NON-SEDATING DEXMEDETOMIDINE TREATMENT REGIMENS
Disclosed herein are methods of administering relatively high doses of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject, without also inducing significant sedation. The disclosed methods are particularly suitable for the treatment of agitation, especially when associated with neurodegenerative and/or neuropsychiatric diseases such as schizophrenia, bipolar illness such as bipolar disorder or mania, dementia, depression, or delirium.
1 - 431 . (canceled)
432 . A method of treating agitation in a human subject with schizophrenia or bipolar disorder, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a total exposure of dexmedetomidine, as measured by plasma AUC 0-inf , from about 600 ng*h/L to about 12600 ng*h/L.
433 . The method of claim 432 , wherein the dose is about 120 μg to about 240 μg.
434 . The method of claim 432 , wherein the human subject has schizophrenia.
435 . The method of claim 432 , wherein the human subject has bipolar disorder.
436 . The method of claim 432 , wherein the AUC 0-inf is about 2300 ng*h/L to about 3600 ng*h/L; and wherein C max is about 300 ng/L to about 500 ng/L.
437 . The method of claim 436 , wherein the C max is within the range of about 80% to about 125% of about 400 ng/L.
438 . The method of claim 436 , wherein the AUC 0-inf is within the range of about 80% to about 125% of about 2900 ng*h/L.
439 . The method of claim 432 , wherein the AUC 0-inf is about 1100 ng*h/L to about 1800 ng*h/L; and wherein C max is about 150 ng/L to about 300 ng/L.
440 . The method of claim 439 , wherein the C max is within the range of about 80% to about 125% of about 220 ng/L.
441 . The method of claim 439 , wherein the AUC 0-inf is within the range of about 80% to about 125% of about 1410 ng*h/L.
442 . The method of claim 439 , wherein the plasma T max is about 1 hour to about 8 hours.
443 . The method of claim 439 , wherein the plasma T max is about 5 minutes to about 4 hours.
444 . The method of claim 432 , wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally, orally, intranasally or parenterally.
445 . The method of claim 444 , wherein the administration is oromucosal.
446 . The method of claim 445 , wherein the administration is sublingual.
447 . The method of claim 445 , wherein the administration is buccal.
448 . The method of claim 432 , wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a tablet, film, spray, gel or drops.
449 . The method of claim 448 , wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a film.
450 . The method of claim 448 , wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film, patch or tablet.
451 . The method of claim 432 , wherein said film is a self-supporting, dissolvable, film, comprising:
(i) dexmedetomidine or a pharmaceutically acceptable salt thereof;
(ii) hydroxypropyl cellulose (40,000 MW);
(iii) hydroxypropyl cellulose (140,000 MW);
(iv) hydroxypropyl cellulose (370,000 MW); and
(v) polyethylene oxide (600,000 MW).
452 . The method of claim 451 , wherein hydroxypropyl cellulose (40,000 MW) is present at about 3% to about 15% w/w of the total film weight, hydroxypropyl cellulose (140,000 MW) is present at about 3% to about 8% w/w of the total film weight, hydroxypropyl cellulose (370,000 MW) is present at about 10% to about 50% w/w of the total film weight, and a polyethylene oxide (600,000 MW) is present at about 40% to about 70% w/w of the total film weight.
453 . The method of claim 432 , wherein the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 180 μg.
454 . The method of claim 432 , wherein the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 120 μg.
455 . The method of claim 432 , wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.
456 . The method of claim 432 further comprising administering a second dose after a period of time ranging from about 30 minutes to about 12 hours.
457 . The method of claim 456 , wherein the second dose is about 60 μg or about 90 μg.
458 . The method of claim 432 , wherein the agitation is reduced, as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline of at least −4 points.
459 . The method of claim 458 , wherein the reduction in agitation is maintained for about 2 hours to about 6 hours.
460 . The method of claim 458 , wherein the agitation is reduced within about 20 minutes to about 1 hour.
461 . The method of claim 432 , wherein the agitation is reduced, as measured by the Agitation-Calmness Evaluation Scale (ACES), wherein the ACES score is a 3 (mild agitation) or 4 (normal behavior).
462 . The method of claim 461 , wherein the reduction in agitation is maintained for about 2 hours to about 6 hours.
463 . The method of claim 461 , wherein the agitation is reduced within about 20 minutes to about 1 hour.