sequences that interact most strongly with the target molecule. The identification of a successful aptamer depends on how easily the aptamer interacts with the analyte, and how unique the analyte is relative to similar compounds. In general, larger targets, such as proteins, present more functional groups, or molecular“handles”, to interact with aptamers, while smaller molecules, such as hormones, have fewer molecular handles. Therefore, aptamers that interact with larger molecules tend to be easier to identify than those for smaller molecules. Tracer molecules optimized for aptamer selection only would have a size of 800 Da or larger and would have multiple functional groups for interacting with the aptamer.

[0060] The above-related criteria for tracer molecule selection present some countervailing considerations. Tracer molecule size, in particular, presents opposing effects on tracer selection. A smaller molecule, while likely emerging in sweat at higher molarities than larger molecules, is likely to be more difficult to match to a selective aptamer sequence. Therefore, it may be desirable to set an ideal size range, e.g., 200 Da to 600 Da, for excipient compounds in order to aid in the selection of tracer candidates. Similarly, timing between administration of the tracer and its emergence in biofluid may be ideal for certain active drugs, but may too rapid or too slow for other active substances. Likewise, rapid emergence of a tracer compound in sweat may depend on characteristics that are otherwise not generally safe for the patient.

[0061] These factors taken together serve to inform the selection or creation of tracers for medication monitoring biofluid sensing applications. There are, in addition, a few other secondary considerations. One such consideration is the need to secure FDA clearance or approval for use of an excipient compound for a particular medication for use with a biofluid sensing device. Choosing among the FDA’s list of thousands of excipient compounds would be desirable from the perspective of ensuring compatibility between the excipient and active drug, and for facilitating FDA approval for the use of the excipient. However, if none of the FDA listed excipients prove suitable for use as a sweat sensing tracer, excipients may need to be custom designed. A first set of options would be to design excipients that are closely related to compounds on the FDA-approved list. Such compounds should be subject to a less intensive approval process by the FDA. Custom designed excipients that differ significantly from FDA-approved compounds could also be formulated, recognizing the increased cost and time required to receive approval for commercial use.

[0062] A variety of pathways for delivering a solute into the body are useful in conjunction with embodiments of the present invention. Delivery methods include, for example, oral ingestion, nasal, anal, transdermal absorption, intravenous, and various types of injection. A solute may also be delivered using devices or engineered products that deliver one or more solutes into the body in a controlled or designed manner. The delivered solute(s) may be, for example, any drug, fluid, vitamin, inert substance, salt, sugar, molecules, grains, excipients, tracers, or other suitable substance or compound. Co-administration of a plurality of such solutes may be accomplished by various means, as are known in the art of pharmaceutical formulation, including various oral medication configurations as discussed above, mixing the active drug and the tracer in an injectable format, or as a combined formulation for topical administration. [0063] The presence or concentration of a primary drug in a bodily fluid or an organ may be determined by measuring or continuously monitoring sweat or other biofluid with a wearable sensing device. Detailed information about the individual’ s dosage level, the drug delivery method (e.g. , oral, transdermal, inj ection, suppository, etc.), the timing of drug delivery, and drug delivery duration maybe considered in monitoring the effectiveness of a drug regimen. Individuals may respond to a drug differently depending on their particular genetic makeup, causing variations in how a person absorbs, distributes, metabolizes, and excretes the drug. The emergence of drugs and their metabolites in biofluid may vary by individual depending on variances in the time of day, the person’s behavior, diet, hydration status, or disease or medical condition. Detailed information about the drug itself, or its metabolites, may be considered as well, including the drug clearance, volume of distribution, half-life, partition coefficient (P), the dissociation constant (pK), and other relevant characteristics. Such information may also be partially supplied by an appropriately configured biofluid sensing device.

[0064] Use of a tracer compound in conjunction with an active drug can have a number of beneficial applications in the areas of medication adherence and drug treatment monitoring. Low patient adherence to prescribed medication regimens costs more than $310 billion annually in the U.S. alone. See“Patient Adherence: The Next Frontier in Patient Care,” Capgemini Consulting, Global Research Report, 2009. For example, patients suffering from hypercholesterolemia are often prescribed statins (HMG-CoA reductase inhibitors) on a long-term basis to reduce LDL cholesterol levels in the blood. Unfortunately, due to a number of factors, including hypercholesterolemia’s lack of symptoms, inconvenience, and adverse events caused by the drugs, patient compliance with statin drug regimens is very low: about 50% of people quit taking statins within the first year, and adherence decreases thereafter. Maningat, P., et ah,“How Do We Improve Patient Compliance and Adherence to Long-Term Statin Therapy?,” Curr. Atheroscler. Rep. 2013 Jan; 15(1): 291. Other conditions for which patient adherence to a drug regimen is a difficulty include the following: Type-2 diabetes mellitus, asthma, chronic obstructive pulmonary disease (COPD), coronary artery disease, heart failure, chronic pain, auto-immune disorders, neuropsychiatric disorders, and chronic infectious diseases. [0065] Orally administered medications can also include two or more different tracer compounds to allow an extended monitoring window after the medication has been administered. With reference to Fig. 4A, an oral medication 400 is configured with a portion containing the active drug 410, as well as a first tracer section 422, a second tracer section 424, and a third tracer section 426. The tracer sections are designed to have different release rates or timing to cover an extended monitoring period. Different release rates may be accomplished by using tracers having different emergence times in the biofluid, by individually coating the tracers with coatings having different dissolve times, or other suitable means. With reference to Fig. 4B, a sweat sensing device can register a concentration for each tracer, so that a first tracer sweat concentration 442 corresponds to the emergence of the first tracer 422 in sweat. As the first tracer moves out of the patient’s system, the second tracer 424 is timed to release, and the device registers the second tracer sweat concentration 444. Subsequently, the third tracer 426 is timed to release and registered by the device as a third tracer sweat concentration 446, and so forth. In this way, a medication may be configured to allow monitoring over an extended period of time. Alternatively, such use of multiple tracers may allow sweat sensing devices with a limited operational window to be used for extended monitoring, for example, by measuring the tracers with multiple devices worn sequentially.

[0066] Adherence includes at least two aspects: initial compliance with the prescribed regimen, and persistence, or continued compliance, over time. Drugs taken over periods of multiple years have very low adherence rates, ranging from a 63% compliance rate for enlarged prostate medication, down to only 50% adherence for depression treatment. Even a modest improvement in these numbers would provide a substantial fiscal and public health benefit. A wearable biofluid sensing device capable of periodic, continuous, or prolonged monitoring for medication adherence can contribute substantially to improving adherence to a drug regimen.

[0067] For some applications, daily or more frequent sweat testing may prove inconvenient for patients or prohibitively expensive. However, if the sweat sensing device is only configured to measure the drug itself, the drug may be eliminated from the body too quickly gain much insight from a once-weekly or once- monthly sweat test. For example, the patient may regularly miss doses, but anticipating a sweat test, could take a single dose just before the test. The test would indicate compliance with the drug regimen, even though the patient had not been taking the drug as prescribed. However, if a drug is co-administered with a tracer having a longer half-life, i.e., longer than the interval between doses, such testing may prove informative, as well as more convenient and less expensive than daily tests. The relationship between a longer half-life tracer, and the drug or a shorter half-life tracer, as illustrated by the following examples, can provide valuable insights while limiting the number of times a patient needs to have sweat samples measured. With a half-life longer than the time between recommended doses, T₂ can build up in the patient’s plasma and sweat to provide a steady state reference concentration for comparison to concentrations of the drug. The ratio of drug or short-term tracer to the longer term tracer will then inform the device user of the consistency with which the patient has taken the drug in the recent past.

[0068] With reference to Fig. 5, a hypothetical drug (D) with a half-life of 6 hours (ti_/2=6 hrs.) is prescribed to be taken at a dosing interval of once every 12 hours. D is co-formulated with a first tracer (Tracer 1 or Ti) also having ti_/2=6 hrs., and a second tracer (Tracer 2 or T₂) with ti_/2=30 hrs. The sweat concentration curves with respect to time in hours for a single dose are shown. Ti and D have similar curves for which the concentration increases to a maximum in sweat at a particular time, ΪMAC, and then declines, reaching half of their maximum concentration at approximately 6 hours after administration, and decreasing to around 25% of maximum concentration at 12 hours after administration. The concentration of T₂ also increases to a maximum concentration, then declines more slowly until half the maximum concentration is reached at about 30 hours after administration (not shown). At the first ΪMAC, the ratio of Ti/T₂ is approximately 1.6. With reference to Fig. 6, steady state concentrations of D, Ti and T₂ are shown for an individual that has consistently taken the medication as directed over a period of time. If taken every 12 hours as prescribed, concentrations of D and Ti will increase slightly to a steady state value, since most of D and Ti is eliminated from the body every 12 hours. However, T₂ will increase to a higher steady state value, since the 12 hours between doses allows the body to eliminate only about a quarter of the second tracer. At the steady state ΪMAC, the ratio Ti/T₂ is approximately 0.2. With reference to Fig. 7, a scenario is depicted in which the individual has been taking the drug as directed, but missed a prior dose. Initially, at the steady state, the ratio T1/T2 is approximately 0.2. However, after the individual misses a dose, D and Ti decrease to nearly 0 concentration in sweat, while T₂ decreases only slightly. After the individual resumes taking the usual dose at the required time, T1/T2 = 0.15, which is lower than the steady state ratio. By tracking this ratio, a biofluid sensing device could identify when an individual was in substantial compliance with a drug regimen, but had recently missed a dose, or more than one doses. With reference to Fig. 8, with the time scale measured in days, a scenario is depicted wherein the individual has been taking the drug as directed, then missed three days of doses, and resumed taking the drug for one dose. After taking the final dose, D and Ti levels are approximately the same as in the previous example, while T₂ has decreased substantially. As a result, Ti/T₂ = 0.75. In alternate embodiments, concentrations of the drug and/or a metabolite may be measured and compared to a steady state concentration of the drug and/or a metabolite to determine longer and shorter term adherence with a drug regimen.

[0069] Fig. 9 depicts a chart outlining some of the various indications that can be obtained from a sweat sensing device configured to measure a longer half-life tracer (T₂) and a shorter half-life tracer (Ti). As described in the table,“Compliance” indicates the patient has taken the drug as directed in the preceding time period. “Non-compliance” indicates that the patient has not taken the drug on one or more occasions in the preceding time period.“Abuse” indicates that the patient has taken more than the prescribed dose on one or more occasions in the preceding time period. An abuse assessment may be particularly pertinent to drugs that cause addiction, such as opioid pain killers.

[0070] Other options for comparative tracer or drug half-lives are possible and contemplated. The longer half-life tracer may have its half-life adjusted to be longer or shorter relative to the dosing schedule, drug half-life, or sweat testing schedule. For instance, in the above example, a T₂ with a 15 hour half-life would be more sensitive to missed doses, i.e._f T₂ would show more variability in response to a missed dose, while a T₂ with a 40 hour half-life would be more sensitive to excessive drug doses, i.e., the accumulation of T₂ would be greater in biofluid than that of a shorter half-life tracer if the patient consistently took higher doses. The shorter half-life tracer could also be adjusted relative to the dosing schedule, drug half-life, or sweat testing schedule. For example, if Ti had a half-life of 12 hours, D had a half-li fe of 6 hours, and T₂ had a half-life of 30 hours, Ti could be used to indicate adherence trends over the previous couple of days, while D provided information for the previous day and T₂ supplied longer term trends in this way, the tracer kinetics can be tailored to suit the particular application of the sweat sensing device

[0071] Other types of medication adherence monitoring may best be accomplished through daily or continuous device wear. For example, patients often miss doses because they simply forget to take their medication. A biofluid sensing device may be worn on a patient’s skin and configured to monitor the patient’s sweat for an active drug or a tracer administered with an active drug. If a patient forgets to take their medication the device could issue an alert to remind the patient to take their medication. Alternatively, the device could transmit a signal to an ancillary device to trigger a caregiver to remind the patient, or to administer the drug to the patient. Similarly, patients sometimes fail to understand treatment instructions. If a disclosed device were configured to monitor the amount of drug taken, such as, for example, by detecting a concentration of the drug in sweat that corresponds to a prescribed dosage of medication, the patient or a caregiver could be alerted if the patient did not take the correct dosage amount. As another example, a biofluid monitoring device may also improve reimbursement or patient communication and tracking. For instance, providers could offer a cost incentive to patients whose biofluid monitoring device reports that they are taking a drug as prescribed. Drug-related non-adherence may be improved as well with a biofluid monitoring device. For example, the device may be used to reduce medication side effects by reducing a prescribed dosage to the minimum effective level. The device could be configured to monitor treatment efficacy, or the prevalence of side-effects, and alert the provider to switch medication or lower the dosage, as will be described in more detail below.

[0072] In one aspect, a wearable biosensing device could assist in determining whether and when a particular drug has been taken by a patient. The device can be alerted when a drug dose is administered. This alert can be provided by a variety of methods or devices. One exemplary device that could provide an alert is Proteus Discover, a digital medicine system from Proteus Digital Health, Inc. Proteus Discover includes an ingestible event marker (IEM) sensor in combination with a drug. The IEM sensor generates a signal from an ingested medication to a wearable sensor. A signal from an IEM sensor could trigger a biosensing device to begin sweat analysis to directly or indirectly detect a drug as it emerges in sweat. Alternatively, an IEM sensor could trigger a timer to count down a specific period of time prior to initiation of sweat analysis. Delaying sweat analysis can allow time for a detectable concentration of the drug or co administered tracer to emerge in sweat. An IEM sensor could be incorporated with sweat monitoring sensors in a single wearable device. Alternatively, the sweat sensing device could be a separate wearable patch which is triggered by a signal from a digital medicine system patch. In another example, an alert can also be provided to the biosensing device through activation of a button or other trigger on the device itself or via an application on a portable computing device. This could take the form of a patient pushing an icon on a smartphone application upon taking a dose of the monitored medication. In another example, the biosensing device could also be alerted when a drug dose is administered by use of an electronic cap on a drug container. In addition to the above, it is envisioned that numerous other devices and methods could be used to alert the biosensing device of a drug dose. When alerted, the biosensing device can time stamp the drug dose and trigger monitoring for emergence of the drug or tracer in the patient’s sweat.

[0073] Medication monitoring applications may be improved or facilitated by various techniques using drug/tracer formulations and biofluid sensing devices. For example, a tracer’s release timing may be coordinated with a device algorithm to provide increased confidence of medication monitoring. In some embodiments, such a techniq ue may allow use of a commonly ingested substance, like vitamin E, as a tracer despite the potential for confounding measurements of dietary vitamin E in sweat. For example, a pill may be formulated with a vitamin E tracer and an ibuprofen tracer, and each tracer may be coated with a timed- release compound that creates coordinated concentration spikes, e.g., ibuprofen spikes in sweat 1 hour after pill ingestion, and then vitami E spikes in sweat 1.5 hours after ingestion. The device, in turn, is configured to look for these coordinated concentration spikes within a set window. In this way. commonly ingested substances can be used as tracers with increased confidence, since the timing and sequence of the concentration spikes in sweat are less likely to be caused by other patient behav ors.

[0074] Similarly, in other embodiments, the tracer used and/or the timing of tracer concentration spikes in the biofluid may be kept confidential from the patient to prevent the patient’s efforts to defeat the medication monitoring protocol. These techniques may exploit current practice in the pharmaceuticalndustry to defeat counterfeit medications, such as administering an undisclosed excipient with oral medications. Bioflnid sensing devices may be configured to detect the confidential excipient, and tests that do not detect the excipient would be reported as non-adherent or that the patient may be using a counterfeit medication. For some applications, the sensing device could be configured to distinguish between a patient taking a counterfeit medication and one not taking the medication at all, for example, by also sampling for the drug itself or a metabol ite of the drug.

[0075] it is anticipated that medication monitoring applications using a wearable biosensing device will go beyond adherence monitoring. Detection of the amounts of a drug taken, or the use of a device to titrate a drug dosage, will require increased sensitivity by sensors, as well as physiological correlation of a biofluid concentration of a drug, a tracer, or other molecule with a blood or tissue concentration of the active drug. Lithium, which is administered as a treatment for severe depression and bipolar disorder, is one example medication that may benefit from the disclosed approach. Lithium dosage amounts are severely restricted due to a narrow window in which the drug is effective but non-toxic. Current titration practice requires the patient to visit a clinic periodically for blood tests. A biofluid sensing device developed in accordance with the disclosed invention may be configured to measure biofluid concentrations related to lithium ingestion, and then use such measurements to develop a precise dosage level for the patient. For another example, organ transplant patients often take immunotherapy drugs to prevent the body’s rejection of the transplanted organ. The proper dosing of immunotherapy drugs is a delicate prospect, which balances the patient’s susceptibility to illness from everyday infection against failure of the transplanted organ. A biofluid sensing device of the disclosed invention may be used to assess this balance on a continuous basis, and therefore allow for precise dosage of the immunotherapy drugs.

[0076] Fig. 10 depicts a representative drug response profile showing the concentration in plasma (depicted on the y-axis) of a typical drug taken for several sequential doses over a period of time in hours (depicted on the x-axis). While the graph depicts drug concentrations in plasma, the concentrations of a drug emerging in sweat will correlate with the concentrations of the drug in plasma at specific points in time, although the sweat concentrations typically will be lower and will emerge somewhat later than those in plasma. As the individual takes the sequential doses, the maximum drug concentration rises until the drug reaches a steady state (SS), at which the rate at which new drug enters plasma is balanced with the rate at which the drug is eliminated. The top dashed line (T) is the level of the drug associated with toxicity or unacceptable harm to the patient, while the lower dashed line (E) is the minimum level required for the drug to provide an intended benefit. The band between the dashed lines T and E represents the safe zone for the patient. The safe zone can be determined by the drug manufacturer and set for all typical applications of a drug. Alternatively, the safe zone can be individualized to a particular patient depending upon a number of factors including, for example: the patient’s diagnosis, the patient’s past history with the medication, the patient’s physical condition, the patient’s body mass or body mass index, the patient’s age, the rate at which the patient uptakes or discharges the drug, or other relevant factors. The patient’s initial uptake of the drug following the first few doses provides beneficial information on how the patient will respond to the drug, and where the appropriate efficacy and toxicity thresholds will occur.

[0077] A biosensing device as described herein can provide the means for assessing uptake and metabolism trends for a drug, by monitoring for the emergence of the drug, metabolite of the drug, co administered tracer, metabolite of the tracer, or other analyte whose presence in biofluid is correlated to the presence of the active drug. Based on the monitoring, dosages and dose intervals may be selected and/or adjusted to assure that the drug concentration levels in a patient remain in the safe zone. During initial uptake, the drug concentration ranges may vary considerably, but will tend to level off as the patient reaches a steady state condition. If monitoring determines that the dosage falls below the efficacy threshold (E) in the steady state condition, or approaches the toxicity threshold (T) at any point during the drug regimen, the dosage can be adjusted. While drug safe zones currently are based on plasma concentrations, for many drugs, concentrations in sweat can be correlated with concentrations in plasma. This correlation would include determining a corresponding safe zone in sweat. As with plasma, a generalized safe zone can be determined for all patients, or safe zones can be determined for individual patients based upon the characteristics of the patient and/or pharmacokinetics of the drug in similar subjects. Once a correlation is established between the plasma and sweat concentrations for a particular drug, sweat can be monitored, either continuously or at periodic intervals, and drug dose quantity or frequency adjusted as needed, to maintain the patient within the safe zone. This will allow for individual patient titration of a drug dose in a non-invasive manner. Using a wearable biosensing device to monitor how a patient metabolizes a drug over an extended period of time will allow drugs to be more effective for the patient, with less risk of toxicity.

[0078] In addition to detecting the drug itself or tracers, a biofluid sensing device may also be configured to detect efficacy or side-effect biomarkers. Such biomarkers may be directly correlated to a desired effect of a drug, e.g., reduced inflammation, improved kidney function, reduced anxiety, or correlated to an undesired side effect, e.g., kidney injury, poor immune response, dehydration. Alternatively, desired effects and side effects may have physical manifestations detectible through various wearable sensor means, such as a volumetric sweat rate sensor to detect excessive sweating, an accelerometer to detect shaking or seizures, a thermometer to detect fever, etc. As an example, while reducing psychosis, the lithium treatment discussed above can harm thyroid and kidney function and affect the body’s Na⁺ and water regulation. Consequently, a device may be configured to monitor cortisol levels to assess desired effects, or may help the patient manage lithium treatment side effects by monitoring kidney function by measuring sweat urea or NGAL levels, tracking sweat Na⁺ levels, and/or detecting indicators of dehydration.

[0079] Another application for the disclosed inventive techniques is monitoring the use, and potential abuse, of prescription opioids. Over 13% of prescription opioid drugs are misused, resulting in more than $2 billion/year being spent on non-medically-used opioids. See Lipari, R.N. and Hughes, A. How people obtain the prescription pain relievers they misuse. The CBHSQ Report: January 12, 2017. Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, Rockville, MD. Additionally, 75% of heroin users report having gotten started on the path to addiction by misusing prescription opioids. Some of the major costs of non-medical opioid abuse are in the resulting hospitalizations, addiction treatment, and lost productivity. The U.S. Department of Health and Human Services reports an economic impact of $55 billion/year in health and social costs related to opioid abuse. A majority (53%) of non-medical opioid abusers get their pills from a friend, relative, or other acquaintance who was prescribed the medication, rather than from a drug dealer. See The CBHSQ Report: January 12, 2017, cited above. This type of illicit drug use is difficult to detect and is often not discovered until the abuser overdoses and presents at a hospital emergency room.

[0080] Using the disclosed invention, opioid levels in sweat may be measured by the device directly, or tracer molecules can be selected that allow a healthcare provider to monitor opioid prescription adherence to detect abuse. The quantity of prescribed opioids consumed by a patient can be measured to track patient compliance. This monitoring may be performed on a regular schedule such as, for example, weekly for an opioid prescription lasting 30 days or longer. Communication between a wearable sensing device worn by the patient and a provider base can permit remote monitoring, by a doctor, caretaker, or other party, to assess prescription compliance. Further investigation can be made upon detection of a lower than anticipated presence of the prescribed opioid in the patient’s sweat in order to verify that the medicine has not been used inappropriately (i.e., stolen, sold, or given away to a friend or relative).

[0081] While multiple exemplary embodiments have been described for selecting tracer compounds, and using tracer compounds for medication monitoring with an EAB biosensor, it is anticipated that other methods, elements, and configurations may also be used, provided the alternative methods, elements, and/or configurations provide tracer compounds that are compatible with the active drug and capable of interacting with an identified aptamer sequence. Various modifications, alterations, and adaptations to the embodiments described herein may occur to persons skilled in the art with attainment of at least some of the advantages. The disclosed embodiments are therefore intended to include all such modifications, alterations, and adaptations without departing from the scope of the embodiments as set forth herein.

[0082] This has been a description of the disclosed invention along with a preferred method of practicing the invention, however the invention itself should only be defined by the appended claims.

Claims

DEVICES AND METHODS FOR MEDICATION MONITORING WHAT IS CLAIMED IS:

1. A method of determining a level of adherence to a drug regimen by a patient, the method comprising:

receiving a measurement of a first concentration of a first tracer in a biofluid sample, wherein the first tracer has a half-life that is longer than a dosing interval of a drug;

receiving a measurement of a second concentration of an analyte in the biofluid sample, wherein the analyte has a half-life that is shorter than the dosing interval, and wherein the analyte is one of: a second tracer, or the drug;

determining a first ratio of the first concentration to the second concentration; and

correlating the first ratio to the level of adherence.

2. The method of claim 1, wherein the level of adherence is one of the following: the patient has taken the drug as prescribed; the patient has missed one or more doses of the drug; the patient has taken more of the drug than prescribed on one or more occasions.

3. The method of claim 1, wherein the first ratio corresponds to steady state concentrations of the first tracer and the analyte in the biofluid sample.

4. The method of claim 1, wherein the analyte is the drug, and further comprising the steps of: measuring a third concentration of a second tracer, wherein the second tracer has a half-life that is between the half-life of the drug and the half-life of the first tracer;

determining a second ratio of the third concentration to the second concentration; and correlating the second ratio to the level of adherence.

5. A method of monitoring a medication in a patient, the method comprising:

using a device to receive and analyze a sample of a biofluid from the skin of the patient;

receiving a measurement of a biofluid concentration of an analyte in the biofluid sample; and correlating the biolluid concentration to a plasma concentration, wherein the plasma concentration is a concentration of the medication in plasma at a point in time.

6. The method of claim 5, wherein the analyte is one of the following: the medication, a metabolite of the medication, or a tracer.

7. The method of claim 5, further comprising the step of comparing the biofluid concentration to one or both of the following: a toxic concentration, and a minimum effective concentration, wherein the toxic concentration is the plasma concentration at which the patient is exposed to unacceptable harm, and the minimum effective concentration is the plasma concentration at which the patient receives an intended benefit.

8. The method of claim 5, further comprising the step of using the biofluid concentration to adjust a regimen of medication dosage to maintain the plasma concentration between the toxic concentration and the minimum effective concentration.

9. The method of claim 5, wherein the biofluid concentration is measured by one or more electrochemical aptamer-based sensors.

10. A method, comprising:

selecting a tracer for co-administration with a drug based on the following:

a percentage of a tracer candidate that emerges in a biofluid after the tracer candidate is introduced into a patient’s body; a molarity of tracer candidate that emerges in the biofluid after the tracer candidate is introduced into the patient’s body; an interval between when the tracer candidate is introduced into the patient’s body and when the tracer candidate emerges in the biofluid; a half-life of the tracer candidate; a mechanism by which the tracer candidate emerges in the biofluid; and an availability of a randomized aptamer sequence that will interact with the tracer candidate.