Drug adherence monitoring system

Abstract

The present invention provides novel methods for monitoring subject adherence in taking prescribed drugs by detecting markers in exhaled breath after a subject takes the prescribed drug. In particular, the present invention provides novel methods for making additives that are combined with the drug(s). Upon biological breakdown of the drug/additive formulation in a subject's body, markers resulting directly from the biological breakdown of the additives are detected in exhaled breath using sensor technology. In certain embodiments of the invention, the drug adherence monitoring systems and methods include a reporting system capable of tracking subject compliance (either remotely or proximately) and of providing necessary alerts to the subject, caregiver, healthcare provider, and the like.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of an additive ester group that is metabolized in the subject's body to an alcohol that is detectable in exhaled breath.

FIG. 2 is an illustration of another additive group that is metabolized via alkaline phosphatase in the subject's body to an alcohol that is detectable in exhaled breath.

FIG. 3 is a schematic illustration of the O-demethylation of dextromethorphan by CYP2D6.

FIG. 4 is a schematic illustration of the synthesis of an additive (O-trifluoroethyl dextrorphan) in accordance with one embodiment of the invention.

FIG. 5 is a graphical illustration of the inhibition of CYP 2D6 activities of AMMC due to increasing concentrations of dextromethorphan and trifluoroethyl dextrorphan from 10⁻¹⁰ M to 10⁻⁵ M.

FIG. 6 is a graphical illustration of the in vivo metabolism of an additive (O-trifluoroethyl dextrorphan) to yield a detectable, volatile marker compound (trifluoroacetaldehyde).

FIGS. 7A and B are graphical illustrations of total-ion chromatogram of trifluoroacetaldehyde 2,4-dinitrophenylhydrazone and its ¹⁵N₄-labeled internal standard, respectively, upon GC/MS analysis.

FIGS. 7C and D are graphical illustrations of full scan NCI mass spectra of trifluoroacetaldehyde 2,4-dinitrophenylhydrazone and its ¹⁵N₄-labeled internal standard, respectively, upon GC/MS analysis.

Claims

1. A system for monitoring subject drug adherence for at least one prescribed drug regimen comprising: a) a means for obtaining a sample of a subject's breath at prescribed intervals;b) a sensor for detecting at least one marker in the breath sample indicative of a subject taking the drug wherein the sensor generates an output signal indicative of the presence or absence of the marker in the breath sample;c) a processing means for receiving the output signal and assessing the concentration of marker present in the breath sample for use in ascertaining subject drug adherence with the drug regimen(s) as prescribed.

2. The system of claim 1, wherein the processing means conducts a comparison of the marker concentration against a predetermined marker concentration of the drug marker to determine drug adherence to the prescribed drug regimen(s).

3. The system of claim 1, further comprising a means for reporting results obtained from the processing means.

4. The system of claim 1, further comprising a means for dispensing the prescribed drug.

5. The system of claim 1, wherein multiple drug regimens are prescribed to the subject.

6. The system of claim 1, wherein the sensor is selected from the group consisting of: High Electron Mobility Transistors (HEMT), metal-insulator-metal ensemple (MIME) sensors, nuclear magnetic resonance (NMR), cross-reactive optical microsensor arrays, fluorescent polymer films, surface enhanced Raman spectroscopy (SERS), diode lasers, selected ion flow tubes, metal oxide sensors (MOS), bulk acoustic wave (BAW) sensors, colorimetric tubes, infrared spectroscopy, gas chromatography-mass spectroscopy (including “miniature” gas chromatography), semiconductive gas sensor technology; mass spectrometers, fluorescent spectrophotometers, conductive polymer gas sensor technology; aptamer sensor technology; amplifying fluorescent polymer (AFP) sensor technology; surface acoustic wave gas sensor technology; or quantum cascade lasers.

7. The system of claim 1, wherein the system is portable.

8. The system of claim 1, wherein the drug marker is detectable in breath upon enzymatic degradation of the drug marker in the subject.

9. The system of claim 1, wherein the breath drug marker is detectable in breath upon spontaneous non-enzymatic conversion of the drug marker in the subject.

10. The system of claim 1, wherein the breath drug marker is detectable in breath without further chemical modification of the drug marker.

11. The system of claim 1, wherein the breath drug marker is the drug, a metabolite of the drug, an additive delivered with the drug regimen, or a metabolite of an additive delivered with the drug.

12. A method for monitoring subject drug adherence with at least one prescribed drug regimen comprising: a) a means for obtaining a sample of a subject's breath at prescribed intervals;b) analyzing the sample with sensor technology to identify the presence of at least one drug marker in the sample; andc) determining the presence of at least one drug marker at a level above a predetermined threshold, which indicates subject adherence to the prescribed drug regimen.

13. The method of claim 12, further comprising the step of d) based on the results generated from step (c), reporting whether subject has adhered to a prescribed drug regimen.

14. The method of claim 12, further comprising the step of altering, maintaining, or canceling the prescribed drug regimen based on the results generated from step (c).

15. The method of claim 12, further comprising the step of assessing the subject's health status by evaluating their pattern of adherence to the prescribed drug regimen.

16. The method of claim 12, further comprising any one or combination of the following steps: identifying a subject with a condition treatable with a prescribed drug regimen; prescribing a drug regimen for the subject; defining an acceptable level of adherence with the prescribed drug regimen; and assessing indicators of progression of patient condition while taking the prescribed drug regimen.

17. The method of claim 12, wherein the step of obtaining the breath sample is performed at each and every prescribed administration of the drug.

18. The method of claim 12, wherein the step of obtaining the breath sample is performed at a prescribed frequency other than every prescribed administration of the drug.

19. The method of claim 12, further comprising the step of obtaining a breath sample prior to administration of the drug to establish a baseline for comparison.

20. The method of claim 12, further comprising the step of administering a drug at prescribed intervals to the subject, wherein the drug is administered orally, via inhalation, intraocularly, transdermally, intravenously, intraperitoneally, or vaginally.

21. A kit for monitoring subject adherence with at least one prescribed drug regimen comprising: a) a means for dispensing a prescribed drug;b) a housing;c) a sensor disposed within the housing, said sensor having the ability to detect the presence of at least one drug marker in breath; andd) a reporting module disposed with or within the housing, wherein said reporting module is operatively connected to the sensor such that detection of the presence of the drug marker in the sample is communicated at prescribed intervals.

22. The kit of claim 21, wherein the drug comprises a marker that is detectable in breath upon enzymatic breakdown of the drug.

23. The kit of claim 21, wherein the drug comprises a marker that is detectable in breath upon spontaneous non-enzymatic activity on the drug in the subject

24. The kit of claim 21, wherein the breath drug marker is the drug, a metabolite of the drug, an additive delivered with the drug regimen, or a metabolite of an additive delivered with the drug.

25. The kit of claim 21, wherein the drug marker is selected from the group consisting of: dimethyl sulfoxide (DMSO), acetaldehyde, acetophenone, trans-Anethole (1-methoxy-4-propenyl benzene) (anise), benzaldehyde (benzoic aldehyde), benzyl alcohol, benzyl cinnamate, cadinene, camphene, camphor, cinnamaldehyde (3-phenylpropenal), garlic, citronellal, cresol, cyclohexane, eucalyptol, and eugenol, eugenyl methyl ether; butyl isobutyrate (n-butyl 2, methyl propanoate) (pineapple); citral (2-trans-3,7-dimethyl-2,6-actadiene-1-al); menthol (1-methyl-4-isopropylcyclohexane-3-ol); α-Pinene (2,6,6-trimethylbicyclo-(3,1,1)-2-heptene); flouroalcohols; and fluoroaldehydes.